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Define angiogenesis and explain the role of the VEGF pathway in tumor vascularization?

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NCI VEGF tumor angiogenesis pathway vascularization

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Angiogenesis is the formation of new blood vessels from pre-existing vessels. In cancer, it is usually a pathologic process in which capillaries sprout into and around a growing tumor.

Why tumors need angiogenesis

Before acquiring a blood supply, a tumor is limited by diffusion of oxygen and nutrients and commonly remains small or in situ. When it undergoes the angiogenic switch, new vessels supply oxygen and nutrients, remove wastes, and provide routes for tumor cells to enter the circulation and metastasize. Tumor vessels are typically abnormal: dilated, tortuous, unevenly connected, and highly permeable.
Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 735.

VEGF pathway in tumor vascularization

The central proangiogenic signal is usually VEGF-A.
  1. Hypoxia initiates VEGF production
    Rapid tumor growth outstrips its blood supply. Low oxygen stabilizes HIF-1alpha, a transcription factor that increases VEGF-A expression. Tumor-associated macrophages, stromal cells, and extracellular-matrix remodeling can also contribute proangiogenic signals.
  2. VEGF binds endothelial-cell receptors
    Secreted VEGF-A binds mainly VEGFR-2 on nearby endothelial cells. VEGFR-2 is a receptor tyrosine kinase and is the major mediator of VEGF-driven vascular growth. VEGF can also bind VEGFR-1, which modifies VEGF signaling and participates in recruitment of some myeloid cells.
  3. Endothelial activation and vessel sprouting
    VEGFR-2 signaling activates pathways including MAPK/ERK, PI3K-AKT, and nitric oxide signaling. These promote:
    • Endothelial-cell survival and proliferation
    • Migration toward the tumor's VEGF gradient
    • Matrix degradation and invasion by endothelial cells
    • Increased vascular permeability
    • Formation of new capillary sprouts and lumens
  4. Tumor vessel formation and progression
    The resulting vessels nourish the tumor but are poorly organized and leaky. This abnormal vasculature also facilitates tumor-cell intravasation and metastasis. Loss of p53 can favor angiogenesis because p53 normally suppresses VEGF and induces antiangiogenic factors such as thrombospondin-1; oncogenic RAS or MYC can increase VEGF expression.
    Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 735.
Clinical relevance: antiangiogenic cancer treatments may neutralize VEGF, block VEGF receptors, or inhibit their downstream signaling. Blocking VEGF can reduce tumor-vessel growth, though tumors may activate alternative proangiogenic pathways. The NCI angiogenesis overview describes how VEGF receptor activation promotes endothelial-cell growth and survival.
In one line: hypoxic tumor -> HIF-1alpha -> increased VEGF-A -> VEGFR-2 activation on endothelial cells -> new, abnormal tumor blood vessels -> tumor growth and metastatic access.
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