Esophageal Squamous Cell Carcinoma

MONDO:0005580 Pathograph 24 Show in embeddings browser esophageal cancer squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is the major squamous malignancy of the esophagus and remains the dominant histologic subtype of esophageal cancer worldwide. It arises from the stratified squamous mucosa of the esophagus and is strongly associated with tobacco smoking, alcohol exposure, and regional environmental or dietary carcinogens. Molecularly, ESCC is characterized by frequent TP53 mutation together with recurrent alterations affecting cell-cycle control, squamous differentiation, NOTCH signaling, and PI3K/AKT signaling. Curative-intent management relies on surgery and chemoradiation for localized disease, while PD-1-directed immunotherapy has become an important option in advanced disease.

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10
Pathophys.
1
Histopath.
5
Phenotypes
24
Pathograph
6
Genes
4
Medical Actions
1
Differentials
1
Datasets
2
Trials
1
Models
1
Deep Research
🏷

Classifications

ICD-O Morphology
Squamous Cell Carcinoma
Harrison's Part
ONCOLOGY HEMATOLOGY
⚙

Pathophysiology

10
Carcinogen-Driven Esophageal Epithelial Injury
Chronic exposure to tobacco smoke and alcohol-derived acetaldehyde injures the esophageal squamous epithelium and promotes carcinogenesis through DNA damage, epigenetic disruption, and repeated mutagenic stress.
squamous epithelial cell CL:0000076 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves squamous epithelial cell (CL:0000076). CL:0000076 is a cell type from the Cell Ontology.
DNA damage response GO:0006974 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal DNA damage response (GO:0006974). GO:0006974 is a biological process from the Gene Ontology. ⚠ ABNORMAL
esophagus UBERON:0001043 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in esophagus (UBERON:0001043). UBERON:0001043 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
TP53 Dysfunction Mutagenic injury selects for loss of p53-mediated genomic surveillance
Show evidence (2 references)
PMID:20224883 SUPPORT Human Clinical
"Both alcohol consumption and cigarette smoking are major risk factors for the development of ESCC."
This review links the major ESCC carcinogen exposures directly to disease development.
PMID:20224883 SUPPORT Human Clinical
"Acetaldehyde is the most toxic ethanol metabolite in alcohol-associated carcinogenesis, while ethanol itself stimulates carcinogenesis by inhibiting DNA methylation and by interacting with retinoid metabolism."
This provides a mechanistic link between alcohol exposure and mutagenic or epigenetic injury in esophageal carcinogenesis.
TP53 Dysfunction
TP53 alteration is the dominant recurrent genetic event in ESCC and compromises cell-cycle checkpoint control, apoptosis, and genome integrity. Loss of p53 function permits survival and expansion of damaged esophageal epithelial clones.
TP53 hgnc:11998 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TP53 (hgnc:11998). hgnc:11998 is a gene from the HUGO Gene Nomenclature Committee.
cell cycle checkpoint signaling GO:0000075 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cell cycle checkpoint signaling (GO:0000075). GO:0000075 is a biological process from the Gene Ontology. ↓ DECREASED apoptotic process GO:0006915 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased apoptotic process (GO:0006915). GO:0006915 is a biological process from the Gene Ontology. ↓ DECREASED
Experimental models
Patient-derived esophageal squamous cell carcinoma organoid library (ESCCO) ORGANOID Reproduces the stabilized-mutant-p53 state of the parental tumor, with matched normal-epithelium organoids from the same patients as the negative comparator.
Downstream
Cell Cycle Dysregulation Loss of p53 checkpoint function enables unchecked cell-cycle progression
Show evidence (1 reference)
PMID:34611831 SUPPORT Human Clinical
"TP53 (68.6%; 95% CI: 61.6-74.9), CCND1 (39.3%; 95% CI: 26.2-54.1), MDM2 (24.9%; 95% CI: 9.5-51.0), NOTCH1/2/3 (17.9%; 95% CI: 15.0-21.2), KMT2D (17.4%; 95% CI: 12.4-23.8), CDKN2A (15.0%; 95% CI: 8.1-26.1), PIK3CA (13.8%; 95% CI: 10.3-18.1), FAT1 (13.3%; 95% CI: 11.7-15.0), and EGFR (9.9%; 95%..."
This meta-analysis identifies TP53 as the most frequent recurrent genetic alteration in ESCC.
Cell Cycle Dysregulation
Recurrent alteration of TP53, CCND1, CDKN2A, and related regulators disrupts G1/S control and promotes persistent proliferation of transformed esophageal squamous cells.
negative regulation of G1/S transition GO:2000134 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased negative regulation of G1/S transition, annotated with negative regulation of G1/S transition of mitotic cell cycle (GO:2000134). GO:2000134 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
SOX2/TP63 Lineage Program Activation Squamous lineage transcription factors reinforce malignant growth programs
PI3K/AKT Signaling Activation Cell-cycle dysregulation cooperates with oncogenic survival signaling
NOTCH Pathway Dysregulation Loss of normal squamous differentiation signaling promotes malignant progression
Show evidence (1 reference)
PMID:38832974 SUPPORT Human Clinical
"Pathway analysis revealed dysregulation of cell cycle regulation, epigenetic regulation, PI3K/AKT signaling, and NOTCH signaling."
This cohort study directly implicates cell-cycle dysregulation as a major altered pathway in ESCC.
SOX2/TP63 Lineage Program Activation
ESCC frequently shows 3q amplification with co-amplification and upregulation of SOX2 and TP63, reinforcing a malignant squamous lineage transcriptional program. SOX2 promotes tumor growth and interacts with oncogenic signaling programs including AKT/mTORC1 and YAP1.
squamous epithelial cell CL:0000076 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves squamous epithelial cell (CL:0000076). CL:0000076 is a cell type from the Cell Ontology.
SOX2 hgnc:11195 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SOX2 (hgnc:11195). hgnc:11195 is a gene from the HUGO Gene Nomenclature Committee. TP63 hgnc:15979 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TP63 (hgnc:15979). hgnc:15979 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
PI3K/AKT Signaling Activation SOX2 can activate growth-promoting AKT/mTORC1 signaling
Increased Tumor Cell Proliferation Squamous lineage oncogene activation promotes ESCC growth
Show evidence (2 references)
PMID:31560173 SUPPORT Human Clinical
"Here, we reveal that SOX2, ACTL6A, and TP63 are co-amplified and upregulated in ESCC samples."
This directly supports structured inclusion of SOX2 and TP63 as recurrent co-amplified squamous lineage regulators in ESCC.
PMID:23510069 SUPPORT In Vitro
"SOX2 promotes ESCC cell proliferation in vitro."
This cell-based evidence supports a mechanistic contribution of SOX2 to proliferative squamous lineage programs in ESCC.
PI3K/AKT Signaling Activation
Recurrent PIK3CA and related pathway alterations increase prosurvival and growth signaling in ESCC, supporting tumor maintenance and therapeutic resistance.
phosphatidylinositol 3-kinase signaling GO:0043491 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased phosphatidylinositol 3-kinase signaling, annotated with phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0043491). GO:0043491 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Increased Tumor Cell Proliferation PI3K/AKT activity promotes growth and survival of ESCC cells
Show evidence (1 reference)
PMID:38832974 SUPPORT Human Clinical
"Pathway analysis revealed dysregulation of cell cycle regulation, epigenetic regulation, PI3K/AKT signaling, and NOTCH signaling."
This study directly reports PI3K/AKT pathway dysregulation in ESCC.
NOTCH Pathway Dysregulation
Alteration of NOTCH pathway genes perturbs normal squamous differentiation programs and contributes to malignant transformation and progression in ESCC.
NOTCH1 hgnc:7881 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NOTCH1 (hgnc:7881). hgnc:7881 is a gene from the HUGO Gene Nomenclature Committee.
Notch signaling pathway GO:0007219 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Notch signaling pathway (GO:0007219). GO:0007219 is a biological process from the Gene Ontology. ⚠ ABNORMAL keratinocyte differentiation GO:0030216 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased keratinocyte differentiation (GO:0030216). GO:0030216 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Increased Tumor Cell Proliferation Impaired squamous differentiation favors tumor expansion
Show evidence (1 reference)
PMID:34611831 SUPPORT Human Clinical
"TP53 (68.6%; 95% CI: 61.6-74.9), CCND1 (39.3%; 95% CI: 26.2-54.1), MDM2 (24.9%; 95% CI: 9.5-51.0), NOTCH1/2/3 (17.9%; 95% CI: 15.0-21.2), KMT2D (17.4%; 95% CI: 12.4-23.8), CDKN2A (15.0%; 95% CI: 8.1-26.1), PIK3CA (13.8%; 95% CI: 10.3-18.1), FAT1 (13.3%; 95% CI: 11.7-15.0), and EGFR (9.9%; 95%..."
This meta-analysis shows recurrent NOTCH pathway gene involvement in ESCC.
Increased Tumor Cell Proliferation
Convergent disruption of DNA damage control, cell-cycle regulation, squamous differentiation, and prosurvival signaling drives continued ESCC cell proliferation, invasion, and progression.
squamous epithelial cell CL:0000076 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves squamous epithelial cell (CL:0000076). CL:0000076 is a cell type from the Cell Ontology.
cell population proliferation GO:0008283 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cell population proliferation (GO:0008283). GO:0008283 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Adaptive Immune Resistance Expanding tumors acquire PD-L1-linked immune escape programs.
Progressive Dysphagia Tumor growth progressively narrows the esophageal lumen and impairs swallowing.
Odynophagia Tumor ulceration and local wall invasion can make swallowing painful.
Chest Pain Locally invasive or ulcerative esophageal tumor growth can produce retrosternal chest pain.
Hematemesis Ulcerative tumor growth can erode mucosa and cause upper gastrointestinal bleeding.
Weight Loss Tumor burden and impaired oral intake contribute to weight loss.
Show evidence (2 references)
PMID:38832974 SUPPORT Human Clinical
"Pathway analysis revealed dysregulation of cell cycle regulation, epigenetic regulation, PI3K/AKT signaling, and NOTCH signaling."
This human ESCC cohort directly supports recurrent dysregulation of cell-cycle programs underlying increased tumor proliferation.
PMID:23510069 SUPPORT Model Organism
"In mouse xenografts, SOX2 promoted in vivo tumor growth of ESCC, which was dependent on AKT/mTORC1 activation."
This mouse xenograft study supports the proliferative consequence of SOX2-driven oncogenic signaling in ESCC.
Adaptive Immune Resistance
A substantial subset of advanced ESCC expresses PD-L1 on tumor cells and tumor-infiltrating immune cells, consistent with a checkpoint-mediated immune-evasion state targetable with PD-1 blockade.
negative regulation of T cell mediated immunity GO:0002710 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased negative regulation of T cell mediated immunity (GO:0002710). GO:0002710 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
T Cell Exhaustion and Immune Escape Chronic checkpoint signaling drives tumor-infiltrating T cells into an exhausted, non-productive state.
Show evidence (1 reference)
PMID:30684971 SUPPORT Human Clinical
"PD-L1 was expressed on 29.9% (113/378) ESCC tumor cells and 40.2% (152/378) tumor-infiltrating immune cells."
This directly supports a clinically relevant PD-L1-positive immune-evasion state in advanced ESCC.
T Cell Exhaustion and Immune Escape
In the immunosuppressive ESCC microenvironment, chronically stimulated tumor-infiltrating T cells acquire an exhausted phenotype with impaired effector cytokine production and cytolytic activity, contributing to immune escape.
exhausted T cell CL:0011025 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves exhausted T cell (CL:0011025). CL:0011025 is a cell type from the Cell Ontology.
exhausted T cell differentiation GO:0160083 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased exhausted T cell differentiation (GO:0160083). GO:0160083 is a biological process from the Gene Ontology. ↑ INCREASED
Show evidence (1 reference)
PMID:26086965 SUPPORT Other
"The exhausted T cells in the tumor microenvironment show overexpressed inhibitory receptors, decreased effector cytokine production and cytolytic activity, leading to the failure of cancer elimination."
This review directly supports an exhausted intratumoral T-cell state as a mechanistic consequence of checkpoint-mediated immune escape.
Chemotherapy Resistance
A subset of ESCC tumors survives platinum and fluoropyrimidine chemotherapy, and the clones that persist drive the high post-treatment recurrence rate. Resistance segregates with a constitutively elevated antioxidant stress response: chemo-resistant patient-derived organoids carry higher expression of antioxidant stress response genes, and more accessible chromatin at those loci, than sensitive organoids from the same library.
esophageal tumor epithelial cell CL:0002252 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves esophageal tumor epithelial cell, annotated with epithelial cell of esophagus (CL:0002252). CL:0002252 is a cell type from the Cell Ontology.
antioxidant stress response GO:0034599 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased antioxidant stress response, annotated with cellular response to oxidative stress (GO:0034599). GO:0034599 is a biological process from the Gene Ontology. ↑ INCREASED
Experimental models
Patient-derived esophageal squamous cell carcinoma organoid library (ESCCO) ORGANOID Reproduces patient-specific resistance to cisplatin and 5-fluorouracil in human tumor cells, and resolves the elevated antioxidant stress response that accompanies it.
Show evidence (2 references)
PMID:40169778 SUPPORT In Vitro
"The ESCCOs respond differently to cisplatin and 5-fluorouracil, chemotherapeutic agents commonly used to treat ESCC patients, with 7 ESCCOs exhibiting potent chemo-resistance."
Establishes that resistance to the two agents used in standard ESCC chemotherapy is a stable, patient-specific property retained by tumor-derived organoids.
PMID:40169778 SUPPORT In Vitro
"the chemo-resistant ESCCOs show higher genes involved in antioxidant stress response pathways and more accessible chromatin at their loci than the sensitive ESCCOs"
Identifies an elevated antioxidant stress response, at both the transcript and chromatin-accessibility level, as the molecular feature that distinguishes chemo-resistant from chemo-sensitive tumors.
✶

Histopathology

1
Squamous Cell Carcinoma
ESCC is the squamous histologic subtype of esophageal cancer and represents the dominant esophageal cancer histology worldwide.
Show evidence (1 reference)
PMID:20224883 SUPPORT Human Clinical
"Esophageal cancers are classified into two histological types; esophageal squamous cell carcinoma (ESCC), and adenocarcinoma"
This review explicitly identifies ESCC as a distinct histologic subtype of esophageal cancer.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Esophageal Squamous Cell Carcinoma Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

5
Digestive 2
Progressive Dysphagia HP:0002015 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysphagia (HP:0002015). HP:0002015 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20448378 SUPPORT Human Clinical
"First symptom was progressive dysphagia in all patients."
This prospective clinical cohort documents progressive dysphagia as the leading presenting symptom in esophageal carcinoma, including squamous cases.
PMID:20950882 SUPPORT Human Clinical
"In longitudinal regression analyses, scores for dysphagia (p=0.00005), odynophagia (p=0.006), regurgitation (p=0.00005), chest pain (p=0.0038) and performance status (p=0.0015) were all significantly improved."
This multicenter randomized trial in squamous oesophageal cancer confirms dysphagia as a core symptom burden in conventional SCC.
Odynophagia HP:0032043 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Odynophagia (HP:0032043). HP:0032043 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20950882 SUPPORT Human Clinical
"In longitudinal regression analyses, scores for dysphagia (p=0.00005), odynophagia (p=0.006), regurgitation (p=0.00005), chest pain (p=0.0038) and performance status (p=0.0015) were all significantly improved."
This multicenter randomized trial in squamous oesophageal cancer documents odynophagia among the core disease-related symptoms.
Constitutional 1
Chest Pain HP:0100749 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chest pain (HP:0100749). HP:0100749 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20950882 SUPPORT Human Clinical
"In longitudinal regression analyses, scores for dysphagia (p=0.00005), odynophagia (p=0.006), regurgitation (p=0.00005), chest pain (p=0.0038) and performance status (p=0.0015) were all significantly improved."
This multicenter randomized trial in squamous oesophageal cancer documents chest pain among the core disease-related symptoms.
Growth 1
Weight Loss HP:0001824 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Weight loss (HP:0001824). HP:0001824 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20448378 SUPPORT Human Clinical
"Subsidiary symptoms were, weight loss in 83.3% (n = 40), abdominal / chest pain in 10 (20.8%), regurgitation in 14 (29.2%), odynophagia in three (6.2%)"
This prospective clinical cohort reports weight loss as a frequent presenting symptom in esophageal carcinoma, including squamous cases.
Other 1
Hematemesis HP:0002248 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hematemesis (HP:0002248). HP:0002248 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28894616 SUPPORT Human Clinical
"We report the case of a 53-year-old female who presented with hematemesis and melena followed by left-sided weakness."
This case report directly documents hematemesis in a patient with esophageal squamous cell carcinoma.
🧬

