Mechanistic insights on the inhibition of tumor angiogenesis.

Angiogenesis, the growth of new vasculature, is an absolute requirement for the maintenance and progression of the overwhelming majority of the solid tumors. Unraveling the mechanisms that govern this complex biological process has become a central issue not only for understanding of the molecular basis of cancer but also for developing new therapeutic approaches that interfere with neovascularization of the tumor mass. Here we discuss the survival and apoptosis of endothelial cells in the context of vessel formation and regression in response to mediators of angiogenesis produced by tumors. It is the balance between proangiogenic and antiangiogenic molecules in the microenvironment of a vessel in vivo that determines whether the existing vasculature will expand, remain the same, or regress. Here we propose that the vascular endothelial cells themselves interpret and respond to these environmental cues by integrating the activities of the survival and apoptotic pathways within the cell. Thus it is the survival or death of the vulnerable cells that venture out to form new vessels that is the ultimate arbiter of whether neovascularization, as well as the growth of a malignancy that depends on it, succeeds or fails.