Tumor development and response to therapeutic intervention.
(1) Small tumors proliferate without angiogenesis to the point where new vasculature is required. The “angiogenic switch” results in increased angiogenic factor expression and development of abnormal tumor vasculature with increased tortuosity, blind ends and poor vessel maturity (2). The tumor lacks lymphatic drainage and has high interstitial pressure limiting diffusion. Anti-vascular targeting agents such as combretastatin cause rapid tumor vascular endothelial cell death and tumor necrosis (3), but cells in the tumor periphery can survive using adjacent normal vascular supplies. Anti-angiogenic treatment causes a transient enhancement of tumor vasculature function and reduced hypoxia (4), but then lead to tumor vascular insufficiency and recurrence of hypoxia (5). Tumor cell oncogenic signaling inhibition (6) leads to sustained normalization of the tumor vasculature and reduced hypoxia. Combining tumor signaling inhibition or anti-angiogenic therapy with radiation or cytotoxic drug treatment during the period of enhanced oxygenation and vascular perfusion may promote tumor killing (7).