Genetic Associations

6
TP53 (Somatic Driver Mutation)
Gene: TP53 hgnc:11998 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TP53 (hgnc:11998). hgnc:11998 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:34611831 SUPPORT Human Clinical
"TP53 (68.6%; 95% CI: 61.6-74.9), CCND1 (39.3%; 95% CI: 26.2-54.1), MDM2 (24.9%; 95% CI: 9.5-51.0), NOTCH1/2/3 (17.9%; 95% CI: 15.0-21.2), KMT2D (17.4%; 95% CI: 12.4-23.8), CDKN2A (15.0%; 95% CI: 8.1-26.1), PIK3CA (13.8%; 95% CI: 10.3-18.1), FAT1 (13.3%; 95% CI: 11.7-15.0), and EGFR (9.9%; 95%..."
This meta-analysis identifies TP53 as the most prevalent recurrent genetic alteration in ESCC.
CCND1 (Copy Number Amplification)
Gene: CCND1 hgnc:1582 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CCND1 (hgnc:1582). hgnc:1582 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:34611831 SUPPORT Human Clinical
"TP53 (68.6%; 95% CI: 61.6-74.9), CCND1 (39.3%; 95% CI: 26.2-54.1), MDM2 (24.9%; 95% CI: 9.5-51.0), NOTCH1/2/3 (17.9%; 95% CI: 15.0-21.2), KMT2D (17.4%; 95% CI: 12.4-23.8), CDKN2A (15.0%; 95% CI: 8.1-26.1), PIK3CA (13.8%; 95% CI: 10.3-18.1), FAT1 (13.3%; 95% CI: 11.7-15.0), and EGFR (9.9%; 95%..."
This meta-analysis identifies CCND1 as a frequent recurrent ESCC genetic alteration.
NOTCH1 (Squamous Differentiation Pathway Alteration)
Gene: NOTCH1 hgnc:7881 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NOTCH1 (hgnc:7881). hgnc:7881 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:34611831 SUPPORT Human Clinical
"TP53 (68.6%; 95% CI: 61.6-74.9), CCND1 (39.3%; 95% CI: 26.2-54.1), MDM2 (24.9%; 95% CI: 9.5-51.0), NOTCH1/2/3 (17.9%; 95% CI: 15.0-21.2), KMT2D (17.4%; 95% CI: 12.4-23.8), CDKN2A (15.0%; 95% CI: 8.1-26.1), PIK3CA (13.8%; 95% CI: 10.3-18.1), FAT1 (13.3%; 95% CI: 11.7-15.0), and EGFR (9.9%; 95%..."
This meta-analysis supports recurrent NOTCH pathway gene alteration in ESCC.
PIK3CA (Oncogenic Signaling Activation)
Gene: PIK3CA hgnc:8975 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PIK3CA (hgnc:8975). hgnc:8975 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:34611831 SUPPORT Human Clinical
"TP53 (68.6%; 95% CI: 61.6-74.9), CCND1 (39.3%; 95% CI: 26.2-54.1), MDM2 (24.9%; 95% CI: 9.5-51.0), NOTCH1/2/3 (17.9%; 95% CI: 15.0-21.2), KMT2D (17.4%; 95% CI: 12.4-23.8), CDKN2A (15.0%; 95% CI: 8.1-26.1), PIK3CA (13.8%; 95% CI: 10.3-18.1), FAT1 (13.3%; 95% CI: 11.7-15.0), and EGFR (9.9%; 95%..."
This meta-analysis supports recurrent PIK3CA alteration in ESCC.
SOX2 (Lineage Oncogene Amplification)
Gene: SOX2 hgnc:11195 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SOX2 (hgnc:11195). hgnc:11195 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:31560173 SUPPORT Human Clinical
"Here, we reveal that SOX2, ACTL6A, and TP63 are co-amplified and upregulated in ESCC samples."
This directly supports SOX2 as a recurrent amplified lineage oncogene in ESCC.
TP63 (Co-amplified Squamous Lineage Transcription Factor)
Gene: TP63 hgnc:15979 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TP63 (hgnc:15979). hgnc:15979 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:31560173 SUPPORT Human Clinical
"Here, we reveal that SOX2, ACTL6A, and TP63 are co-amplified and upregulated in ESCC samples."
This directly supports TP63 as a recurrent co-amplified squamous lineage regulator in ESCC.
💊

Medical Actions

4
Esophagectomy
Action: surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Surgical resection is a core curative-intent treatment for resectable localized ESCC, typically used in multimodality management.
Definitive Chemoradiation
Action: concurrent chemoradiationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is concurrent chemoradiation, annotated with Chemoradiotherapy (NCIT:C94626). NCIT:C94626 is a clinical intervention from the NCI Thesaurus. Ontology label: Chemoradiotherapy NCIT:C94626
Agent: cisplatin CHEBI:27899 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses cisplatin (CHEBI:27899). CHEBI:27899 is a therapeutic agent from Chemical Entities of Biological Interest. 5-fluorouracil CHEBI:46345 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses 5-fluorouracil (CHEBI:46345). CHEBI:46345 is a therapeutic agent from Chemical Entities of Biological Interest.
Concurrent chemoradiation is a standard organ-preserving approach for locally advanced or unresectable localized ESCC and is also used as part of neoadjuvant therapy strategies.
Show evidence (1 reference)
PMID:40507565 SUPPORT Human Clinical
"Conclusions: Although cervical ESCC had a poor prognosis due to its higher T-stage and worse differentiation compared to other locations, outcomes were similar when treated with definitive chemoradiotherapy."
This ESCC cohort directly documents definitive chemoradiotherapy as an established treatment modality.
Nivolumab
Action: immunotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is immunotherapy (NCIT:C15262). NCIT:C15262 is a clinical intervention from the NCI Thesaurus. Ontology label: Immunotherapy NCIT:C15262
Agent: nivolumab NCIT:C68814 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses nivolumab (NCIT:C68814). NCIT:C68814 is a therapeutic agent from the NCI Thesaurus.
Anti-PD-1 immunotherapy used in advanced or previously treated ESCC. It improves overall survival compared with chemotherapy in the post-platinum setting and is now part of the immunotherapy treatment landscape for ESCC.
Mechanism Target:
INHIBITS Adaptive Immune Resistance — PD-1 blockade counteracts PD-L1-mediated immune escape in ESCC.
Show evidence (1 reference)
PMID:35294546 SUPPORT Human Clinical
"Nivolumab as second-line therapy demonstrated clinically meaningful long-term improvement in OS compared with chemotherapy in previously treated patients with advanced ESCC."
The survival benefit supports therapeutic inhibition of checkpoint-mediated immune escape.
Show evidence (1 reference)
PMID:35294546 SUPPORT Human Clinical
"Nivolumab as second-line therapy demonstrated clinically meaningful long-term improvement in OS compared with chemotherapy in previously treated patients with advanced ESCC."
ATTRACTION-3 provides direct clinical evidence supporting nivolumab use in previously treated advanced ESCC.
Pembrolizumab-Based Therapy
Action: immunotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is immunotherapy (NCIT:C15262). NCIT:C15262 is a clinical intervention from the NCI Thesaurus. Ontology label: Immunotherapy NCIT:C15262
Agent: pembrolizumab NCIT:C106432 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses pembrolizumab (NCIT:C106432). NCIT:C106432 is a therapeutic agent from the NCI Thesaurus.
Pembrolizumab-containing regimens are used in advanced ESCC, particularly in biomarker-selected settings and combination regimens involving chemotherapy.
Mechanism Target:
INHIBITS Adaptive Immune Resistance — Pembrolizumab targets PD-1 to reverse checkpoint-mediated immune resistance in ESCC.
Show evidence (1 reference)
PMID:34454674 SUPPORT Human Clinical
"Compared with placebo plus chemotherapy, pembrolizumab plus chemotherapy improved overall survival in patients with previously untreated, advanced oesophageal squamous cell carcinoma and PD-L1 CPS of 10 or more, and overall survival and progression-free survival in patients with oesophageal..."
This phase III result supports checkpoint blockade as a therapeutically relevant mechanism in advanced ESCC.
Show evidence (1 reference)
PMID:34454674 SUPPORT Human Clinical
"Compared with placebo plus chemotherapy, pembrolizumab plus chemotherapy improved overall survival in patients with previously untreated, advanced oesophageal squamous cell carcinoma and PD-L1 CPS of 10 or more, and overall survival and progression-free survival in patients with oesophageal..."
KEYNOTE-590 provides direct phase 3 clinical evidence supporting pembrolizumab-based therapy in advanced ESCC.
🌍

Environmental Factors

2
Tobacco Smoking
exposure to tobacco smoking ECTO:6000029 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to tobacco smoking (ECTO:6000029). ECTO:6000029 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Cigarette smoking is a major modifiable risk factor for ESCC. Tobacco smoke exposes the esophageal epithelium to carcinogens that drive DNA damage and cooperate with alcohol-related injury in upper aerodigestive tract carcinogenesis.
Show evidence (1 reference)
PMID:20224883 SUPPORT Human Clinical
"Both alcohol consumption and cigarette smoking are major risk factors for the development of ESCC."
This review explicitly identifies cigarette smoking as a major ESCC risk factor.
Mechanism Target:
TRIGGERS Carcinogen-Driven Esophageal Epithelial Injury — The node is named for carcinogen-driven injury and its own description names tobacco smoke, so the exposure is part of what the node asserts rather than something inferred onto it. The link type is not taken from the grading of any one sentence: the route from smoke to epithelial injury runs through carcinogen adducts and DNA damage, and the fetched sentence says as much in the authors' own words, that these mechanisms are well established.
Show evidence (2 references)
PMID:20224883 SUPPORT Human Clinical
"Cigarette smoke contains more than 60 carcinogens and there are strong links between some of these carcinogens and various smoking-induced cancers; these mechanisms are well established"
Puts carcinogen content and established mechanism in one sentence, which is this node's content. It says smoking-induced cancers generally rather than this one, so it carries the mechanism and not the site.
PMID:20224883 SUPPORT Human Clinical
"Both alcohol consumption and cigarette smoking are major risk factors for the development of ESCC."
Names cigarette smoking a major risk factor for the disease. This node grades the same sentence as supporting, and the difference is deliberate rather than an oversight: the node claims that carcinogen-driven injury occurs in this disease, which a risk-factor sentence does support, whereas this link claims that smoking produces that injury, which it only reaches by way of the disease. The narrower claim gets the weaker grade, and the first item does the mechanistic work.
Ethanol Exposure
exposure to ethanol ECTO:9000027 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to ethanol (ECTO:9000027). ECTO:9000027 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Named and bound for the chemical (ECTO:9000027, which involves CHEBI ethanol) rather than the drinking behaviour (ECTO:0001082) because the mechanism curated here is ethanol oxidation to acetaldehyde. Renamed from "Alcohol Consumption" so the binding is derivable from the entry's own name.
Alcohol use is a major ESCC risk factor and acts synergistically with tobacco. Acetaldehyde exposure, ALDH2-dependent susceptibility, and interaction with tobacco carcinogens increase mutational burden in the esophageal squamous epithelium.
Show evidence (1 reference)
PMID:20224884 SUPPORT Human Clinical
"Our case-control study revealed the odds ratio of ESCC to be 50.1 for those who were both heavy smokers and heavy drinkers in comparison to people who neither drank nor smoked."
This epidemiologic review quantifies the strong combined ESCC risk from heavy alcohol and tobacco exposure.
Mechanism Target:
TRIGGERS Carcinogen-Driven Esophageal Epithelial Injury — Graded level with the tobacco link into the same node, because the node's description names alcohol-derived acetaldehyde alongside tobacco smoke and the same paper supplies a metabolite-level sentence for it. The second item is the strongest number in this entry, but it measures the two exposures together rather than alcohol alone, so it is carried at partial and the explanation says which claim it can and cannot settle.
Show evidence (2 references)
PMID:20224883 SUPPORT Human Clinical
"Acetaldehyde is the most toxic ethanol metabolite in alcohol-associated carcinogenesis, while ethanol itself stimulates carcinogenesis by inhibiting DNA methylation and by interacting with retinoid metabolism"
Names the intervening chemistry this link relies on: acetaldehyde as the toxic metabolite and ethanol acting through DNA methylation and retinoid metabolism. Carried at support to match the same paper's grading on this node.
PMID:20224884 SUPPORT Human Clinical
"Our case-control study revealed the odds ratio of ESCC to be 50.1 for those who were both heavy smokers and heavy drinkers in comparison to people who neither drank nor smoked."
A case-control odds ratio of 50.1 for people who were both heavy smokers and heavy drinkers against people who were neither. It measures the two exposures jointly, so it sizes the combination and cannot separate the alcohol contribution this link asserts.
🔬

Biochemical Markers

2
PD-L1 Immunohistochemistry
Squamous Cell Carcinoma Antigen
🔬

Diagnosis

1
Endoscopic ultrasonography
Endoscopic ultrasonography is used for clinical T staging of ESCC before definitive local therapy.
endoscopic ultrasonography NCIT:C16546 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:29667114 SUPPORT Human Clinical
"EUS is in general feasible for classifying clinical T category for ESCC."
This directly supports endoscopic ultrasonography as a staging procedure in ESCC.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Esophageal Squamous Cell Carcinoma:

Esophageal adenocarcinoma MONDO:0005028
Overlapping Features Esophageal adenocarcinoma is the main histologic differential because it shares an anatomic site with ESCC but differs in precursor lesions, epidemiology, and tumor biology.
Distinguishing Features
  • ESCC arises from squamous mucosa and is strongly linked to tobacco and alcohol exposure.
  • Esophageal adenocarcinoma usually arises in distal esophagus from Barrett metaplastic mucosa.
Show evidence (1 reference)
PMID:20224883 SUPPORT Human Clinical
"Esophageal cancers are classified into two histological types; esophageal squamous cell carcinoma (ESCC), and adenocarcinoma"
This directly supports adenocarcinoma as the key alternative esophageal histologic diagnosis.
📊

Related Datasets

1
Safety and efficacy of neoadjuvant radiotherapy and immunotherapy in the treatment of esophageal squamous cell carcinoma geo:GSE289185
Bulk transcriptomic resource from ESCC tumors sampled before and after neoadjuvant radiotherapy and immunotherapy, linked to PD-L1 analysis and pathologic response.
human BULK RNA SEQ
Conditions: pre-treatment esophageal squamous cell carcinoma post-neoadjuvant radiotherapy and immunotherapy esophageal squamous cell carcinoma
Show evidence (1 reference)
GEO:GSE289185 SUPPORT Human Clinical
"Patients receiving NRIT were subjected to whole-exome sequencing, RNA sequencing, and immunohistochemistry (IHC) analysis of programmed death-ligand 1 (PD-L1) on paraffin-embedded tissue sections obtained before and after treatment."
This directly supports the dataset as a clinically linked ESCC molecular resource spanning immunotherapy exposure.
🔬

Clinical Trials

2
NCT03143153 PHASE_III COMPLETED
Phase III first-line study of nivolumab plus ipilimumab or nivolumab plus fluorouracil and cisplatin versus chemotherapy in advanced ESCC.
Show evidence (1 reference)
clinicaltrials:NCT03143153 SUPPORT Human Clinical
"The main purpose of this study is to compare how long subjects with esophageal cancer live overall or live without disease progression after receiving nivolumab and ipilimumab or nivolumab combined with fluorouracil plus cisplatin versus fluorouracil plus cisplatin"
This directly supports pivotal checkpoint-based first-line trial coverage in ESCC.
NCT03189719 PHASE_III COMPLETED
Phase III KEYNOTE-590 first-line pembrolizumab plus cisplatin and 5-FU trial in advanced or metastatic esophageal carcinoma with ESCC-specific efficacy hypotheses.
Show evidence (1 reference)
clinicaltrials:NCT03189719 SUPPORT Human Clinical
"The purpose of this trial is to evaluate efficacy and safety of pembrolizumab plus standard of care (SOC) chemotherapy with cisplatin and 5-fluorouracil (5-FU) versus placebo plus SOC chemotherapy with cisplatin and 5-FU as first-line treatment in participants with locally advanced or metastatic..."
This directly supports ESCC-specific phase III checkpoint-chemotherapy evaluation.
🧫

