CELLULAR EFFECTS OF ANGIOGENESIS INHIBITORS ON BLOOD VESSELS

Blood vessels in tumors have multiple molecular and cellular abnormalities that provide targets for diagnostics and therapeutics. These abnormalities involve all components of the vessel wall, including endothelial cells, pericytes (mural cells), and vascular basement membrane. Endothelial cells of tumor vessels express abnormal proteins, undergo sprouting and proliferation, and have a defective barrier function. Many tumor vessels depend on vascular endothelial growth factor (VEGF) for survival. In addition, pericytes have an abnormal association with endothelial cells and may express abnormal proteins. The vascular basement membrane of tumor vessels has redundant loose layers that reflect the dynamic nature of the vasculature. Leakiness of tumor blood vessels has important functional implications. Leakage of fibrin contributes to the provisional extracellular matrix that facilitates vessel growth. Leakiness also enables antibodies and other macromolecules to reach tumor tissue from the bloodstream. Yet, in tumors, vessel leakiness contributes to high interstitial pressure that restricts drug delivery to tumor cells. Also, because of heterogeneity of the leakiness, antibodies and other proteins extravasate in a patchy distribution and do not have uniform access to targets withi