Evading Growth Suppressors Module

Module evading_growth_suppressors 6 disorders Pathograph 4

A conserved mechanism module for the second hallmark of cancer (Hanahan & Weinberg): the evasion of antiproliferative programs governed by tumor suppressors. Two master tumor-suppressor circuits enforce these programs: the retinoblastoma protein (RB) pathway, which integrates extracellular antigrowth signals to gate the G1/S transition, and the TP53 (p53) pathway, which senses intracellular stress (DNA damage, oncogene-induced hyperproliferation, hypoxia) and triggers cell-cycle arrest, senescence, or apoptosis. The conserved causal chain runs from inactivation of an RB- or p53-axis tumor suppressor (RB1/CDKN2A loss, cyclin D/CDK4-6 amplification, TP53 mutation, MDM2 amplification) through loss of cell-cycle-checkpoint and antiproliferative control, and additionally through loss of contact inhibition, to unrestrained proliferation. This is the antiproliferative-brake counterpart to sustaining_proliferative_signaling: that module models acquisition of growth-promoting drive, this one models loss of growth-restraining control. Individual disorder entries declare conformance via conforms_to, substituting the tumor-type-specific tumor-suppressor lesion (e.g., biallelic RB1 in retinoblastoma, germline TP53 in Li-Fraumeni, APC/Wnt in familial adenomatous polyposis, NF1 in neurofibromatosis).

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Pathophysiology Nodes

4 shared nodes are defined in this module.

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Cell Types

No cell types are annotated for this module.

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Biological Processes

Notes

This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g., "evading_growth_suppressors#Loss of Cell-Cycle Checkpoint Control"). The module defines the expected pathophysiology structure; conforming nodes in disorder files should include the corresponding biological processes and causal edges, specialized to their tumor context. Key tumor-specific substitutions: retinoblastoma uses biallelic RB1 inactivation (the two-hit paradigm); Li-Fraumeni uses germline TP53 loss; many sporadic cancers use CDKN2A (p16INK4A) deletion or MDM2 amplification. The senescence arm of tumor suppression is elaborated in senescence_tumor_suppression. Key conformance target: "evading_growth_suppressors#Loss of Cell-Cycle Checkpoint Control".

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Used By Disorder Entries

ER-Positive Breast Cancer via Cell Cycle Progression → Loss of Cell-Cycle Checkpoint Control

Hepatocellular Carcinoma via TP53 Pathway Inactivation → Tumor Suppressor Inactivation

Pancreatic Ductal Adenocarcinoma via Tumor Suppressor Inactivation

Retinoblastoma via RB1 Tumor Suppressor Inactivation → Tumor Suppressor Inactivation , Loss of Cell Cycle Checkpoint Control → Loss of Cell-Cycle Checkpoint Control , Uncontrolled Retinal Cell Proliferation → Unrestrained Proliferation

Sezary Syndrome via Cell-cycle checkpoint and tumor suppressor loss → Loss of Cell-Cycle Checkpoint Control

Small Cell Lung Cancer via Loss of Cell Cycle Checkpoints → Loss of Cell-Cycle Checkpoint Control

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence-backed metadata.

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Pathophysiology

Tumor Suppressor Inactivation

trigger

A genetic or epigenetic lesion inactivates an RB- or p53-axis tumor suppressor. Routes include biallelic loss of RB1, deletion or silencing of CDKN2A (encoding p16INK4A and p14ARF), amplification of cyclin D/CDK4-6 that hyperphosphorylates RB, loss-of-function mutation of TP53 (the most frequently mutated gene in human cancer), or amplification of the p53 antagonists MDM2/MDM4. Each route disables a node that normally enforces antiproliferative control.

Signal Transduction by p53 Class Mediator GO:0072331 DECREASED

Used by disorders

Hepatocellular Carcinoma as TP53 Pathway Inactivation

Pancreatic Ductal Adenocarcinoma

Retinoblastoma as RB1 Tumor Suppressor Inactivation

Downstream

Loss of Cell-Cycle Checkpoint Control Inactivation of the RB or p53 axis removes the brakes that gate cell-cycle progression and stress responses.

Loss of Cell-Cycle Checkpoint Control

central effector

With the RB and/or p53 circuits disabled, the cell loses the antiproliferative checkpoints that normally halt division. RB-pathway loss permits unrestrained G1/S transit regardless of antigrowth signals; p53-pathway loss abolishes the stress-induced cell-cycle arrest, senescence, and apoptosis that would otherwise eliminate incipient tumor cells. This is the conserved central node disorder-specific lesions converge upon.

Negative Regulation of Cell Cycle GO:0045786 DECREASED Negative Regulation of Cyclin-Dependent Protein Kinase Activity GO:1904030 DECREASED

Used by disorders

ER-Positive Breast Cancer as Cell Cycle Progression

Retinoblastoma as Loss of Cell Cycle Checkpoint Control

Sezary Syndrome as Cell-cycle checkpoint and tumor suppressor loss

Small Cell Lung Cancer as Loss of Cell Cycle Checkpoints

Downstream

Loss of Contact Inhibition Disabled tumor-suppressor circuits also relax density-dependent restraints on proliferation.
Unrestrained Proliferation Removal of antiproliferative checkpoints permits continued division of cells that should have arrested or died.

Loss of Contact Inhibition

effector

Normal epithelial and mesenchymal cells cease proliferating when they reach high density (contact inhibition), a tumor-suppressive restraint mediated in part by the Hippo-YAP/TAZ pathway, NF2/Merlin, and LKB1-AMPK. Cancer cells lose contact inhibition, continuing to divide and pile up beyond a confluent monolayer.

Contact Inhibition GO:0060242 DECREASED

Downstream

Unrestrained Proliferation

Unrestrained Proliferation

consequence

The combined loss of cell-cycle-checkpoint control and contact inhibition yields unrestrained proliferation: cells divide despite antigrowth signals, high density, and intracellular stress that would normally trigger arrest or death. This is the defining phenotype of the evading-growth-suppressors hallmark.

Cell Population Proliferation GO:0008283 INCREASED

Used by disorders

Retinoblastoma as Uncontrolled Retinal Cell Proliferation