Experimental Models

1
Patient-derived esophageal squamous cell carcinoma organoid library (ESCCO) ORGANOID namo:Organoid
A library of tumor organoids grown from resected primary tumors of 24 ESCC patients spanning a range of stages, ages, and prior treatments, alongside organoids from each patient's tumor-free marginal esophageal epithelium. A non-animal New Approach Methodology that retains the oncogenic mutations of the parental tumor and the patient-specific chemotherapy response, and that was used to identify the antioxidant stress response as the feature separating chemo-resistant from chemo-sensitive disease.
esophageal squamous cell carcinoma cisplatin and 5-fluorouracil exposure chemotherapy-resistant disease
esophageal tumor epithelial cell CL:0002252 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses esophageal tumor epithelial cell, annotated with epithelial cell of esophagus (CL:0002252). CL:0002252 is a cell type from the Cell Ontology.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Tissue
esophagus UBERON:0001043 Uberon multi-species anatomy ontology (UBERON) Relation: this experimental model uses this anatomical location This experimental model uses esophagus (UBERON:0001043). UBERON:0001043 is an anatomical location from the Uberon multi-species anatomy ontology.
Cell source
Organoids established from resected primary ESCC tissue of 24 patients, with paired organoids from tumor-free marginal esophageal epithelium as the non-malignant comparator
Culture
Three-dimensional organoid culture supported by Noggin, EGF, R-spondin 1 and the ROCK inhibitor Y-27632
Publication
PMID:40169778
Pathograph links
Chemotherapy Resistance recapitulates fidelity: moderate Reproduces patient-specific resistance to cisplatin and 5-fluorouracil in human tumor cells, and resolves the elevated antioxidant stress response that accompanies it.
Limitations: The organoids are composed exclusively of tumor cells, so stromal, vascular and immune contributions to chemotherapy resistance are outside what this system reports. Resistance is measured as organoid survival under drug exposure rather than as clinical response in the source patient.
Readouts
Cisplatin and 5-fluorouracil sensitivity across the organoid library
Direction: ALTERED
Interpretation: Drug response varied between organoid lines from different patients, with 7 of 24 lines potently resistant, so resistance behaves as a heritable property of the tumor cells rather than of the treatment context.
Show evidence (1 reference)
PMID:40169778 SUPPORT In Vitro
"The ESCCOs respond differently to cisplatin and 5-fluorouracil, chemotherapeutic agents commonly used to treat ESCC patients, with 7 ESCCOs exhibiting potent chemo-resistance."
Reports the measured drug-response spread across the library and the number of resistant lines.
Antioxidant stress response gene expression and chromatin accessibility
antioxidant stress response GO:0034599 Gene Ontology (GO) Relation: this readout reports on this biological process This readout reports on antioxidant stress response, annotated with cellular response to oxidative stress (GO:0034599). GO:0034599 is a biological process from the Gene Ontology.
Direction: INCREASED
Interpretation: Chemo-resistant lines showed higher antioxidant stress response gene expression and more open chromatin at those loci than sensitive lines, which is the molecular correlate this node describes.
Show evidence (1 reference)
PMID:40169778 SUPPORT In Vitro
"the chemo-resistant ESCCOs show higher genes involved in antioxidant stress response pathways and more accessible chromatin at their loci than the sensitive ESCCOs"
Reports both measurements and their direction in resistant relative to sensitive organoids.
Fedratinib-induced cell death in chemo-resistant organoids
Direction: INCREASED
Interpretation: Screening the library identified a compound that kills the resistant lines, showing the model can be used to look for treatments for the resistant state and not only to describe it.
Show evidence (1 reference)
PMID:40169778 SUPPORT In Vitro
"Through drug screening using the ESCCO library, we reveal that fedratinib effectively induces cell death in chemo-resistant ESCCOs."
Reports increased cell death in the resistant lines on fedratinib exposure, measured in the organoid system.
Show evidence (1 reference)
PMID:40169778 SUPPORT In Vitro
"the chemo-resistant ESCCOs show higher genes involved in antioxidant stress response pathways and more accessible chromatin at their loci than the sensitive ESCCOs"
Ties the model's measurements to the mechanism this node asserts, establishing it as informative for chemotherapy resistance in ESCC.
TP53 Dysfunction recapitulates fidelity: moderate Reproduces the stabilized-mutant-p53 state of the parental tumor, with matched normal-epithelium organoids from the same patients as the negative comparator.
Limitations: Nuclear p53 accumulation detects stabilized missense p53 and does not register truncating or deletion alleles: the TP53-deleted line in this library was p53-negative by the same stain despite carrying a TP53 lesion. The readout is protein localization rather than a functional assay of p53 transcriptional output.
Readouts
Nuclear p53 accumulation in tumor versus normal epithelial organoids
Direction: INCREASED
Interpretation: Every analyzed tumor organoid line reproduced the nuclear p53 accumulation of its parental tissue, and organoids from the same patients' normal epithelium did not, so the model carries this node's defining lesion rather than acquiring it in culture.
Show evidence (1 reference)
PMID:40169778 SUPPORT In Vitro
"the nuclear accumulation of p53 protein was confirmed in all analyzed ESCCOs and their parent tumor tissues, but not in ENOs or normal esophageal tissues"
Reports the measurement in tumor organoids, parental tissue, and the matched normal comparator.
Show evidence (1 reference)
PMID:40169778 SUPPORT In Vitro
"These ESCCOs faithfully recapitulate the oncogenic mutations observed in the original ESCC tissues"
Establishes that the organoids retain the parental tumor's oncogenic mutations, which is what makes them informative for a mutation-defined node.
Curated for the NAMeRS 2026 symposium New Approach Methodology pass (monarch-initiative/dismech#4873, sub-issue #9793). The sibling entry Esophageal_Adenocarcinoma carries an equivalent organ-chip record; this closes the same gap on the squamous side with a squamous-specific source.
Show evidence (1 reference)
PMID:40169778 SUPPORT In Vitro
"we established an ESCC organoid (ESCCO) library from 24 ESCC patients of various stages, ages, and treatments"
Establishes the scale and patient derivation of this human, animal-free ESCC model system.
{ }

