SN5 SHORT NOTE 5M ★ High-yield

Describe tumour angiogenesis with its regulation and clinical significance.

Pathology · 2nd Professional — Para-Clinical

Definition

Angiogenesis is the formation of new blood vessels from existing ones, and is essential for a tumour to grow beyond about 1 to 2 mm.

Below that size a tumour survives by diffusion alone; beyond it the centre becomes hypoxic and necrotic unless a blood supply is recruited
The "angiogenic switch" is the point at which the balance of promoters and inhibitors tips in favour of vessel growth — a discrete step in tumour progression

Regulation

Promoters	Inhibitors
VEGF — the most important; induced by hypoxia through hypoxia-inducible factor 1-alpha	Thrombospondin-1 (induced by p53)
Basic fibroblast growth factor (FGF-2)	Angiostatin, endostatin, tumstatin
Matrix metalloproteinases — release matrix-bound factors	Tissue inhibitors of metalloproteinases
Loss of p53 removes an inhibitor	Interferon-alpha

Tumour outgrows its diffusion limit → central hypoxia → HIF-1α is stabilised (it is degraded in normoxia, by the VHL protein) → Transcription of VEGF and other factors → Endothelial cells in nearby venules are activated → Basement membrane is degraded; endothelial cells migrate and proliferate → New capillaries form — leaky, tortuous and irregular → Tumour resumes growth, and the new vessels also provide a route for metastasis

CLINICAL PEARL

VHL disease is the clearest proof of this pathway. The VHL protein normally degrades HIF-1α in the presence of oxygen. When VHL is lost, HIF-1α persists as though the cell were permanently hypoxic, VEGF is produced continuously, and the resulting tumours — renal cell carcinoma and haemangioblastoma — are among the most vascular in the body.

Features of Tumour Vessels

Structurally abnormal — irregular calibre, tortuous, with blind ends and arteriovenous shunts
Leaky, because of gaps between endothelial cells and an incomplete basement membrane — which contributes to the raised interstitial pressure inside tumours
Lack pericyte support and smooth muscle, so they do not respond normally to vasoactive stimuli
The abnormality impairs drug delivery, and paradoxically "normalising" the vasculature with anti-angiogenic drugs can improve chemotherapy penetration

Applied Aspects

Bevacizumab, a monoclonal antibody against VEGF, is used in colorectal, lung, renal and ovarian cancer; its adverse effects — hypertension, bleeding, impaired wound healing, gastrointestinal perforation — all follow from blocking normal angiogenesis
Tyrosine kinase inhibitors of VEGF receptors (sunitinib, sorafenib, pazopanib) are the mainstay of treatment in metastatic renal cell carcinoma, which is exceptionally angiogenesis-dependent
Anti-VEGF therapy in the eye — ranibizumab and bevacizumab for wet age-related macular degeneration and diabetic retinopathy — the same biology applied outside oncology
Microvessel density in a tumour correlates with metastatic potential and with prognosis in several cancers
Anti-angiogenic therapy rarely cures; tumours adapt by using alternative pathways, so these drugs are generally combined with cytotoxic treatment
Thalidomide, notorious as a teratogen, is anti-angiogenic and is used in multiple myeloma — the same property that damaged fetal limb buds is exploited against tumour vessels
Necrosis at the centre of a tumour is direct evidence that angiogenesis has failed to keep pace with growth
Hypoxia also drives resistance — radiotherapy requires oxygen to generate the free radicals that damage DNA, so hypoxic tumour centres are relatively radioresistant

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