Tumors have been recently recognized as aberrant organs composed of a
complex mixture of highly interactive cells that in addition to the
cancer cell include stroma (fibroblasts, adipocytes, and myofibroblasts), inflammatory (innate and adaptive immune cells), and vascular cells (endothelial and mural cells). While initially
cancer cells co-opt tissue-resident vessels, the
tumor eventually recruits its own vascular supply. The process of
tumor neovascularization proceeds through the combined output of inductive signals from the entire cellular constituency of the
tumor. During the last two decades, the identification and mechanistic outcome of signaling pathways that mediate
tumor angiogenesis have been elucidated. Interestingly, many of the genes and signaling pathways activated in
tumor angiogenesis are identical to those operational during developmental vascular growth, but they lack feedback regulatory control and are highly affected by inflammatory cells and
hypoxia. Consequently,
tumor vessels are abnormal, fragile, and hyperpermeable. The lack of hierarchy and inconsistent investment of mural cells dampen the ability of the vessels to effectively perfuse the
tumor, and the resulting
hypoxia installs a vicious cycle that continuously perpetuates a state of vascular inefficiency. Pharmacological targeting of blood vessels, mainly through the
VEGF signaling pathway, has proven effective in normalizing
tumor vessels. This normalization improves perfusion and distribution of chemotherapeutic drugs with resulting
tumor suppression and moderate increase in overall survival. However, resistance to antiangiogenic
therapy occurs frequently and constitutes a critical barrier in the inhibition of
tumor growth. A concrete understanding of the chief signaling pathways that stimulate vascular growth in
tumors and their cross-talk will continue to be essential to further refine and effectively abort the angiogenic response in
cancer.