Source YAML

click to show 
name: Esophageal Squamous Cell Carcinoma
creation_date: "2026-04-11T00:00:00Z"
description: >-
  Esophageal squamous cell carcinoma (ESCC) is the major squamous malignancy of
  the esophagus and remains the dominant histologic subtype of esophageal cancer
  worldwide. It arises from the stratified squamous mucosa of the esophagus and
  is strongly associated with tobacco smoking, alcohol exposure, and regional
  environmental or dietary carcinogens. Molecularly, ESCC is characterized by
  frequent TP53 mutation together with recurrent alterations affecting cell-cycle
  control, squamous differentiation, NOTCH signaling, and PI3K/AKT signaling.
  Curative-intent management relies on surgery and chemoradiation for localized
  disease, while PD-1-directed immunotherapy has become an important option in
  advanced disease.
categories:
- Gastrointestinal Cancer
- Solid Tumor
- Environmental Cancer
- Tobacco-Related Cancer
disease_term:
  preferred_term: esophageal squamous cell carcinoma
  term:
    id: MONDO:0005580
    label: esophageal squamous cell carcinoma
parents:
- esophageal cancer
- squamous cell carcinoma
environmental:
- name: Tobacco Smoking
  influences_mechanisms:
  - target: Carcinogen-Driven Esophageal Epithelial Injury
    environmental_effect: TRIGGERS
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The node is named for carcinogen-driven injury and its own description
      names tobacco smoke, so the exposure is part of what the node asserts
      rather than something inferred onto it. The link type is not taken from
      the grading of any one sentence: the route from smoke to epithelial
      injury runs through carcinogen adducts and DNA damage, and the fetched
      sentence says as much in the authors' own words, that these mechanisms
      are well established.
    evidence:
    - reference: PMID:20224883
      reference_title: "Alcohol drinking, cigarette smoking, and the development of squamous cell carcinoma of the esophagus: molecular mechanisms of carcinogenesis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Cigarette smoke contains more than 60 carcinogens and there are strong links between some of these carcinogens and various smoking-induced cancers; these mechanisms are well established"
      explanation: >-
        Puts carcinogen content and established mechanism in one sentence,
        which is this node's content. It says smoking-induced cancers
        generally rather than this one, so it carries the mechanism and not
        the site.
    - reference: PMID:20224883
      reference_title: "Alcohol drinking, cigarette smoking, and the development of squamous cell carcinoma of the esophagus: molecular mechanisms of carcinogenesis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Both alcohol consumption and cigarette smoking are major risk factors for the development of ESCC."
      explanation: >-
        Names cigarette smoking a major risk factor for the disease. This node
        grades the same sentence as supporting, and the difference is
        deliberate rather than an oversight: the node claims that
        carcinogen-driven injury occurs in this disease, which a risk-factor
        sentence does support, whereas this link claims that smoking produces
        that injury, which it only reaches by way of the disease. The narrower
        claim gets the weaker grade, and the first item does the mechanistic
        work.
  description: >-
    Cigarette smoking is a major modifiable risk factor for ESCC. Tobacco smoke
    exposes the esophageal epithelium to carcinogens that drive DNA damage and
    cooperate with alcohol-related injury in upper aerodigestive tract
    carcinogenesis.
  exposure_term:
    preferred_term: exposure to tobacco smoking
    term:
      id: ECTO:6000029
      label: exposure to tobacco smoking
  evidence:
  - reference: PMID:20224883
    reference_title: "Alcohol drinking, cigarette smoking, and the development of squamous cell carcinoma of the esophagus: molecular mechanisms of carcinogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both alcohol consumption and cigarette smoking are major risk factors for
      the development of ESCC.
    explanation: >-
      This review explicitly identifies cigarette smoking as a major ESCC risk
      factor.
- name: Ethanol Exposure
  influences_mechanisms:
  - target: Carcinogen-Driven Esophageal Epithelial Injury
    environmental_effect: TRIGGERS
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Graded level with the tobacco link into the same node, because the
      node's description names alcohol-derived acetaldehyde alongside tobacco
      smoke and the same paper supplies a metabolite-level sentence for it.
      The second item is the strongest number in this entry, but it measures
      the two exposures together rather than alcohol alone, so it is carried
      at partial and the explanation says which claim it can and cannot
      settle.
    evidence:
    - reference: PMID:20224883
      reference_title: "Alcohol drinking, cigarette smoking, and the development of squamous cell carcinoma of the esophagus: molecular mechanisms of carcinogenesis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Acetaldehyde is the most toxic ethanol metabolite in alcohol-associated carcinogenesis, while ethanol itself stimulates carcinogenesis by inhibiting DNA methylation and by interacting with retinoid metabolism"
      explanation: >-
        Names the intervening chemistry this link relies on: acetaldehyde as
        the toxic metabolite and ethanol acting through DNA methylation and
        retinoid metabolism. Carried at support to match the same paper's
        grading on this node.
    - reference: PMID:20224884
      reference_title: "Alcohol drinking, cigarette smoking, and the development of squamous cell carcinoma of the esophagus: epidemiology, clinical findings, and prevention."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our case-control study revealed the odds ratio of ESCC to be 50.1 for those who were both heavy smokers and heavy drinkers in comparison to people who neither drank nor smoked."
      explanation: >-
        A case-control odds ratio of 50.1 for people who were both heavy
        smokers and heavy drinkers against people who were neither. It
        measures the two exposures jointly, so it sizes the combination and
        cannot separate the alcohol contribution this link asserts.
  description: >-
    Alcohol use is a major ESCC risk factor and acts synergistically with
    tobacco. Acetaldehyde exposure, ALDH2-dependent susceptibility, and
    interaction with tobacco carcinogens increase mutational burden in the
    esophageal squamous epithelium.
  notes: >-
    Named and bound for the chemical (ECTO:9000027, which involves CHEBI ethanol)
    rather than the drinking behaviour (ECTO:0001082) because the mechanism curated
    here is ethanol oxidation to acetaldehyde. Renamed from "Alcohol Consumption" so
    the binding is derivable from the entry's own name.
  exposure_term:
    preferred_term: exposure to ethanol
    term:
      id: ECTO:9000027
      label: exposure to ethanol
  evidence:
  - reference: PMID:20224884
    reference_title: "Alcohol drinking, cigarette smoking, and the development of squamous cell carcinoma of the esophagus: epidemiology, clinical findings, and prevention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our case-control study revealed the odds ratio of ESCC to be 50.1 for
      those who were both heavy smokers and heavy drinkers in comparison to
      people who neither drank nor smoked.
    explanation: >-
      This epidemiologic review quantifies the strong combined ESCC risk from
      heavy alcohol and tobacco exposure.
pathophysiology:
- name: Carcinogen-Driven Esophageal Epithelial Injury
  description: >-
    Chronic exposure to tobacco smoke and alcohol-derived acetaldehyde injures
    the esophageal squamous epithelium and promotes carcinogenesis through DNA
    damage, epigenetic disruption, and repeated mutagenic stress.
  cell_types:
  - preferred_term: squamous epithelial cell
    term:
      id: CL:0000076
      label: squamous epithelial cell
  locations:
  - preferred_term: esophagus
    term:
      id: UBERON:0001043
      label: esophagus
  biological_processes:
  - preferred_term: DNA damage response
    modifier: ABNORMAL
    term:
      id: GO:0006974
      label: DNA damage response
  evidence:
  - reference: PMID:20224883
    reference_title: "Alcohol drinking, cigarette smoking, and the development of squamous cell carcinoma of the esophagus: molecular mechanisms of carcinogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both alcohol consumption and cigarette smoking are major risk factors for
      the development of ESCC.
    explanation: >-
      This review links the major ESCC carcinogen exposures directly to disease
      development.
  - reference: PMID:20224883
    reference_title: "Alcohol drinking, cigarette smoking, and the development of squamous cell carcinoma of the esophagus: molecular mechanisms of carcinogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Acetaldehyde is the most toxic ethanol metabolite in alcohol-associated
      carcinogenesis, while ethanol itself stimulates carcinogenesis by
      inhibiting DNA methylation and by interacting with retinoid metabolism.
    explanation: >-
      This provides a mechanistic link between alcohol exposure and mutagenic or
      epigenetic injury in esophageal carcinogenesis.
  downstream:
  - target: TP53 Dysfunction
    description: Mutagenic injury selects for loss of p53-mediated genomic surveillance
- name: TP53 Dysfunction
  description: >-
    TP53 alteration is the dominant recurrent genetic event in ESCC and
    compromises cell-cycle checkpoint control, apoptosis, and genome integrity.
    Loss of p53 function permits survival and expansion of damaged esophageal
    epithelial clones.
  genes:
  - preferred_term: TP53
    term:
      id: hgnc:11998
      label: TP53
  biological_processes:
  - preferred_term: cell cycle checkpoint signaling
    modifier: DECREASED
    term:
      id: GO:0000075
      label: cell cycle checkpoint signaling
  - preferred_term: apoptotic process
    modifier: DECREASED
    term:
      id: GO:0006915
      label: apoptotic process
  evidence:
  - reference: PMID:34611831
    reference_title: "Systematic Review and Meta-analysis of the Most Common Genetic Mutations in Esophageal Squamous Cell Carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TP53 (68.6%; 95% CI: 61.6-74.9), CCND1 (39.3%; 95% CI: 26.2-54.1), MDM2
      (24.9%; 95% CI: 9.5-51.0), NOTCH1/2/3 (17.9%; 95% CI: 15.0-21.2),
      KMT2D (17.4%; 95% CI: 12.4-23.8), CDKN2A (15.0%; 95% CI: 8.1-26.1),
      PIK3CA (13.8%; 95% CI: 10.3-18.1), FAT1 (13.3%; 95% CI: 11.7-15.0),
      and EGFR (9.9%; 95% CI: 5.6-17.0) were the most common involved genetic
      factors in developing ESCC.
    explanation: >-
      This meta-analysis identifies TP53 as the most frequent recurrent genetic
      alteration in ESCC.
  downstream:
  - target: Cell Cycle Dysregulation
    description: Loss of p53 checkpoint function enables unchecked cell-cycle progression
- name: Cell Cycle Dysregulation
  description: >-
    Recurrent alteration of TP53, CCND1, CDKN2A, and related regulators disrupts
    G1/S control and promotes persistent proliferation of transformed esophageal
    squamous cells.
  biological_processes:
  - preferred_term: negative regulation of G1/S transition
    modifier: DECREASED
    term:
      id: GO:2000134
      label: negative regulation of G1/S transition of mitotic cell cycle
  evidence:
  - reference: PMID:38832974
    reference_title: "Prognostic value of genomic mutation signature associated with immune microenvironment in southern Chinese patients with esophageal squamous cell carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathway analysis revealed dysregulation of cell cycle regulation,
      epigenetic regulation, PI3K/AKT signaling, and NOTCH signaling.
    explanation: >-
      This cohort study directly implicates cell-cycle dysregulation as a major
      altered pathway in ESCC.
  downstream:
  - target: SOX2/TP63 Lineage Program Activation
    description: Squamous lineage transcription factors reinforce malignant growth programs
  - target: PI3K/AKT Signaling Activation
    description: Cell-cycle dysregulation cooperates with oncogenic survival signaling
  - target: NOTCH Pathway Dysregulation
    description: Loss of normal squamous differentiation signaling promotes malignant progression
- name: SOX2/TP63 Lineage Program Activation
  description: >-
    ESCC frequently shows 3q amplification with co-amplification and
    upregulation of SOX2 and TP63, reinforcing a malignant squamous lineage
    transcriptional program. SOX2 promotes tumor growth and interacts with
    oncogenic signaling programs including AKT/mTORC1 and YAP1.
  cell_types:
  - preferred_term: squamous epithelial cell
    term:
      id: CL:0000076
      label: squamous epithelial cell
  genes:
  - preferred_term: SOX2
    term:
      id: hgnc:11195
      label: SOX2
  - preferred_term: TP63
    term:
      id: hgnc:15979
      label: TP63
  evidence:
  - reference: PMID:31560173
    reference_title: "SOX2 antagonizes WWC1 to drive YAP1 activation in esophageal squamous cell carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we reveal that SOX2, ACTL6A, and TP63 are co-amplified and
      upregulated in ESCC samples.
    explanation: >-
      This directly supports structured inclusion of SOX2 and TP63 as recurrent
      co-amplified squamous lineage regulators in ESCC.
  - reference: PMID:23510069
    reference_title: "SOX2 promotes tumor growth of esophageal squamous cell carcinoma through the AKT/mammalian target of rapamycin complex 1 signaling pathway."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      SOX2 promotes ESCC cell proliferation in vitro.
    explanation: >-
      This cell-based evidence supports a mechanistic contribution of SOX2 to
      proliferative squamous lineage programs in ESCC.
  downstream:
  - target: PI3K/AKT Signaling Activation
    description: SOX2 can activate growth-promoting AKT/mTORC1 signaling
  - target: Increased Tumor Cell Proliferation
    description: Squamous lineage oncogene activation promotes ESCC growth
- name: PI3K/AKT Signaling Activation
  description: >-
    Recurrent PIK3CA and related pathway alterations increase prosurvival and
    growth signaling in ESCC, supporting tumor maintenance and therapeutic
    resistance.
  biological_processes:
  - preferred_term: phosphatidylinositol 3-kinase signaling
    modifier: INCREASED
    term:
      id: GO:0043491
      label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
  evidence:
  - reference: PMID:38832974
    reference_title: "Prognostic value of genomic mutation signature associated with immune microenvironment in southern Chinese patients with esophageal squamous cell carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathway analysis revealed dysregulation of cell cycle regulation,
      epigenetic regulation, PI3K/AKT signaling, and NOTCH signaling.
    explanation: >-
      This study directly reports PI3K/AKT pathway dysregulation in ESCC.
  downstream:
  - target: Increased Tumor Cell Proliferation
    description: PI3K/AKT activity promotes growth and survival of ESCC cells
- name: NOTCH Pathway Dysregulation
  description: >-
    Alteration of NOTCH pathway genes perturbs normal squamous differentiation
    programs and contributes to malignant transformation and progression in ESCC.
  genes:
  - preferred_term: NOTCH1
    term:
      id: hgnc:7881
      label: NOTCH1
  biological_processes:
  - preferred_term: Notch signaling pathway
    modifier: ABNORMAL
    term:
      id: GO:0007219
      label: Notch signaling pathway
  - preferred_term: keratinocyte differentiation
    modifier: DECREASED
    term:
      id: GO:0030216
      label: keratinocyte differentiation
  evidence:
  - reference: PMID:34611831
    reference_title: "Systematic Review and Meta-analysis of the Most Common Genetic Mutations in Esophageal Squamous Cell Carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TP53 (68.6%; 95% CI: 61.6-74.9), CCND1 (39.3%; 95% CI: 26.2-54.1), MDM2
      (24.9%; 95% CI: 9.5-51.0), NOTCH1/2/3 (17.9%; 95% CI: 15.0-21.2),
      KMT2D (17.4%; 95% CI: 12.4-23.8), CDKN2A (15.0%; 95% CI: 8.1-26.1),
      PIK3CA (13.8%; 95% CI: 10.3-18.1), FAT1 (13.3%; 95% CI: 11.7-15.0),
      and EGFR (9.9%; 95% CI: 5.6-17.0) were the most common involved genetic
      factors in developing ESCC.
    explanation: >-
      This meta-analysis shows recurrent NOTCH pathway gene involvement in ESCC.
  downstream:
  - target: Increased Tumor Cell Proliferation
    description: Impaired squamous differentiation favors tumor expansion
- name: Increased Tumor Cell Proliferation
  description: >-
    Convergent disruption of DNA damage control, cell-cycle regulation, squamous
    differentiation, and prosurvival signaling drives continued ESCC cell
    proliferation, invasion, and progression.
  cell_types:
  - preferred_term: squamous epithelial cell
    term:
      id: CL:0000076
      label: squamous epithelial cell
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  evidence:
  - reference: PMID:38832974
    reference_title: "Prognostic value of genomic mutation signature associated with immune microenvironment in southern Chinese patients with esophageal squamous cell carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathway analysis revealed dysregulation of cell cycle regulation,
      epigenetic regulation, PI3K/AKT signaling, and NOTCH signaling.
    explanation: >-
      This human ESCC cohort directly supports recurrent dysregulation of
      cell-cycle programs underlying increased tumor proliferation.
  - reference: PMID:23510069
    reference_title: "SOX2 promotes tumor growth of esophageal squamous cell carcinoma through the AKT/mammalian target of rapamycin complex 1 signaling pathway."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In mouse xenografts, SOX2 promoted in vivo tumor growth of ESCC, which
      was dependent on AKT/mTORC1 activation.
    explanation: >-
      This mouse xenograft study supports the proliferative consequence of
      SOX2-driven oncogenic signaling in ESCC.
  downstream:
  - target: Adaptive Immune Resistance
    description: Expanding tumors acquire PD-L1-linked immune escape programs.
  - target: Progressive Dysphagia
    description: Tumor growth progressively narrows the esophageal lumen and impairs swallowing.
  - target: Odynophagia
    description: Tumor ulceration and local wall invasion can make swallowing painful.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Chest Pain
    description: Locally invasive or ulcerative esophageal tumor growth can produce retrosternal chest pain.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Hematemesis
    description: Ulcerative tumor growth can erode mucosa and cause upper gastrointestinal bleeding.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Weight Loss
    description: Tumor burden and impaired oral intake contribute to weight loss.
- name: Adaptive Immune Resistance
  conforms_to: "immune_checkpoint_blockade#Adaptive Immune Resistance"
  description: >-
    A substantial subset of advanced ESCC expresses PD-L1 on tumor cells and
    tumor-infiltrating immune cells, consistent with a checkpoint-mediated
    immune-evasion state targetable with PD-1 blockade.
  biological_processes:
  - preferred_term: negative regulation of T cell mediated immunity
    modifier: INCREASED
    term:
      id: GO:0002710
      label: negative regulation of T cell mediated immunity
  evidence:
  - reference: PMID:30684971
    reference_title: "PD-L1 expression and its clinicopathological correlation in advanced esophageal squamous cell carcinoma in a Chinese population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PD-L1 was expressed on 29.9% (113/378) ESCC tumor cells and 40.2% (152/378) tumor-infiltrating immune cells."
    explanation: This directly supports a clinically relevant PD-L1-positive immune-evasion state in advanced ESCC.
  downstream:
  - target: T Cell Exhaustion and Immune Escape
    description: Chronic checkpoint signaling drives tumor-infiltrating T cells into an exhausted, non-productive state.
- name: T Cell Exhaustion and Immune Escape
  conforms_to: "immune_checkpoint_blockade#T Cell Exhaustion and Immune Escape"
  description: >-
    In the immunosuppressive ESCC microenvironment, chronically stimulated
    tumor-infiltrating T cells acquire an exhausted phenotype with impaired
    effector cytokine production and cytolytic activity, contributing to immune
    escape.
  cell_types:
  - preferred_term: exhausted T cell
    term:
      id: CL:0011025
      label: exhausted T cell
  biological_processes:
  - preferred_term: exhausted T cell differentiation
    modifier: INCREASED
    term:
      id: GO:0160083
      label: exhausted T cell differentiation
  evidence:
  - reference: PMID:26086965
    reference_title: "T-cell exhaustion in the tumor microenvironment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The exhausted T cells in the tumor microenvironment show overexpressed inhibitory receptors, decreased effector cytokine production and cytolytic activity, leading to the failure of cancer elimination."
    explanation: This review directly supports an exhausted intratumoral T-cell state as a mechanistic consequence of checkpoint-mediated immune escape.
- name: Chemotherapy Resistance
  biological_scale: CELLULAR
  description: >-
    A subset of ESCC tumors survives platinum and fluoropyrimidine chemotherapy,
    and the clones that persist drive the high post-treatment recurrence rate.
    Resistance segregates with a constitutively elevated antioxidant stress
    response: chemo-resistant patient-derived organoids carry higher expression of
    antioxidant stress response genes, and more accessible chromatin at those
    loci, than sensitive organoids from the same library.
  cell_types:
  - preferred_term: esophageal tumor epithelial cell
    term:
      id: CL:0002252
      label: epithelial cell of esophagus
  biological_processes:
  - preferred_term: antioxidant stress response
    description: Basal activation of the antioxidant stress response distinguishes chemo-resistant from chemo-sensitive ESCC organoids
    modifier: INCREASED
    term:
      id: GO:0034599
      label: cellular response to oxidative stress
  evidence:
  - reference: PMID:40169778
    reference_title: "An organoid library of human esophageal squamous cell carcinomas (ESCCs) uncovers the chemotherapy-resistant ESCC features."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The ESCCOs respond differently to cisplatin and 5-fluorouracil, chemotherapeutic agents commonly used to treat ESCC patients, with 7 ESCCOs exhibiting potent chemo-resistance."
    explanation: Establishes that resistance to the two agents used in standard ESCC chemotherapy is a stable, patient-specific property retained by tumor-derived organoids.
  - reference: PMID:40169778
    reference_title: "An organoid library of human esophageal squamous cell carcinomas (ESCCs) uncovers the chemotherapy-resistant ESCC features."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the chemo-resistant ESCCOs show higher genes involved in antioxidant stress response pathways and more accessible chromatin at their loci than the sensitive ESCCOs"
    explanation: Identifies an elevated antioxidant stress response, at both the transcript and chromatin-accessibility level, as the molecular feature that distinguishes chemo-resistant from chemo-sensitive tumors.
  notes: >-
    No causal edge is asserted into or out of this node. The organoid library
    establishes that chemo-resistance segregates with an elevated antioxidant
    stress response, but not which of the upstream nodes curated here produces
    that state, so an edge would over-assert.
phenotypes:
- category: Gastrointestinal
  name: Progressive Dysphagia
  description: >-
    Progressive difficulty swallowing is the most common presenting symptom as
    the luminal tumor narrows the esophagus.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:20448378
    reference_title: "Delay in the diagnosis of esophageal carcinoma: experience of a single unit from a developing country."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      First symptom was progressive dysphagia in all patients.
    explanation: >-
      This prospective clinical cohort documents progressive dysphagia as the
      leading presenting symptom in esophageal carcinoma, including squamous
      cases.
  - reference: PMID:20950882
    reference_title: "Adding external beam to intra-luminal brachytherapy improves palliation in obstructive squamous cell oesophageal cancer: a prospective multi-centre randomized trial of the International Atomic Energy Agency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In longitudinal regression analyses, scores for dysphagia (p=0.00005),
      odynophagia (p=0.006), regurgitation (p=0.00005), chest pain (p=0.0038)
      and performance status (p=0.0015) were all significantly improved.
    explanation: >-
      This multicenter randomized trial in squamous oesophageal cancer confirms
      dysphagia as a core symptom burden in conventional SCC.
- category: Constitutional
  name: Weight Loss
  description: >-
    Weight loss is common because of impaired oral intake, cancer-associated
    catabolism, and advanced disease burden.
  phenotype_term:
    preferred_term: Weight loss
    term:
      id: HP:0001824
      label: Weight loss
  evidence:
  - reference: PMID:20448378
    reference_title: "Delay in the diagnosis of esophageal carcinoma: experience of a single unit from a developing country."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Subsidiary symptoms were, weight loss in 83.3% (n = 40), abdominal /
      chest pain in 10 (20.8%), regurgitation in 14 (29.2%), odynophagia in
      three (6.2%)
    explanation: >-
      This prospective clinical cohort reports weight loss as a frequent
      presenting symptom in esophageal carcinoma, including squamous cases.
- category: Gastrointestinal
  name: Odynophagia
  description: >-
    Painful swallowing may occur when the tumor ulcerates or deeply invades the
    esophageal wall.
  phenotype_term:
    preferred_term: Odynophagia
    term:
      id: HP:0032043
      label: Odynophagia
  evidence:
  - reference: PMID:20950882
    reference_title: "Adding external beam to intra-luminal brachytherapy improves palliation in obstructive squamous cell oesophageal cancer: a prospective multi-centre randomized trial of the International Atomic Energy Agency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In longitudinal regression analyses, scores for dysphagia (p=0.00005),
      odynophagia (p=0.006), regurgitation (p=0.00005), chest pain (p=0.0038)
      and performance status (p=0.0015) were all significantly improved.
    explanation: >-
      This multicenter randomized trial in squamous oesophageal cancer
      documents odynophagia among the core disease-related symptoms.
- category: Gastrointestinal
  name: Chest Pain
  description: >-
