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Tumor Angiogenesis Module

Module tumor_angiogenesis 3 disorders Pathograph 3
A conserved mechanism module for the fifth hallmark of cancer (Hanahan & Weinberg): the induction of angiogenesis. Tumors larger than ~1-2 mm outgrow the diffusion limit for oxygen and nutrients and must recruit new blood vessels to survive and grow. The conserved causal chain runs from intratumoral hypoxia and oncogenic signaling that stabilize hypoxia-inducible factor (HIF), through an "angiogenic switch" in which the balance of pro- and anti-angiogenic factors tips toward pro-angiogenic signals - chiefly VEGF-A acting on endothelial VEGFR2, with contributions from FGF, PDGF, and angiopoietins - to endothelial proliferation and sprouting that produce a structurally abnormal, leaky, tortuous tumor vasculature. This neovasculature sustains tumor growth and provides a route for metastatic dissemination, and is the target of anti-angiogenic therapy (anti-VEGF antibodies, VEGFR tyrosine kinase inhibitors). Individual disorder entries declare conformance via conforms_to, substituting tumor-type-specific drivers (e.g., VHL loss constitutively stabilizing HIF in clear cell renal cell carcinoma; VEGF-driven angiogenesis in glioblastoma). The anti-angiogenic drug-mechanism view can be captured with target_mechanisms on conforming treatments.
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Pathophysiology Nodes

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3 shared nodes are defined in this module.
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Cell Types

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Endothelial Cell CL:0000115
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Biological Processes

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Response to Hypoxia GO:0001666 INCREASED Positive Regulation of Angiogenesis GO:0045766 INCREASED VEGF Receptor Signaling Pathway GO:0048010 INCREASED Angiogenesis GO:0001525 INCREASED
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Notes

This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g., "tumor_angiogenesis#Angiogenic Switch and VEGF-Driven Neovascularization"). The module defines the expected pathophysiology structure; conforming nodes in disorder files should include the corresponding cell types, biological processes, and causal edges, specialized to their tumor context. Key tumor-specific substitutions: clear cell renal cell carcinoma uses VHL loss that constitutively stabilizes HIF-2alpha and drives VEGF independent of hypoxia; glioblastoma and colorectal cancer use VEGF-A-driven angiogenesis treated with bevacizumab/VEGFR TKIs. Key conformance / treatment target: "tumor_angiogenesis#Angiogenic Switch and VEGF-Driven Neovascularization".
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Used By Disorder Entries

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Clear Cell Renal Cell Carcinoma via HIF-2ฮฑ Stabilization โ†’ Intratumoral Hypoxia and HIF Stabilization , VEGF-Driven Angiogenesis โ†’ Angiogenic Switch and VEGF-Driven Neovascularization
Hepatocellular Carcinoma via Angiogenesis and VEGF Signaling โ†’ Angiogenic Switch and VEGF-Driven Neovascularization
Non-Small Cell Lung Cancer via Angiogenesis โ†’ Angiogenic Switch and VEGF-Driven Neovascularization
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Pathograph

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Pathograph: causal mechanism network for Tumor Angiogenesis Module Interactive directed graph showing how this shared module's pathophysiology nodes connect.
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Pathophysiology

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Intratumoral Hypoxia and HIF Stabilization
trigger
As a tumor expands beyond the oxygen diffusion limit, regions become hypoxic. Hypoxia (and, in some tumors, oncogenic signaling or loss of the VHL E3 ubiquitin ligase) stabilizes hypoxia-inducible factor (HIF-1 and HIF-2), a transcription factor that activates a pro-angiogenic gene program including VEGFA. This establishes the demand signal for new vasculature.
Response to Hypoxia GO:0001666 INCREASED
Used by disorders
Clear Cell Renal Cell Carcinoma as HIF-2ฮฑ Stabilization
Downstream
  • Angiogenic Switch and VEGF-Driven Neovascularization HIF-driven VEGF expression tips the angiogenic balance toward new vessel formation.
Angiogenic Switch and VEGF-Driven Neovascularization
central effector
The angiogenic switch is thrown when pro-angiogenic factors (VEGF-A, FGF2, PDGF, angiopoietin-2) outweigh endogenous inhibitors (thrombospondin-1, angiostatin). Secreted VEGF-A binds VEGFR2 on quiescent endothelial cells, triggering their proliferation, migration, and sprouting from existing vessels (and recruitment of endothelial progenitors). This is the conserved central node and the target of anti-angiogenic therapy.
Endothelial Cell CL:0000115
Positive Regulation of Angiogenesis GO:0045766 INCREASED VEGF Receptor Signaling Pathway GO:0048010 INCREASED
Used by disorders
Clear Cell Renal Cell Carcinoma as VEGF-Driven Angiogenesis
Hepatocellular Carcinoma as Angiogenesis and VEGF Signaling
Non-Small Cell Lung Cancer as Angiogenesis
Downstream
  • Abnormal Tumor Vasculature Sustaining Growth
Abnormal Tumor Vasculature Sustaining Growth
consequence
Sustained, unbalanced pro-angiogenic signaling produces a chaotic, structurally abnormal vasculature: vessels are tortuous, dilated, leaky, and irregularly perfused, with an incomplete pericyte coat and basement membrane. This neovasculature supplies oxygen and nutrients that sustain tumor growth, yet its abnormal architecture creates regions of persistent hypoxia and elevated interstitial pressure, and the leaky walls provide a portal for tumor-cell intravasation and metastatic spread.
Angiogenesis GO:0001525 INCREASED