01Oxygen limits size
Oxygen diffuses only ~100–200 µm through tissue. A tumor can't grow beyond about 1–2 mm without new blood vessels. As the core becomes hypoxic, HIF-1α escapes degradation (normally VHL tags it in the presence of oxygen) and switches on VEGF.
VEGF binds receptors on endothelial cells, which sprout and form new capillaries — the angiogenic switch. In clear-cell kidney cancer, VHL loss keeps HIF permanently on, which is why these tumors are so vascular.
02Leaky, chaotic vessels
Tumor vessels are tortuous and leaky, so delivery of oxygen and drugs is uneven. Anti-VEGF drugs like bevacizumab and VEGFR kinase inhibitors like sunitinib can starve tumors and 'normalize' vessels, improving chemotherapy delivery for a time.