    Retrosternal chest pain can accompany locally invasive or ulcerative
    esophageal tumors.
  phenotype_term:
    preferred_term: Chest pain
    term:
      id: HP:0100749
      label: Chest pain
  evidence:
  - reference: PMID:20950882
    reference_title: "Adding external beam to intra-luminal brachytherapy improves palliation in obstructive squamous cell oesophageal cancer: a prospective multi-centre randomized trial of the International Atomic Energy Agency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In longitudinal regression analyses, scores for dysphagia (p=0.00005),
      odynophagia (p=0.006), regurgitation (p=0.00005), chest pain (p=0.0038)
      and performance status (p=0.0015) were all significantly improved.
    explanation: >-
      This multicenter randomized trial in squamous oesophageal cancer
      documents chest pain among the core disease-related symptoms.
- category: Gastrointestinal
  name: Hematemesis
  description: >-
    Tumor ulceration may cause upper gastrointestinal bleeding with vomiting of
    blood.
  phenotype_term:
    preferred_term: Hematemesis
    term:
      id: HP:0002248
      label: Hematemesis
  evidence:
  - reference: PMID:28894616
    reference_title: "Esophageal Squamous Cell Carcinoma Presenting with Streptococcus intermedius Cerebral Abscess."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report the case of a 53-year-old female who presented with
      hematemesis and melena followed by left-sided weakness.
    explanation: >-
      This case report directly documents hematemesis in a patient with
      esophageal squamous cell carcinoma.
histopathology:
- name: Squamous Cell Carcinoma
  finding_term:
    preferred_term: Squamous Cell Carcinoma
    term:
      id: NCIT:C2929
      label: Squamous Cell Carcinoma
  description: >-
    ESCC is the squamous histologic subtype of esophageal cancer and represents
    the dominant esophageal cancer histology worldwide.
  evidence:
  - reference: PMID:20224883
    reference_title: "Alcohol drinking, cigarette smoking, and the development of squamous cell carcinoma of the esophagus: molecular mechanisms of carcinogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Esophageal cancers are classified into two histological types; esophageal
      squamous cell carcinoma (ESCC), and adenocarcinoma
    explanation: >-
      This review explicitly identifies ESCC as a distinct histologic subtype of
      esophageal cancer.
diagnosis:
- name: Endoscopic ultrasonography
  description: >-
    Endoscopic ultrasonography is used for clinical T staging of ESCC before
    definitive local therapy.
  diagnosis_term:
    preferred_term: endoscopic ultrasonography
    term:
      id: NCIT:C16546
      label: Endoscopic Procedure
  evidence:
  - reference: PMID:29667114
    reference_title: "Efficacy of Endoscopic Ultrasonography for Determining Clinical T Category for Esophageal Squamous Cell Carcinoma: Data From 1434 Surgical Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "EUS is in general feasible for classifying clinical T category for ESCC."
    explanation: This directly supports endoscopic ultrasonography as a staging procedure in ESCC.
differential_diagnoses:
- name: Esophageal adenocarcinoma
  disease_term:
    preferred_term: esophageal adenocarcinoma
    term:
      id: MONDO:0005028
      label: esophageal adenocarcinoma
  description: >-
    Esophageal adenocarcinoma is the main histologic differential because it
    shares an anatomic site with ESCC but differs in precursor lesions,
    epidemiology, and tumor biology.
  distinguishing_features:
  - ESCC arises from squamous mucosa and is strongly linked to tobacco and alcohol exposure.
  - Esophageal adenocarcinoma usually arises in distal esophagus from Barrett metaplastic mucosa.
  evidence:
  - reference: PMID:20224883
    reference_title: "Alcohol drinking, cigarette smoking, and the development of squamous cell carcinoma of the esophagus: molecular mechanisms of carcinogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Esophageal cancers are classified into two histological types; esophageal squamous cell carcinoma (ESCC), and adenocarcinoma"
    explanation: This directly supports adenocarcinoma as the key alternative esophageal histologic diagnosis.
biochemical:
- name: PD-L1 Immunohistochemistry
  notes: >-
    PD-L1 testing, often reported as combined positive score (CPS), helps guide
    use of immune checkpoint inhibitors in advanced disease.
- name: Squamous Cell Carcinoma Antigen
  notes: >-
    Serum squamous cell carcinoma antigen may correlate with tumor burden and
    prognosis in a subset of patients, but it is not sufficiently specific for
    diagnosis.
genetic:
- name: TP53
  gene_term:
    preferred_term: TP53
    term:
      id: hgnc:11998
      label: TP53
  association: Somatic Driver Mutation
  notes: >-
    TP53 is the most common recurrently altered gene in ESCC and is associated
    with genomic instability and loss of checkpoint control.
  evidence:
  - reference: PMID:34611831
    reference_title: "Systematic Review and Meta-analysis of the Most Common Genetic Mutations in Esophageal Squamous Cell Carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TP53 (68.6%; 95% CI: 61.6-74.9), CCND1 (39.3%; 95% CI: 26.2-54.1), MDM2
      (24.9%; 95% CI: 9.5-51.0), NOTCH1/2/3 (17.9%; 95% CI: 15.0-21.2),
      KMT2D (17.4%; 95% CI: 12.4-23.8), CDKN2A (15.0%; 95% CI: 8.1-26.1),
      PIK3CA (13.8%; 95% CI: 10.3-18.1), FAT1 (13.3%; 95% CI: 11.7-15.0),
      and EGFR (9.9%; 95% CI: 5.6-17.0) were the most common involved genetic
      factors in developing ESCC.
    explanation: >-
      This meta-analysis identifies TP53 as the most prevalent recurrent genetic
      alteration in ESCC.
- name: CCND1
  gene_term:
    preferred_term: CCND1
    term:
      id: hgnc:1582
      label: CCND1
  association: Copy Number Amplification
  notes: >-
    CCND1 amplification contributes to cell-cycle acceleration and is among the
    most frequent recurrent driver alterations in ESCC.
  evidence:
  - reference: PMID:34611831
    reference_title: "Systematic Review and Meta-analysis of the Most Common Genetic Mutations in Esophageal Squamous Cell Carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TP53 (68.6%; 95% CI: 61.6-74.9), CCND1 (39.3%; 95% CI: 26.2-54.1), MDM2
      (24.9%; 95% CI: 9.5-51.0), NOTCH1/2/3 (17.9%; 95% CI: 15.0-21.2),
      KMT2D (17.4%; 95% CI: 12.4-23.8), CDKN2A (15.0%; 95% CI: 8.1-26.1),
      PIK3CA (13.8%; 95% CI: 10.3-18.1), FAT1 (13.3%; 95% CI: 11.7-15.0),
      and EGFR (9.9%; 95% CI: 5.6-17.0) were the most common involved genetic
      factors in developing ESCC.
    explanation: >-
      This meta-analysis identifies CCND1 as a frequent recurrent ESCC genetic
      alteration.
- name: NOTCH1
  gene_term:
    preferred_term: NOTCH1
    term:
      id: hgnc:7881
      label: NOTCH1
  association: Squamous Differentiation Pathway Alteration
  notes: >-
    NOTCH pathway alteration disrupts normal squamous differentiation programs
    and contributes to ESCC pathogenesis.
  evidence:
  - reference: PMID:34611831
    reference_title: "Systematic Review and Meta-analysis of the Most Common Genetic Mutations in Esophageal Squamous Cell Carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TP53 (68.6%; 95% CI: 61.6-74.9), CCND1 (39.3%; 95% CI: 26.2-54.1), MDM2
      (24.9%; 95% CI: 9.5-51.0), NOTCH1/2/3 (17.9%; 95% CI: 15.0-21.2),
      KMT2D (17.4%; 95% CI: 12.4-23.8), CDKN2A (15.0%; 95% CI: 8.1-26.1),
      PIK3CA (13.8%; 95% CI: 10.3-18.1), FAT1 (13.3%; 95% CI: 11.7-15.0),
      and EGFR (9.9%; 95% CI: 5.6-17.0) were the most common involved genetic
      factors in developing ESCC.
    explanation: >-
      This meta-analysis supports recurrent NOTCH pathway gene alteration in
      ESCC.
- name: PIK3CA
  gene_term:
    preferred_term: PIK3CA
    term:
      id: hgnc:8975
      label: PIK3CA
  association: Oncogenic Signaling Activation
  notes: >-
    PIK3CA mutation is a recurrent ESCC event that contributes to PI3K/AKT
    pathway activation.
  evidence:
  - reference: PMID:34611831
    reference_title: "Systematic Review and Meta-analysis of the Most Common Genetic Mutations in Esophageal Squamous Cell Carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TP53 (68.6%; 95% CI: 61.6-74.9), CCND1 (39.3%; 95% CI: 26.2-54.1), MDM2
      (24.9%; 95% CI: 9.5-51.0), NOTCH1/2/3 (17.9%; 95% CI: 15.0-21.2),
      KMT2D (17.4%; 95% CI: 12.4-23.8), CDKN2A (15.0%; 95% CI: 8.1-26.1),
      PIK3CA (13.8%; 95% CI: 10.3-18.1), FAT1 (13.3%; 95% CI: 11.7-15.0),
      and EGFR (9.9%; 95% CI: 5.6-17.0) were the most common involved genetic
      factors in developing ESCC.
    explanation: >-
      This meta-analysis supports recurrent PIK3CA alteration in ESCC.
- name: SOX2
  gene_term:
    preferred_term: SOX2
    term:
      id: hgnc:11195
      label: SOX2
  association: Lineage Oncogene Amplification
  notes: >-
    SOX2 is a recurrent 3q amplification target in ESCC that reinforces
    malignant squamous lineage programs and proliferative signaling.
  evidence:
  - reference: PMID:31560173
    reference_title: "SOX2 antagonizes WWC1 to drive YAP1 activation in esophageal squamous cell carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we reveal that SOX2, ACTL6A, and TP63 are co-amplified and
      upregulated in ESCC samples.
    explanation: >-
      This directly supports SOX2 as a recurrent amplified lineage oncogene in
      ESCC.
- name: TP63
  gene_term:
    preferred_term: TP63
    term:
      id: hgnc:15979
      label: TP63
  association: Co-amplified Squamous Lineage Transcription Factor
  notes: >-
    TP63 is recurrently co-amplified with SOX2 in ESCC and supports the
    malignant squamous transcriptional state.
  evidence:
  - reference: PMID:31560173
    reference_title: "SOX2 antagonizes WWC1 to drive YAP1 activation in esophageal squamous cell carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we reveal that SOX2, ACTL6A, and TP63 are co-amplified and
      upregulated in ESCC samples.
    explanation: >-
      This directly supports TP63 as a recurrent co-amplified squamous lineage
      regulator in ESCC.
treatments:
- name: Esophagectomy
  description: >-
    Surgical resection is a core curative-intent treatment for resectable
    localized ESCC, typically used in multimodality management.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
- name: Definitive Chemoradiation
  description: >-
    Concurrent chemoradiation is a standard organ-preserving approach for
    locally advanced or unresectable localized ESCC and is also used as part of
    neoadjuvant therapy strategies.
  treatment_term:
    preferred_term: concurrent chemoradiation
    term:
      id: NCIT:C94626
      label: Chemoradiotherapy
    therapeutic_agent:
    - preferred_term: cisplatin
      term:
        id: CHEBI:27899
        label: cisplatin
    - preferred_term: 5-fluorouracil
      term:
        id: CHEBI:46345
        label: 5-fluorouracil
  evidence:
  - reference: PMID:40507565
    reference_title: "Clinical Features and Prognosis of Cervical Esophageal Cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Conclusions: Although cervical ESCC had a poor prognosis due to its
      higher T-stage and worse differentiation compared to other locations,
      outcomes were similar when treated with definitive chemoradiotherapy.
    explanation: >-
      This ESCC cohort directly documents definitive chemoradiotherapy as an
      established treatment modality.
- name: Nivolumab
  description: >-
    Anti-PD-1 immunotherapy used in advanced or previously treated ESCC. It
    improves overall survival compared with chemotherapy in the post-platinum
    setting and is now part of the immunotherapy treatment landscape for ESCC.
  treatment_term:
    preferred_term: immunotherapy
    term:
      id: NCIT:C15262
      label: Immunotherapy
    therapeutic_agent:
    - preferred_term: nivolumab
      term:
        id: NCIT:C68814
        label: Nivolumab
  evidence:
  - reference: PMID:35294546
    reference_title: "Three-Year Follow-Up and Response-Survival Relationship of Nivolumab in Previously Treated Patients with Advanced Esophageal Squamous Cell Carcinoma (ATTRACTION-3)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nivolumab as second-line therapy demonstrated clinically meaningful
      long-term improvement in OS compared with chemotherapy in previously
      treated patients with advanced ESCC.
    explanation: >-
      ATTRACTION-3 provides direct clinical evidence supporting nivolumab use in
      previously treated advanced ESCC.
  target_mechanisms:
  - target: Adaptive Immune Resistance
    treatment_effect: INHIBITS
    description: PD-1 blockade counteracts PD-L1-mediated immune escape in ESCC.
    evidence:
    - reference: PMID:35294546
      reference_title: "Three-Year Follow-Up and Response-Survival Relationship of Nivolumab in Previously Treated Patients with Advanced Esophageal Squamous Cell Carcinoma (ATTRACTION-3)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Nivolumab as second-line therapy demonstrated clinically meaningful long-term improvement in OS compared with chemotherapy in previously treated patients with advanced ESCC."
      explanation: The survival benefit supports therapeutic inhibition of checkpoint-mediated immune escape.
- name: Pembrolizumab-Based Therapy
  description: >-
    Pembrolizumab-containing regimens are used in advanced ESCC, particularly in
    biomarker-selected settings and combination regimens involving chemotherapy.
  treatment_term:
    preferred_term: immunotherapy
    term:
      id: NCIT:C15262
      label: Immunotherapy
    therapeutic_agent:
    - preferred_term: pembrolizumab
      term:
        id: NCIT:C106432
        label: Pembrolizumab
  evidence:
  - reference: PMID:34454674
    reference_title: "Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Compared with placebo plus chemotherapy, pembrolizumab plus chemotherapy
      improved overall survival in patients with previously untreated, advanced
      oesophageal squamous cell carcinoma and PD-L1 CPS of 10 or more, and
      overall survival and progression-free survival in patients with
      oesophageal squamous cell carcinoma, PD-L1 CPS of 10 or more, and in all
      randomised patients regardless of histology, and had a manageable safety
      profile in the total as-treated population.
    explanation: >-
      KEYNOTE-590 provides direct phase 3 clinical evidence supporting
      pembrolizumab-based therapy in advanced ESCC.
  target_mechanisms:
  - target: Adaptive Immune Resistance
    treatment_effect: INHIBITS
    description: Pembrolizumab targets PD-1 to reverse checkpoint-mediated immune resistance in ESCC.
    evidence:
    - reference: PMID:34454674
      reference_title: "Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Compared with placebo plus chemotherapy, pembrolizumab plus chemotherapy improved overall survival in patients with previously untreated, advanced oesophageal squamous cell carcinoma and PD-L1 CPS of 10 or more, and overall survival and progression-free survival in patients with oesophageal squamous cell carcinoma, PD-L1 CPS of 10 or more, and in all randomised patients regardless of histology, and had a manageable safety profile in the total as-treated population."
      explanation: This phase III result supports checkpoint blockade as a therapeutically relevant mechanism in advanced ESCC.
clinical_trials:
- name: NCT03143153
  phase: PHASE_III
  status: COMPLETED
  description: >-
    Phase III first-line study of nivolumab plus ipilimumab or nivolumab plus
    fluorouracil and cisplatin versus chemotherapy in advanced ESCC.
  evidence:
  - reference: clinicaltrials:NCT03143153
    reference_title: "A Randomized Phase 3 Study of Nivolumab Plus Ipilimumab or Nivolumab Combined With Fluorouracil Plus Cisplatin Versus Fluorouracil Plus Cisplatin in Subjects With Unresectable Advanced, Recurrent or Metastatic Previously Untreated Esophageal Squamous Cell Carcinoma"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The main purpose of this study is to compare how long subjects with esophageal cancer live overall or live without disease progression after receiving nivolumab and ipilimumab or nivolumab combined with fluorouracil plus cisplatin versus fluorouracil plus cisplatin
    explanation: This directly supports pivotal checkpoint-based first-line trial coverage in ESCC.
- name: NCT03189719
  phase: PHASE_III
  status: COMPLETED
  description: >-
    Phase III KEYNOTE-590 first-line pembrolizumab plus cisplatin and 5-FU
    trial in advanced or metastatic esophageal carcinoma with ESCC-specific
    efficacy hypotheses.
  evidence:
  - reference: clinicaltrials:NCT03189719
    reference_title: "A Randomized, Double-Blind, Placebo-Controlled Phase III Clinical Trial of Pembrolizumab (MK-3475) in Combination With Cisplatin and 5-Fluorouracil Versus Placebo in Combination With Cisplatin and 5-Fluorouracil as First-Line Treatment in Subjects With Advanced/Metastatic Esophageal Carcinoma (KEYNOTE-590)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The purpose of this trial is to evaluate efficacy and safety of pembrolizumab plus standard of care (SOC) chemotherapy with cisplatin and 5-fluorouracil (5-FU) versus placebo plus SOC chemotherapy with cisplatin and 5-FU as first-line treatment in participants with locally advanced or metastatic esophageal carcinoma.
    explanation: This directly supports ESCC-specific phase III checkpoint-chemotherapy evaluation.
experimental_models:
- name: Patient-derived esophageal squamous cell carcinoma organoid library (ESCCO)
  description: >-
    A library of tumor organoids grown from resected primary tumors of 24 ESCC
    patients spanning a range of stages, ages, and prior treatments, alongside
    organoids from each patient's tumor-free marginal esophageal epithelium. A
    non-animal New Approach Methodology that retains the oncogenic mutations of
    the parental tumor and the patient-specific chemotherapy response, and that
    was used to identify the antioxidant stress response as the feature separating
    chemo-resistant from chemo-sensitive disease.
  experimental_model_type: ORGANOID
  namo_type: namo:Organoid
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: esophagus
    term:
      id: UBERON:0001043
      label: esophagus
  cell_types:
  - preferred_term: esophageal tumor epithelial cell
    term:
      id: CL:0002252
      label: epithelial cell of esophagus
  conditions:
  - esophageal squamous cell carcinoma
  - cisplatin and 5-fluorouracil exposure
  - chemotherapy-resistant disease
  cell_source: >-
    Organoids established from resected primary ESCC tissue of 24 patients, with
    paired organoids from tumor-free marginal esophageal epithelium as the
    non-malignant comparator
  culture_system: >-
    Three-dimensional organoid culture supported by Noggin, EGF, R-spondin 1 and
    the ROCK inhibitor Y-27632
  publication: PMID:40169778
  modeled_mechanisms:
  - target: Chemotherapy Resistance
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces patient-specific resistance to cisplatin and 5-fluorouracil in
      human tumor cells, and resolves the elevated antioxidant stress response
      that accompanies it.
    limitations: >-
      The organoids are composed exclusively of tumor cells, so stromal, vascular
      and immune contributions to chemotherapy resistance are outside what this
      system reports. Resistance is measured as organoid survival under drug
      exposure rather than as clinical response in the source patient.
    readouts:
    - name: Cisplatin and 5-fluorouracil sensitivity across the organoid library
      target: Chemotherapy Resistance
      direction: ALTERED
      interpretation: >-
        Drug response varied between organoid lines from different patients, with
        7 of 24 lines potently resistant, so resistance behaves as a heritable
        property of the tumor cells rather than of the treatment context.
      evidence:
      - reference: PMID:40169778
        reference_title: "An organoid library of human esophageal squamous cell carcinomas (ESCCs) uncovers the chemotherapy-resistant ESCC features."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "The ESCCOs respond differently to cisplatin and 5-fluorouracil, chemotherapeutic agents commonly used to treat ESCC patients, with 7 ESCCOs exhibiting potent chemo-resistance."
        explanation: Reports the measured drug-response spread across the library and the number of resistant lines.
    - name: Antioxidant stress response gene expression and chromatin accessibility
      target: Chemotherapy Resistance
      direction: INCREASED
      biological_processes:
      - preferred_term: antioxidant stress response
        description: Transcript-level and chromatin-accessibility readout of the antioxidant stress response in resistant lines
        term:
          id: GO:0034599
          label: cellular response to oxidative stress
      interpretation: >-
        Chemo-resistant lines showed higher antioxidant stress response gene
        expression and more open chromatin at those loci than sensitive lines,
        which is the molecular correlate this node describes.
      evidence:
      - reference: PMID:40169778
        reference_title: "An organoid library of human esophageal squamous cell carcinomas (ESCCs) uncovers the chemotherapy-resistant ESCC features."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "the chemo-resistant ESCCOs show higher genes involved in antioxidant stress response pathways and more accessible chromatin at their loci than the sensitive ESCCOs"
        explanation: Reports both measurements and their direction in resistant relative to sensitive organoids.
    - name: Fedratinib-induced cell death in chemo-resistant organoids
      target: Chemotherapy Resistance
      direction: INCREASED
      interpretation: >-
        Screening the library identified a compound that kills the resistant
        lines, showing the model can be used to look for treatments for the
        resistant state and not only to describe it.
      evidence:
      - reference: PMID:40169778
        reference_title: "An organoid library of human esophageal squamous cell carcinomas (ESCCs) uncovers the chemotherapy-resistant ESCC features."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Through drug screening using the ESCCO library, we reveal that fedratinib effectively induces cell death in chemo-resistant ESCCOs."
        explanation: Reports increased cell death in the resistant lines on fedratinib exposure, measured in the organoid system.
    evidence:
    - reference: PMID:40169778
      reference_title: "An organoid library of human esophageal squamous cell carcinomas (ESCCs) uncovers the chemotherapy-resistant ESCC features."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "the chemo-resistant ESCCOs show higher genes involved in antioxidant stress response pathways and more accessible chromatin at their loci than the sensitive ESCCOs"
      explanation: Ties the model's measurements to the mechanism this node asserts, establishing it as informative for chemotherapy resistance in ESCC.
  - target: TP53 Dysfunction
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the stabilized-mutant-p53 state of the parental tumor, with
      matched normal-epithelium organoids from the same patients as the negative
      comparator.
    limitations: >-
      Nuclear p53 accumulation detects stabilized missense p53 and does not
      register truncating or deletion alleles: the TP53-deleted line in this
      library was p53-negative by the same stain despite carrying a TP53 lesion.
      The readout is protein localization rather than a functional assay of p53
      transcriptional output.
    readouts:
    - name: Nuclear p53 accumulation in tumor versus normal epithelial organoids
      target: TP53 Dysfunction
      direction: INCREASED
      interpretation: >-
        Every analyzed tumor organoid line reproduced the nuclear p53
        accumulation of its parental tissue, and organoids from the same
        patients' normal epithelium did not, so the model carries this node's
        defining lesion rather than acquiring it in culture.
      evidence:
      - reference: PMID:40169778
        reference_title: "An organoid library of human esophageal squamous cell carcinomas (ESCCs) uncovers the chemotherapy-resistant ESCC features."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "the nuclear accumulation of p53 protein was confirmed in all analyzed ESCCOs and their parent tumor tissues, but not in ENOs or normal esophageal tissues"
        explanation: Reports the measurement in tumor organoids, parental tissue, and the matched normal comparator.
    evidence:
    - reference: PMID:40169778
      reference_title: "An organoid library of human esophageal squamous cell carcinomas (ESCCs) uncovers the chemotherapy-resistant ESCC features."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "These ESCCOs faithfully recapitulate the oncogenic mutations observed in the original ESCC tissues"
      explanation: Establishes that the organoids retain the parental tumor's oncogenic mutations, which is what makes them informative for a mutation-defined node.
  evidence:
  - reference: PMID:40169778
    reference_title: "An organoid library of human esophageal squamous cell carcinomas (ESCCs) uncovers the chemotherapy-resistant ESCC features."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we established an ESCC organoid (ESCCO) library from 24 ESCC patients of various stages, ages, and treatments"
    explanation: Establishes the scale and patient derivation of this human, animal-free ESCC model system.
  notes: >-
    Curated for the NAMeRS 2026 symposium New Approach Methodology pass
    (monarch-initiative/dismech#4873, sub-issue #9793). The sibling entry
    Esophageal_Adenocarcinoma carries an equivalent organ-chip record; this
    closes the same gap on the squamous side with a squamous-specific source.
datasets:
- accession: geo:GSE289185
  title: Safety and efficacy of neoadjuvant radiotherapy and immunotherapy in the treatment of esophageal squamous cell carcinoma
  description: >-
    Bulk transcriptomic resource from ESCC tumors sampled before and after
    neoadjuvant radiotherapy and immunotherapy, linked to PD-L1 analysis and
    pathologic response.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  conditions:
  - pre-treatment esophageal squamous cell carcinoma
  - post-neoadjuvant radiotherapy and immunotherapy esophageal squamous cell carcinoma
  evidence:
  - reference: GEO:GSE289185
    reference_title: "Safety and efficacy of neoadjuvant radiotherapy and immunotherapy in the treatment of esophageal squamous cell carcinoma"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients receiving NRIT were subjected to whole-exome sequencing, RNA sequencing, and immunohistochemistry (IHC) analysis of programmed death-ligand 1 (PD-L1) on paraffin-embedded tissue sections obtained before and after treatment."
    explanation: This directly supports the dataset as a clinically linked ESCC molecular resource spanning immunotherapy exposure.
classifications:
  icdo_morphology:
    classification_value: Squamous Cell Carcinoma
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
📚

