Home / Deep Research / Esophageal Squamous Cell Carcinoma

Esophageal Squamous Cell Carcinoma

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

2026-04-21
Asta MONDO:0005580 Model: Asta Scientific Corpus Retrieval 20 citations

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.