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".
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.
Downstream
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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.
Downstream
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Abnormal Tumor Vasculature Sustaining Growth
Show evidence (2 references)
"Inhibiting angiogenesis is a promising strategy for treatment of cancer and several other disorders, including age-related macular degeneration."
Establishes tumor angiogenesis as a validated therapeutic target, supporting the VEGF-driven angiogenic switch as the central effector of this module. Evidence source is OTHER because this is a review article.
"They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis."
Hanahan & Weinberg list inducing angiogenesis as a core hallmark capability modeled here. Evidence source is OTHER because this is a review article.
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.