References & Deep Research

Deep Research

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Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Esophageal Squamous Cell Carcinoma. Core disease mechanisms, molecular and...
Asta Scientific Corpus Retrieval 20 citations 2026-04-21T08:23:41.328935

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Esophageal Squamous Cell Carcinoma. Core disease mechanisms, molecular and...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 20
  • Snippets retrieved: 20

Relevant Papers

[1] Diagnostic and Prognostic Value of DACH1 Methylation in the Sensitivity of Esophageal Cancer to Radiotherapy

  • Authors: Jing Huang, Wei-Guo Zhu, Wanwei Wang, Yingying Xu, Lei Jiang et al.
  • Year: 2022
  • Venue: Contrast Media & Molecular Imaging
  • URL: https://www.semanticscholar.org/paper/59daed9cc99408b36618a873693ea715cfd08eaa
  • DOI: 10.1155/2022/6857685
  • PMID: 36247858
  • PMCID: 9537014
  • Citations: 3
  • Summary: The methylation status of DACH1 in esophageal cancer tissues was higher than that in paracancerous tissues and normal tissues, and the differences were statistically significant (P < 0.05).
  • Evidence snippets:
  • Snippet 1 (score: 0.581) > Esophageal cancer is one of the most common malignant tumors in clinical practice. In its early stages, it can have the feeling of a foreign body in the pharynx. With the increase of tumor volume and the progress of the disease, it can have typical progressive symptoms such as eating obstruction, pharyngeal sensation, and poststernal pain after eating. e incidence rate of esophageal cancer ranks seventh among the incidence rates of malignant tumors in the world, and it is also the sixth most common cause of cancer death [1]. China is one of the regions with the highest incidence of esophageal cancer in the world, with the fifth highest incidence rate and an average of about 150,000 deaths per year, among which esophageal squamous cell carcinoma accounts for up to 90% of the deaths and is the deadliest type [2]. Most patients with esophageal cancer have no obvious early symptoms and are already in the middle to late stages when they are diagnosed, losing the best opportunity for surgery [3]. e carcinogenesis and development mechanism of esophageal cancer is a complex process involving the accumulation and interaction of multifactor, multistage, and multigene mutations. > is process may occur at the level of genomic DNA, mRNA, or protein. In recent years, molecular biology research on the mechanism of esophageal cancer suggests that this process presents a multistage evolution, accompanied by the interaction and superposition of multiple genes, especially the activation of oncogenes and the inactivation of tumor suppressor genes, which is an important basis for abnormal cell proliferation and carcinogenesis. e molecular biological mechanisms of cell cycle regulation, signal transduction, cell differentiation, damage repair, and apoptosis are indispensable factors leading to the occurrence and development of tumors. erefore, exploring the biological mechanism of esophageal cancer radiotherapy sensitivity and finding novel markers that can predict the sensitivity of esophageal cancer radiotherapy has become a current research hotspot. Molecular mechanism studies have shown that the development of esophageal cancer is closely related to genetic and epigenetic genetic alterations. Epigenetics is a branch of genetics that studies the herita

[2] An effective multistage mouse model of esophageal carcinogenesis for preclinical and computational pathology applications

  • Authors: Yuxia Fu, Guoqing Zhang, Yue Liu, Lei Xu, Yuanyuan Hu et al.
  • Year: 2025
  • Venue: Neoplasia (New York, N.Y.)
  • URL: https://www.semanticscholar.org/paper/ffdff183908a603852094cab79014c936468ed96
  • DOI: 10.1016/j.neo.2025.101217
  • PMID: 40774225
  • PMCID: 12347694
  • Summary: The tumor-promoting role of SOR is defined by activating the Raf-MEK-ERK pathway in SSE by activating the Raf-MEK-ERK pathway in SSE to establish a novel and effective mouse CIMCM of ESCC using 4NQO and SOR.
  • Evidence snippets:
  • Snippet 1 (score: 0.579) > Esophageal cancer is one of the most common malignancies of the gastrointestinal tract and is the seventh leading cause of cancer death worldwide [1,2]. Esophageal cancer mainly manifests as esophageal squamous cell carcinoma (ESCC) in Asia, but due to the lack of obvious symptoms in the early stages and effective diagnostic methods, the majority of ESCC patients are diagnosed in the late stages, resulting in poor prognosis and high mortality [2,3]. Therefore, the development of feasible, effective and reliable preclinical and clinical models/methods for early detection and treatment of ESCC is essential for improving survival. > Like many types of squamous cell carcinoma (SCC), ESCC carcinogenesis is an intricate, multifactorial, and multistep process involving genetic susceptibility, lifestyle factors, and environmental exposures that sequentially progresses from normal esophageal epithelium (NOR) to hyperplasia (HYP) to dysplasia (DYS) to invasive carcinoma (CAR) [4,5]. Over the past two decades, advances in multiomic techniques have identified dozens of cancer driver genes and their associated molecular pathways involved in the carcinogenesis of human ESCC [6,7]. However, considering that the mammalian esophageal stratified squamous epithelium (SSE) is one of the most rapidly renewing tissues in the body, cancer driver gene mutations have also been frequently identified in normal esophageal SSE specimens [8]. These findings indicate that the initiation and progression of ESCC are not only dependent on the accumulation of mutations in cancer driver genes and their associated pathways but may also be influenced by other non-mutagenic factors such as tumor-promoting factors, tissue injury/inflammatory effects and/or environmental/microenvironmental exposures [9]. Thus, accumulating evidence demonstrates that genetic together with epigenetic/environmental alterations contribute to ESCC carcinogenesis, although the precise mechanisms underlying ESCC initiation and progression remain largely unknown.

[3] The detective, prognostic, and predictive value of DNA methylation in human esophageal squamous cell carcinoma

  • Authors: K. Ma, Baoping Cao, M. Guo
  • Year: 2016
  • Venue: Clinical Epigenetics
  • URL: https://www.semanticscholar.org/paper/2db8a3a5602e97d5a1e5bfe3a6060ddc43991244
  • DOI: 10.1186/s13148-016-0210-9
  • Summary: Characterization of the DNA methylome in ESCC will help to better understand its mechanisms and develop improved therapies, as well as serve as diagnostic, prognostic, and chemo-sensitive markers.
  • Evidence snippets:
  • Snippet 1 (score: 0.577) > Esophageal carcinoma is the sixth leading cause of cancer-related mortality and the eighth most common cancer worldwide [1]. Esophageal cancer has two main subtypes-esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). ESCC is the predominant histological type and accounts for 90 % of the cases of esophageal carcinoma worldwide [2]. Tobacco smoking and alcohol consumption are two major risk factors in ESCC [3][4][5], while gastroesophageal reflux disease (GERD) [6], obesity, and diet [7] were recognized as risk factors for EAC. Despite surgery or chemoradiotherapy, the prognosis of esophageal cancerstill remains poor with the overall 5-year survival ranging from 15 to 25 % [2,8,9]. The mechanisms involved in ESCC remain unclear. Therefore, a clearer understanding of esophageal cancer and subsequent treatment advances are in urgent need. > Both aberrant genetic and epigenetic changes have been demonstrated to contribute to human ESCC initiation and progression [10][11][12]. This review focuses on recent advances involving DNA methylation and its clinical application in human ESCC.

[4] IFI6 depletion inhibits esophageal squamous cell carcinoma progression through reactive oxygen species accumulation via mitochondrial dysfunction and endoplasmic reticulum stress

  • Authors: Zhenchuan Liu, Shaorui Gu, Tiancheng Lu, Kaiqin Wu, Lei Li et al.
  • Year: 2020
  • Venue: Journal of Experimental & Clinical Cancer Research : CR
  • URL: https://www.semanticscholar.org/paper/0b87cd536c2f33e42532b457c9a2b754edebdc28
  • DOI: 10.1186/s13046-020-01646-3
  • PMID: 32727517
  • PMCID: 7388476
  • Citations: 76
  • Influential citations: 1
  • Summary: A novel redox homeostasis signaling pathway that regulates ESCC pathobiology and identifies IFI6 as a potential druggable target in ESCC is unveiled.
  • Evidence snippets:
  • Snippet 1 (score: 0.566) > Esophageal carcinoma is one of the most lethal adult digestive tract tumors with serious malignant characteristics in terms of both mortality and prognosis [1]. In China, esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype of esophageal carcinoma [2]. The current standard of care for ESCC management consists of complete surgical resection followed by chemotherapy as well as radiation [3,4]. Although enormous advancement has been made in diagnostic technologies and comprehensive management approaches for ESCC, the overall 5-year survival rate for ESCC remains unsatisfactory [5]. Currently, the specific mechanism underlying ESCC onset and progression remains to be further defined. Above all, identifying the molecular mechanisms involved in ESCC development and progression, ultimately facilitating the development of more effective treatment strategies against ESCC, is crucial. > Emerging evidence indicates that oxidative stress, which occurs in response to excessive reactive oxygen species (ROS) accumulation and dysregulated cellular redox dynamics, plays diverse and important roles in modulating various aspects of cell behavior, ranging from inducing oxidative damage and subsequent cell death to modulating cell proliferation and survival [6]. Not surprisingly, therefore, the control of ROS production has been associated with many aspects of carcinogenesis, metabolic reprogramming, aggressive cancer phenotypes, and drug resistance development [7]. Numerous lines of evidence support the idea that the role of ROS in transformed cells is highly complex and somewhat controversial. For instance, mitochondriaderived ROS are necessary for Kras-mediated tumorigenicity [8]. In contrast, ROS can enhance chronic inflammation and induce genotoxic damage in cancer cells [9,10]. However, subsequent studies support the idea that although moderately increased oxidative stress is essential for the initiation and progression of carcinoma, cancer cells inherently exhibit a high ROS burden in response to aberrant oncogenic pathways and microenvironments. Multiple concomitant, highly efficient antioxidant mechanisms that are not necessarily needed in normal cells must exist to ensure the survival of these cancer cells.

[5] Molecular mechanism detection of stage I to stage II transition of esophageal squamous cell carcinoma: a system biology approach

  • Authors: Mitra Rezaei, F. Bandarian, F. Razi, Zahra Razzaghi, Ayad Bahadori Monfared et al.
  • Year: 2024
  • Venue: Gastroenterology and Hepatology From Bed to Bench
  • URL: https://www.semanticscholar.org/paper/a864ddd321f38a91a7b7c804b1300287ab90ff4d
  • DOI: 10.22037/ghfbb.v17i4.3013
  • PMID: 40406432
  • PMCID: 12094509
  • Summary: PPI network analysis associated with gene expression assessment showed that COL1A1, SERPINE1, PDGFRB, AURKA, TGFBI, LGALS3, BRCA1, and TFRC are the critical DEGs which are related to ESCC transition state from stage I to II of disease.
  • Evidence snippets:
  • Snippet 1 (score: 0.556) > Introduction 1 Esophageal cancer (EC) is a very poor prognosis malignancy with a high prevalence rate within the northern Iran, southern Russia, central Asian countries, and northern China (1)(2)(3). Esophageal adenocarcinoma and esophageal squamous cell carcinoma are the two main types of EC. Esophageal adenocarcinoma is more common than the other type. Based on pathological features, EC has 0-IV stages. As a rule, the lower the number of stages, the less the cancer has spread. A higher number means cancer has spread more (4,5). > Understanding the molecular mechanism of the cancer process and discovering new biomarkers for early diagnosis is very important. Gene product and proteomic examinations via protein-protein interaction (PPI) network analysis are efficient tools commonly used in clinical research and finding diagnosis biomarker panels related to diseases. There are heterogeneous findings about gene expression changes related to the clinical outcome of esophageal cancer (6)(7)(8). Using PPI network analysis, genes or proteins concerned to a certain disease are retrieved and attributed in a collaborative structure with central elements (9). Hubs, bottlenecks, and hubbottlenecks are the crucial elements of a PPI network, which are used frequently to detect molecular mechanisms of many diseases (10). Rezaei-tavirani et al. have introduced TP53, EGFR, AKT1, ERBB2, MYC, CCND1, CTNNB1, CDH1, and BCL2L1 as a candidate biomarker panel for esophageal adenocarcinoma (11). > As Jiang S et al. reported, 21 biomarker candidates, including 7 individuals confirmed by literature, are introduced for esophageal squamous carcinoma. They suggested that RBPMS2, PDK4, IGK, SBSN, IFIT3, and HSPB6 are biomarkers of tumorigenesis for esophageal squamous carcinoma (12).

[6] ESCCdb: A comprehensive database and key regulator exploring platform based on cross dataset comparisons for esophageal squamous cell carcinoma

  • Authors: Jian Yang, Liyun Bi, Chen Wang, G. Wang, Yixiong Gou et al.
  • Year: 2023
  • Venue: Computational and Structural Biotechnology Journal
  • URL: https://www.semanticscholar.org/paper/dbaac08770fef8920b126aeedc9b000c6ddc1954
  • DOI: 10.1016/j.csbj.2023.03.026
  • PMID: 36968016
  • PMCID: 10036886
  • Citations: 3
  • Summary: An integrated database for ESCC called ESCCdb is presented, which includes a total of 56 datasets and published studies from the GEO, Xena or SRA databases and related publications, and identifies 789 consistently differential expressed genes that may be stable biomarkers or important players during ESCC development.
  • Evidence snippets:
  • Snippet 1 (score: 0.554) > Esophageal cancer is a highly prevalent cancer type with an estimated 572,000 new cases and 509,000 deaths worldwide in 2018, accounting for 3.2 % of all cancer cases and 5.3 % of all cancer deaths, respectively [1]. As the major histological type, esophageal squamous cell carcinoma (ESCC) accounts for about 87 % of all esophageal cancers. It is a critical health-threatening disease owing to its low survival rate; the five-year survival rate is about 20 %, falling to even lower than 5 % in some low-and middle-income countries [2]. Therefore, there is an urgent need to study the etiology, mechanisms, prognostics, and treatment options of ESCC. > Recently, whole-genome and whole-exome sequencing identified somatic mutations and copy number changes that usually disrupt several cancer-related pathways in ESCC. These include p53 signaling, PI3K/AKT pathway, RTK-Ras, cell cycle, Wnt and Notch pathways [2]. Some of the candidates identified in these studies have been comfirmed to be involved in the progression of ESCC. For instance, ZNF750 is frequently mutated in ESCC and has recently been characterized as a lineage-specific tumor suppressor in ESCC [3]. However, the molecular mechanisms of ESCC still need to be explored in detail. > In recent years, rapid development in high throughput sequencing technologies has generated enormous biological data that is distributed in some databases, such as The Cancer Genome Atlas (TCGA), Sequence Read Archive (SRA), and Gene Expression Omnibus (GEO). Several web servers based on TCGA such as GEPIA (http:// gepia.cancer-pku.cn/) [4], Xena (http://xena.ucsc.edu/) [5] and cBioPortal (https://www.cbioportal.org/) [6] provide advanced functionality for visualization and analysis of the TCGA datasets. However, there are only 96 ESCC cases in TCGA and only 227 cases in cBioPortal.

