Tumor Angiogenesis

In a seminal New England Journal of Medicine article, published 40 years ago, Folkman proposed the concept that angiogenesis could be a target for cancer therapy [1]. This proposal emerged from early observations that some tumors cells were capable of stimulating endothelial cells to form new capillary sprouts and that nonvascularized tumors were held in a dormant state, unable to grow beyond a size larger than 2-3 mm 3. These and related observations led Folkman to cautiously conclude that ". . .the mechanism by which tumor implants stimulate neovascularization must be well understood before therapy based upon interference with angiogenesis can be devised. " Since then, a wide variety of antiangiogenic therapies have been tested in clinical trails, with relatively modest improvements in patient outcomes and unforeseen therapeutic challenges. These initial setbacks call for a reinvigorated research effort to better understand the complex molecular and biological relations between tumor cells and endothelial cells within a neoplasm and the development of new, more effective, therapeutic tools targeting tumor angiogenesis. Encouraging this research is the theme of this special issue of the Journal of Oncology. Folkman's original proposal to target angiogenesis for cancer therapy relied on several assumptions. One key assumption was that solid tumors would only grow beyond a size of 2-3 mm 3 after vascularization was established, leading to more efficient diffusion of oxygen, nutrients, and wastes. A second assumption was that tumor cells produce angiogenesis in part by stimulating the growth of endothelial cells from surrounding vessels. A third assumption was that blocking angiogenesis would suppress tumor growth and result in resumption of tumor dormancy. The fourth assumption was that antiangiogenic cancer therapy could be delivered chronically because angiogenic activity is of minimal importance to healthy tissues. Since Folkman's landmark paper, several factors have been recognized as critical for the induction of tumor angiogenesis, with one of these being vascular endothelial growth factor (VEGF) and its interaction with VEGF receptors. Many therapeutic strategies were developed to either block VEGF, block VEGF binding to its receptor, or interfere with intracellular signaling in the VEGF receptor pathway. Early work in preclinical models led to clinical studies and the development of a multitude of antibodies and small molecules that target tumor angiogenesis. Several clinical trials provided encouraging evidence supporting the use of these agents in the treatment of breast cancer, lung cancer, kidney cancer, and colon cancer. However, resistance to antiangiogenic agents …