[7] IFI6 is an effective therapeutic target in esophageal squamous cell carcinoma via the modulation of oxidative stress

  • Authors: Zhenchuan Liu, Shaorui Gu, Tiancheng Lu, Kaiqin Wu, Lei Li et al.
  • Year: 2020
  • Venue: Unknown venue
  • URL: https://www.semanticscholar.org/paper/e6d22ee09e429080d13f90a6d8193deb2fb8236e
  • DOI: 10.21203/rs.3.rs-21256/v2
  • Summary: A novel redox homeostasis signaling pathway that regulates ESCC pathobiology and identifies IFI6 as a potential druggable target in ESCC is unveiled.
  • Evidence snippets:
  • Snippet 1 (score: 0.550) > Esophageal carcinoma is one of the most lethal adult digestive tract tumors with serious malignant characteristics in terms of both mortality and prognosis [1]. In China, esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype of esophageal carcinoma [2]. The current standard of care for ESCC management consists of complete surgical resection followed by chemotherapy as well as radiation [3,4]. Although enormous advancement has been made in diagnostic technologies and comprehensive management approaches for ESCC, the overall 5-year survival rate for ESCC remains unsatisfactory [5]. Currently, the speci c mechanism underlying ESCC onset and progression remains to be further de ned. Above all, identifying the molecular mechanisms involved in ESCC development and progression, ultimately facilitating the development of more effective treatment strategies against ESCC, is crucial. > Emerging evidence indicates that oxidative stress, which occurs in response to excessive reactive oxygen species (ROS) accumulation and dysregulated cellular redox dynamics, plays diverse and important roles in modulating various aspects of cell behavior, ranging from inducing oxidative damage and subsequent cell death to modulating cell proliferation and survival [6]. Not surprisingly, therefore, the control of ROS production has been associated with many aspects of carcinogenesis, metabolic reprogramming, aggressive cancer phenotypes, and drug resistance development [7]. Numerous lines of evidence support the idea that the role of ROS in transformed cells is highly complex and somewhat controversial. For instance, mitochondria-derived ROS are necessary for Kras-mediated tumorigenicity [8]. In contrast, ROS can enhance chronic in ammation and induce genotoxic damage in cancer cells [9,10]. However, subsequent studies support the idea that although moderately increased oxidative stress is essential for the initiation and progression of carcinoma, cancer cells inherently exhibit a high ROS burden in response to aberrant oncogenic pathways and microenvironments. Multiple concomitant, highly e cient antioxidant mechanisms that are not necessarily needed in normal cells must exist to ensure the survival of these cancer cells.

[8] Esophageal Cancer Development: Crucial Clues Arising from the Extracellular Matrix

  • Authors: A. Palumbo, N. Meireles Da Costa, Bruno Pontes, Felipe Leite de Oliveira, Matheus Lohan Codeço et al.
  • Year: 2020
  • Venue: Cells
  • URL: https://www.semanticscholar.org/paper/b5fff733540f6d16dccbddf4be8d9cc0dd633c53
  • DOI: 10.3390/cells9020455
  • PMID: 32079295
  • PMCID: 7072790
  • Citations: 50
  • Influential citations: 2
  • Summary: The growing body of evidence on ECM’s role along esophageal carcinogenesis might provide a solid base to improve its management in the future and, due to the scarce knowledge on the cellular and molecular mechanisms involved in EC development, the wide spectrum of interactions potentially mediated by ECM may represent a singular intervention scenario in esophagesia carcinogenesis natural history.
  • Evidence snippets:
  • Snippet 1 (score: 0.548) > This lethal tumor confers a 5-year survival rate of about 15-25% of patients, demonstrating its poor prognosis [17]. There are two main EC histopathological subtypes: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), which widely differ considering populations affected, etiological factors, and molecular alterations, among others. Although ESCC development is highly associated with tobacco and alcohol abuse and ingestion of high temperature beverages, for EAC, the main associated risk factors are obesity, gastroesophageal reflux disease (GERD), and Barrett's esophagus (BE), an intestinal metaplasia where the normal stratified squamous esophageal epithelium is replaced by a columnar intestinal-like one [18,19]. ESCC represents the predominant EC histotype; nevertheless, along with the increase in obesity rates in some western countries, the incidence of EAC has increased sharply over the past few decades [20,21]. Although EC is a remarkably incident and lethal cancer, the knowledge on its biology is still scarce. EC poor prognosis is directly associated with its late detection, which is a consequence of the lack of clinical symptoms in early tumor stages. Thus, the deeper understanding of the mechanisms involved in its genesis and/or progression may be useful in identifying potential markers for diagnosis and prognosis, as well as potential therapeutic targets. Therefore, the reciprocal interactions that occur between the cells and the surrounding ECM orchestrate a complex cascade of events during esophageal malignant transformation, where the adhesion mediated by glycoproteins and proteoglycans triggers signaling pathways, which induce the expression and activation of catalytic enzymes that, in turn, promote structural alterations in ECM stiffness and remodeling [15]. These alterations culminate in the activation of signaling pathways in a feedback loop mechanism (Figure 1). In this context, the interactions between EC and ECM may shed some light on the cellular and molecular mechanisms that govern the malignant development of these tumors.

[9] Expression of P-EGFR and P-Akt protein in esophageal squamous cell carcinoma and its prognosis

  • Authors: Zheng-zheng Shan, Peinan Chen, Feng Wang, Jun Wang, Q. Fan
  • Year: 2017
  • Venue: Oncology Letters
  • URL: https://www.semanticscholar.org/paper/edb2994536623e2affc261aadbf46d3f0623aafe
  • DOI: 10.3892/ol.2017.6526
  • PMID: 28927043
  • PMCID: 5588122
  • Citations: 27
  • Influential citations: 1
  • Summary: P-EGFR and P-Akt protein expression is closely related to the incidence of ESCC and mediates the development of invasive cancer and metastasis and may represent a new therapeutic target for the disease.
  • Evidence snippets:
  • Snippet 1 (score: 0.545) > Esophageal cancer is a common malignant tumor with an increasing incidence and mortality. Surgery combined with radiotherapy and chemotherapy is indicated for esophageal cancer. However, many patients are diagnosed in advanced stages of esophageal cancer, resulting in poor treatment with poor prognosis (1). Clinical practice suggests (2) that recurrence and metastasis are important factors contributing to the death of patients with esophageal cancer. Epidermal growth factor receptor (EGF) is a tyrosine kinase present on cell surface receptors, which affects several growth factors. > Phosphorylated epidermal growth factor receptor (P-EGFR) activates a variety of intracellular signaling pathways, inducing cell proliferation and survival (3). Akt signaling pathway is an important pathway regulating downstream signaling by EGFR (4). Phosphorylated Akt (p-Akt) activates Akt signaling, and the downstream genes in the signaling pathways. It controls the evolution, invasion, development and apoptosis of cancer cells. > Esophageal squamous cell carcinoma (ESCC) is a common pathological type of esophageal cancer. China has a high proportion of ESCC, prompting studies investigating the genetic mechanisms underlying the disease (5)(6)(7)(8). However, the pathogenesis of ESCC is not very clear, and the tumor markers for the diagnosis of ESCC are few in number. Therefore, it is imperative to undertake an in-depth study into the genetic and molecular mechanisms underlying the pathogenesis of ESCC. Development of ESCC markers with strong specificity and high sensitivity, and molecular therapeutic targets has significant clinical implications. In this study, we investigated 83 cases of esophageal squamous carcinoma tissue compared with the corresponding normal esophageal mucosa, from January 2009 to October 2010 at the First Affiliated Hospital of Zhengzhou University. The expression of P-EGFR and p-Akt was detected immunohistochemically using the SP method. Its prognostic value was analyzed to provide a valuable standard of reference for diagnosis and prediction of survival.

[10] Molecular aspects of esophageal squamous cell carcinoma carcinogenesis.

  • Authors: D. M. Lehrbach, M. Nita, I. Cecconello
  • Year: 2003
  • Venue: Arquivos de gastroenterologia
  • URL: https://www.semanticscholar.org/paper/2862c49572554e0bb2b3f4e36a730185be772e8b
  • DOI: 10.1590/S0004-28032003000400011
  • PMID: 15264049
  • Citations: 68
  • Influential citations: 4
  • Summary: Better understanding of molecular alterations during carcinogenesis is expected to improve tumor control and prevention and also may lead to better disease management.
  • Evidence snippets:
  • Snippet 1 (score: 0.543) > Most of the cancer cells contain genetic alterations that related to the control of these process, including transcription factors, such as p53, and apoptosis related proteins (16,18) . Two basic type of genetic damage are Lehrbach DM, Nita ME, Cecconello I, Clinical Genomics of Esophageal Cancer Group. Molecular aspects of esophageal squamous cell carcinoma carcinogenesis encountered frequently in cancer cells: dominant (with targets known as oncogenes) and recessive (with targets known as tumor suppressor genes). The genetic events affecting oncogenes often result in increased stimulatory function, whereas those affecting tumor suppressor genes may cause loss of inhibitory function. > There are several major biochemical mechanisms of action for oncogenes: 1. abnormal signaling by a structurally abnormal cytokine/ growth factor including amplification, deletion, rearrangement and point mutation of the gene; 2. aberrant phosphorylation of proteins at either serine, threonine or tyrosine residues by altered receptors and other signal transducing kinases; and 3. disturbed regulation of gene transcription by abnormal transcription factors. > Tumor suppressor genes can be def ined as genes whose inactivation -by mutation, methylation or chromossomal loss, results in cell transformation. The advances in the f ield of molecular biology have let us to deeper our knowledge of the process of carcinogenesis of the esophagus (Table 1). Ideally, this knowledge should be translated in benefits for patients suffering from cancer. However a new class of gene to have any clinical meaning has to have a clear role in at least one of these fields of cancer management: 1) prevention; 2) diagnosis; 3) prediction of prognosis; or 4) treatment. Thus, better understanding of the molecular alterations during carcinogenesis is expected to improve tumor control and prevention and also may lead to better disease management. In this review, the current knowledge of the genetic profile of this subtype of esophageal tumor is discussed, focusing on the potential of the development of novel tools for clinical management of ESCC.

[11] Targeting Strategies for Aberrant Lipid Metabolism Reprogramming and the Immune Microenvironment in Esophageal Cancer: A Review

  • Authors: Meng-Ying Cui, X. Yi, Z. Cao, Danxia Zhu, Jun Wu
  • Year: 2022
  • Venue: Journal of Oncology
  • URL: https://www.semanticscholar.org/paper/44074dff443e17204841618d09d9e6e8eec6cfb3
  • DOI: 10.1155/2022/4257359
  • PMID: 36106333
  • PMCID: 9467784
  • Citations: 16
  • Summary: Aberrant lipid metabolism and associated signaling pathways are likely to serve as a novel strategy to treat esophageal cancer through lipid metabolism reprogramming.
  • Evidence snippets:
  • Snippet 1 (score: 0.538) > e specific mechanisms of the above fatty acid metabolism, which play a certain role in regulating esophageal squamous cell carcinoma, have been rarely known. Besides, the role played by lipid metabolism in regulating immune cells has aroused extensive attention. Furthermore, immunocytes are critical to an esophageal cancer microenvironment and exhibit complex crosstalk with cancer cells. us, the key pathway to the identification of esophageal cancer's metabolism can significantly explore the occurrence of the esophagus, and it can present novel insights into the diagnosis and treatment of esophageal cancer. It is desirable to develop ESCC new biological markers and immune environment drug resistance mechanisms and lay a theoretical basis for targeted treatment.

[12] Down-Regulation of MiR-1294 is Related to Dismal Prognosis of Patients with Esophageal Squamous Cell Carcinoma through Elevating C-MYC Expression

  • Authors: Kai Liu, Liyi Li, Aizemaiti Rusidanmu, Yongqing Wang, X. Lv
  • Year: 2015
  • Venue: Cellular Physiology and Biochemistry
  • URL: https://www.semanticscholar.org/paper/f978967e1fbb497423a7b2338075c1f4f8060b01
  • DOI: 10.1159/000374056
  • PMID: 25925090
  • Citations: 39
  • Influential citations: 1
  • Summary: Investigation in patients with esophageal squamous cell carcinoma and its effect on prognosis found down-regulation of miR-1294 correlates with poor prognosis of ESCC, partially due to the reduced function of c-MYC.
  • Evidence snippets:
  • Snippet 1 (score: 0.536) > Esophageal cancer is now the eighth most common cancer and the sixth most common cause of cancer deaths worldwide. Histologically, in approximately 95% of cases, the disease occurs as esophageal squamous cell carcinoma (ESCC) or esophageal adenocarcinoma (EAC). Barrett's adenocarcinoma is the most rapidly increasing cancer in Western countries, while esophageal squamous cell carcinoma (ESCC) dominant in East Asia. Although surgical and medical treatments for ESCC has been improved in recent years, the overall outcome of patients with ESCC is dismal, with a 5 year survival rate of less than 10%. And the diagnosis of early stage ESCC is also challenging [1]. Thus, elucidating the molecular mechanisms of ESCC pathogenesis will help to identify specific tumor markers for early detection, risk assessment, and therapeutic target. > MicroRNA (miRNA) is a kind of short non-coding RNAs that suppress the expression of protein coding genes by partial complementary binding, especially to the 3' untranslated regions (UTRs) of messenger RNAs (mRNAs). MiRNA expression alterations are involved in the initiation, progression, and metastasis of human cancer and it is believed that miRNAs function both as tumor suppressors and oncogenes in cancer development [2,3]. > C-Myc is a transcription factor acting as a master regulator of genes involved in cell cycle progression, cell growth, differentiation, metabolism and apoptosis. It is also a potent cellular oncogene that is found frequently deregulated in human cancers. This pathological upregulation is frequently due to chromosomal translocations leading to promoter rearrangement [4][5][6][7], gene amplification [7] and viral mediated insertional mutagenesis [8]. There is also evidence that c-MYC expression is suppressed by miRNAs [9,10]. > In this study, we first detected 6 candidate miRNAs expression in 79 ESCC tissues and found the expression of miR-205, miR-34b and miR-1294 was significantly reduced.

[13] Rab25 is a tumor suppressor gene with antiangiogenic and anti-invasive activities in esophageal squamous cell carcinoma.

  • Authors: M. Tong, K. Chan, Jessie Y. J. Bao, K. Wong, Jinna Chen et al.
  • Year: 2012
  • Venue: Cancer research
  • URL: https://www.semanticscholar.org/paper/3489e6f6cd1716e88c4f568daf398a385200acfa
  • DOI: 10.1158/0008-5472.CAN-12-1269
  • PMID: 22991305
  • Citations: 112
  • Influential citations: 5
  • Summary: Functional studies using lentiviral-based overexpression and suppression systems lent direct support of Rab25 to function as an important tumor suppressor with both anti-invasive and -angiogenic abilities, through a deregulated FAK-Raf-MEK1/2-ERK signaling pathway.
  • Evidence snippets:
  • Snippet 1 (score: 0.533) > Esophageal cancer ranks as the sixth leading cause of cancer-related deaths worldwide, with distinctly high incidences and mortality rates particularly in East Asia, Africa, and North America (1). Esophageal squamous cell carcinoma (ESCC) is the most common form of esophageal cancer. The disease is characterized by regional variation in incidences. More than 50% of all ESCC cases in the world occur in China. In Linzhou and nearby cities in Henan Province of Northern China, ESCC constitutes more than 90% of all esophageal cancer cases in the area and has the highest incidences and mortality rates of esophageal cancer reported in the world (1,2). Despite advances in diagnostic techniques and therapeutic modalities, ESCC remains a devastating malignancy due to late diagnoses and the aggressive nature of the disease. A better understanding of the recurrent genetic alterations and underlying molecular mechanisms involved in ESCC development and progression will facilitate the identification of novel targets, allowing for more sensitive methods of detection, facilitating earlier diagnosis, and prolonging patient survival. > With the advent of next-generation sequencing technologies in recent years, a new sequencing platform, called transcriptome sequencing (RNA-Seq), has been applied to delineate changes at the transcriptomic level. The development of ESCCs, like many other cancers, is believed to be driven by the accumulation of genetic alterations, causing the transformation of normal cells to malignant cells. Thus, studying recurrent changes at the levels of functional transcripts in malignant cells compared with nontumor cells may aid in the identification of deregulated molecular events and pathways involved in driving ESCCs. In the present study, we conducted RNA-Seq analysis on 12 patient-derived nontumor and ESCC clinical samples and identified a number of commonly and significantly differentially expressed genes. Pathway enrichment analysis (DAVID databases) found the deregulated genes to be commonly associated with a number of cancer-related pathways. Of these, 2 of the most significantly enriched pathways are related to integrin signaling, which is commonly known to influence important cellular processes critical to tumor development and progression, including cell proliferation, cell survival, angiogenesis, cell motility, and invasiveness (3)(4)

[14] Concept of histone deacetylases in cancer: Reflections on esophageal carcinogenesis and treatment

  • Authors: Dimitrios Schizas, Aikaterini Mastoraki, L. Naar, E. Spartalis, D. Tsilimigras et al.
  • Year: 2018
  • Venue: World Journal of Gastroenterology
  • URL: https://www.semanticscholar.org/paper/e4390e8bb28e69f42c4736274f2ec3d609b146be
  • DOI: 10.3748/wjg.v24.i41.4635
  • PMID: 30416311
  • PMCID: 6224471
  • Citations: 25
  • Summary: The aim of this survey is to elucidate the molecular identity and mechanism of action of HDAC inhibitors as well as verify their potential utility as anti-cancer agents in esophageal cancer.
  • Evidence snippets:
  • Snippet 1 (score: 0.530) > Esophageal cancer (EC) remains one of the most lethal malignancies worldwide, mainly due to its aggressive nature and the eight most common malignancy of the gastrointestinal (GI) tract [1] . It is also often diagnosed in late stages, making a curative approach less likely. The 5-year survival rate ranges from 15%-25% and disease outcome is strongly associated with early diagnosis [2] . Squamous cell carcinoma (SCC) is described as the most common histological type worldwide, though in many countries a continuous increase in esophageal adenocarcinomas has been reported. The incidence of EC is 2-4 times higher in males compared to females [3] . There is a slight difference in the predisposing parameters associated with each subtype of esophageal carcinoma, with smoking and alcohol consumption being the most important risk factors for SCC and gastroesophageal reflux disease, Barrett's esophagus and obesity being implicated in adenocarcinomas [3] . Well defined molecular pathways and targets involved in esophageal carcinogenesis include tissue inhibitors of metalloproteinase (TIMP) 3 and 4 and vascular endothelial growth factor receptor (VEGFR). Expression of human epidermal growth factor receptor 2 (HER2)/neu and c-kit is also high in EC, with slightly higher rates of expression in adenocarcinomas rather than SCCs [4] . During the last decades there has been a lot of effort in overcoming chemotherapy resistance in tumor cells. This has led to the investigation of more cellular compounds implicated in gene expression and transcription processes. Among the findings, it was discovered that histone acetylation/deacetylation equilibrium is affected in carcinogenesis, leading to modified chromatin structure and therefore changes in gene expression [5] . It is common knowledge that in eukaryotic cells, DNA is tightly developed around a histone core, forming the nucleosome, which is the basic DNA structure. Further coiling of the nucleosomes leads to the formation of the chromosomes.

[15] Untargeted serum metabolomics reveals potential biomarkers and metabolic pathways associated with esophageal cancer

  • Authors: Xiao-Li Yang, Peng Wang, H. Ye, Ming Jiang, Yu Su et al.
  • Year: 2022
  • Venue: Frontiers in Oncology
  • URL: https://www.semanticscholar.org/paper/25d767023ab3c38a77d9801477447e11ddeb25ee
  • DOI: 10.3389/fonc.2022.938234
  • PMID: 36176418
  • PMCID: 9513043
  • Citations: 11
  • Summary: Comparative metabolomics showed that most metabolic differences were determined between the early stage (0–II) and the late stage (III and IV) among the 0–IV stages of esophageal cancer and between patients who received treatment and those who did not receive treatment.
  • Evidence snippets:
  • Snippet 1 (score: 0.525) > Esophageal cancer is a common malignant gastrointestinal tumor that ranks seventh and sixth in global cancer incidence and mortality, respectively. The cancer is known for typical geographic distribution in incidence and poor prognosis (1,2). According to the data released by the International Agency for Research on Cancer (IARC), there were 604,100 new cases of esophageal cancer and 544,076 deaths due to the disease worldwide in 2020, with China accounting for 53.7% and 55.4%, respectively (3). Notably, it is predicted that the incidence and mortality of esophageal cancer will rise yearly owing to the increasing aging of the population, posing a major challenge for health practitioners and a huge threat to human health (4). Thus, understanding the pathogenesis of esophageal cancer is helpful to identify new biomarkers for disease progression judgment and treatment prognosis. > Esophageal cancer is generally divided into two subtypes, namely, esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC); most esophageal cancers are ESCC. ESCC carcinogenesis is related to external and internal factors and, thus, is a multifactorial disease. External factors include tobacco, alcohol, and behavior at high temperature (5)(6)(7), while internal factors are attributed to molecular events. However, the precise molecular events underlying ESCC etiology are only partially understood and thereby the detailed mechanism of occurrence and progression of ESCC has not been holistically revealed yet (8,9). These cause limited targeted therapies and insufficient clinical management in ESCC patients. Therefore, further understanding the pathogenesis of esophageal cancer and identifying diagnosis biomarkers can markedly improve the prognosis and therapy of patients with esophageal cancer. > Recently developed metabolomics provides an efficient approach to achieve a global assessment and validation of endogenous small-molecule metabolites within a cell or biologic system including cancer samples (10,11). Metabolomics is a key tool for biomarker discovery and personalized medicine including cancers (12,13).

[16] miR-25 promotes metastasis via targeting FBXW7 in esophageal squamous cell carcinoma.

  • Authors: Y. Hua, Kai Zhao, G. Tao, C. Dai, Yuting Su
  • Year: 2017
  • Venue: Oncology reports
  • URL: https://www.semanticscholar.org/paper/373d9481658b0668ca23d810fbca4acc48c8382c
  • DOI: 10.3892/or.2017.5995
  • PMID: 29048664
  • Citations: 16
  • Summary: The present study supports the potential of miR-25 as a prognostic predictor with its high expression in cancer tissues and its association with tumor progression by targeting FBXW7 in ESCC.
  • Evidence snippets:
  • Snippet 1 (score: 0.517) > Esophageal cancer is a highly lethal malignancy. As the main type of esophageal cancer, esophageal squamous cell carcinoma (ESCC) accounts for ~90% of all esophageal cancer cases (1,2). However, patients with ESCC are usually diagnosed at advanced stages (3). Recently, advances in the application of combined chemotherapy and radiotherapy, alone or as an adjunct regimen to surgery, have improved the prognosis of ESCC patients (4). Cumulative evidence suggests that a number of oncogenic and tumor-suppressive genes are associated with the initiation and progression of ESCC (3). Yet, the molecular mechanisms underlying the deregulation of the cellular phenotype in ESCC have not been fully clarified. Elucidation of the genetic alterations and underlying molecular pathways involved in ESCC may facilitate the identification of novel targets, as well as improve disease diagnosis and therapy. > MicroRNAs (miRNAs), a kind of endogenous RNA gene products consisting of 18-25 nucleotides, have been identified as important regulators of human malignancies (5). Recently, using detection techniques such as RNA sequencing and microarray, there are various findings that have illustrated the expression profile of miRNAs in ESCC. Moreover, research concerning miRNAs and their target genes and the molecular mechanisms involved in the carcinogenesis of ESCC suggests the enormous therapeutic-clinical potential of miRNAs (6). miR-25 is one of the oncogenes has been reported to be upregulated in several cancers such as hepatocellular carcinoma (7), lung (8), prostate (9) and gastric cancer (10). In addition, plasma miRNA profiles have revealed miR-25 as a novel diagnostic and monitoring biomarker in ESCC (11). Desmocollin 2 (DSC2), a desmosomal cadherin protein which promotes cell aggressiveness by redistributing adherens junctions and activating β-catenin signaling in ESCC, has been identified as a downstream target of miR-25 (12).

[17] The Clinicopathological Correlations of hTERC Amplification with Esophageal Squamous Cell Precursor Lesions

  • Authors: Yan-qiong Hu, X. Teng, Linlin Wu, Wei Liu, Jia-Qi An
  • Year: 2018
  • Venue: Digestive Diseases and Sciences
  • URL: https://www.semanticscholar.org/paper/efdbf7def137df2fe2706c8bc3a635c37dc40802
  • DOI: 10.1007/s10620-018-5318-7
  • PMID: 30311151
  • PMCID: 6318245
  • Citations: 3
  • Summary: hTERC amplification with increasing grading of esophageal squamous cell precursor lesions and the presence of ulcer characteristics might provide an important molecular and pathological marker for the diagnosis and clinical prognosis of esphageal Squamous Cell precursor lesions, especially for those ambiguous cases with more divergence in classification.
  • Evidence snippets:
  • Snippet 1 (score: 0.516) > The incidence of esophageal carcinoma has been increasing in recent years, making it the eighth most common malignancy and the sixth highest in terms of mortality worldwide [1]. There are approximately 400,000 newly diagnosed cases of esophageal carcinoma and approximately 300,000 related deaths worldwide each year, highlighting that this disease poses a serious threat to human health [2]. However, with ongoing advances in fiberoptic scopes to improve the detection rate of early-stage esophageal squamous cell carcinoma (ESCC), more cases of early-stage ESCC are being cured with surgery or radiotherapy; yet, most cases do not have obvious clinical symptoms, and most patients are diagnosed at an advanced stage of the disease, which is usually associated with a poor prognosis. Moreover, the prognosis of ESCC is still not as optimistic as other cancers of the digestive system, such as colorectal cancer. And the reported 5-year overall survival rate ranges from 15 to 40% [3,4]. Therefore, early diagnosis and treatment of ESCC is an effective and critical approach to improve the patient survival rate. > ESCC undergoes a similar progression as squamous cell carcinoma in other tissue types, with a multistage, multifactorial, and progressive carcinogenic process. As an important stage in the progression of ESCC, esophageal squamous cell precursor lesions (ESPLs) have become the most controversial topics of the current research in terms of precise pathological grading, molecular mechanism, clinical management, and prognosis, and ESPLs are observed frequently in clinical and pathological practice. The histopathological manifestations of ESPLs are structural abnormalities (i.e., structural destruction of squamous epithelium and loss of normal cellular polarity) and cytological abnormalities (i.e., irregular size and shape of squamous cells, deeply stained nucleus, increased ratio of nucleus to cytoplasm, and more mitotic figures).

[18] Novel BRCA2-Interacting Protein, LIMD1, Is Essential for the Centrosome Localization of BRCA2 in Esophageal Cancer Cell

  • Authors: Xiaobin Hou, Tinghui Li, Z. Ren, Yang Liu
  • Year: 2016
  • Venue: Oncology Research
  • URL: https://www.semanticscholar.org/paper/a9f1def011bdc56981129de70ea810bf526ea0d0
  • DOI: 10.3727/096504016X14652175055765
  • PMID: 27656835
  • PMCID: 7838625
  • Citations: 10
  • Summary: LIMD1 is a novel BRCA2-interacting protein and is involved in the centrosome localization of BRC a2 and suppression of LIMD1, causing abnormal cell division in EC cells.
  • Evidence snippets:
  • Snippet 1 (score: 0.513) > Esophageal cancer (EC) is a cancer arising from the esophagus. It is the eighth most common cancer worldwide, with 400,000 deaths every year (1). The major histological types include esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC) (2). The risk factors for both types of EC have been proven to be different (3). The most common causes of ESCC are smoking, alcohol, hot drinks, and poor diet, while the most common causes of EAC are smoking, obesity, and acid reflux (4). Of note, the genetic aspect is a risk factor in both types of EC. The treatment of EC is based on the cancer's type, stage, and location. Surgery is generally accepted as the main treatment, and chemotherapy or radiation therapy is used along with surgery (5). Despite the amount of effort that has gone into developing treatments for this disease, outcomes remain unfavorable, and the overall 5-year survival rates are around 16.9% to 20.9% (6). > Breast cancer 2, early onset (BRCA2), together with breast cancer 1, early onset (BRCA1), are major hereditary breast cancer susceptibility genes (7). Multiple studies have demonstrated that alteration of the BRCA2 gene gives an increased risk factor for tumorigenesis and progression in a variety of cancers, including breast cancer, ovarian cancer, and EC (8,9). The germline mutation of the BRCA2 gene has been monitored in several high-risk EC populations from northwest China, northeast India, and Turkmen of Iran. The BRCA2 mutation has been identified as a vital risk factor in EC (10). Clinical investigations in patients with EC have shown that BRCA2 might impact patient survival and could be a potential genomic predictor of clinical response to DNA-damaging treatment (11). However, the detailed function of BRCA2 on EC cells and its underlying molecular mechanisms have not been well clarified. > The centrosome is an important organelle in cells and is closely associated to mitosis.

[19] Comprehensive analysis based on the ubiquitination- and deubiquitylation-related genes reveals the function of NEURL3 in esophageal squamous cell carcinoma

  • Authors: Yi-Wei Lin, Huie Li, Chaoquan Hong, Zi-Ang Chen, Shu-Ping Liu et al.
  • Year: 2025
  • Venue: Frontiers in Immunology
  • URL: https://www.semanticscholar.org/paper/7c12cf2de7f307e187232cb9e28c159903af6fec
  • DOI: 10.3389/fimmu.2025.1632090
  • PMID: 40918133
  • PMCID: 12408286
  • Citations: 1
  • Summary: A novel nomogram was constructed that could serve as a potentially reliable prognostic model and provide theoretical basis for uncovering potential therapeutic target in the treatment of ESCC.
  • Evidence snippets:
  • Snippet 1 (score: 0.512) > Esophageal cancer (EC) is a kind of gastrointestinal tumor which is highly invasive and prone to metastasis and recurrence. According to the data released by Global Cancer database, the global incidence of esophageal cancer ranks 11th, and the mortality rate ranks 7th (1). In China, the main pathological type of EC is esophageal squamous cell carcinoma (ESCC), ranking 7th in incidence and 5th in mortality (2). At present, under the combined treatments involving surgery, radiotherapy and chemotherapy, the prognosis of ESCC patients is still poor with a five-year survival rate of less than 20% (3). Therefore, it is urgent to identify some pivotal genes for predicting prognosis and serving as novel therapeutic targets for ESCC. > Recently, there has been growing evidence that post-translational modification (PTM) is one of the key mechanisms for tumorigenesis, such as ubiquitination and deubiquitylation (4). Ubiquitination and deubiquitylation are important physiological processes to determine the fate of substrates, either inducing the specific degradation of multiple proteins, as in most cases, or altering their interactions, localization, or enzymatic activities (5). Most cellular biological mechanisms involve the ubiquitination proteasome pathway to regulate DNA damage repair, participate in aging cell differentiation, affect tumor malignant transformation and mediate drug resistance (6). For example, USP5 is regarded to serve as a novel deubiquitinase for the protooncogene c-Myc, providing a mechanism governing the fate of c-Myc in hepatocellular carcinoma (7). In myelodysplastic neoplasm, the differential expression of USP15-USP7 axis and UBE2T may predict pathogenesis and poor prognosis of patients (8). USP9X is involved in multiple critical cellular processes, vital molecular pathways and specific immunological regulations in tumor microenvironment (TME) (9).

[20] EZH2 regulates oncomiR-200c and EMT markers in esophageal squamous cell carcinomas

  • Authors: Fatemeh Nourmohammadi, M. Forghanifard, M. Abbaszadegan, V. Zarrinpour
  • Year: 2022
  • Venue: Scientific Reports
  • URL: https://www.semanticscholar.org/paper/440611350be2b54681a6f1b4d777c783f217c66c
  • DOI: 10.1038/s41598-022-23253-2
  • PMID: 36316365
  • PMCID: 9622866
  • Citations: 16
  • Influential citations: 1
  • Summary: It is demonstrated that EZH2 regulates the expression of miR-200c and critical EMT genes, implying that overexpression of Zeb2, Fibronectin, N-cadherin, and Vimentin lead to a mesenchymal phenotype and morphology while underexpressive of epithelial genes, enhance cell migration after enforced expression of EZh2 in ESCCs.
  • Evidence snippets:
  • Snippet 1 (score: 0.512) > Esophageal cancer (EC) is the seventh most common cancer and the sixth leading cause of cancer-related mortality worldwide with five-year survival rates of less than 20% 1 . EC presents two major histological types including esophageal adenocarcinoma and esophageal squamous cell carcinoma (ESCC) 2 . ESCC is considered as the main histological type (90% of patients) with poor prognosis in the East and the Middle East of Asia, Africa, South America, and Southern Europe [3][4][5] . Although extensive studies have been performed on the ESCC tumorigenesis, the cellular and molecular mechanisms of ESCC progression and development are inadequately identified. Metastasis, tumor relapses and drug resistance are three major difficulties in the treatment of the ESCC malignancy which are associated with high morbidity and mortality of the disease 6 . > Presented treatments for ESCC are including esophagectomy, local mucosal resection or ablation therapies, chemotherapy, and radiation therapy which are approved by the National Comprehensive Cancer Network (NCCN). For many clinical consequences, there are no sufficient conclusive results to assist EC treatment. Esophagectomy, as one of the most complicated cancer surgeries, has a 5% in-hospital mortality rate and a recovery period of nearly a year 7 . Due to the poor prognoses, esophageal cancer almost found at an advanced stage when traditional treatment modalities cannot accomplish the therapy 8 . Furthermore, a large proportion of treated patients (60-70%) do not respond well to neoadjuant therapies and experience serious side effects (vomiting, fluid and electrolyte imbalance, stomatitis/mucositis, renal, hearing, and peripheral neuropathy [8][9][10] . > Vector, kindly provided by Dr. Moein Farshchian, (Molecular Medicine Research Department, ACECR-Khorasan Razavi Branch, Mashhad, Iran) was used to downregulate EZH2 in YM-1 and KYSE-30 cells 37 .

Notes

  • This provider combines search_papers_by_relevance with snippet_search.
  • No synthesis or second-stage model call is performed.