109IN - Cancer: An Angiogenic Disease?

Abstract

ABSTRACT The angiogenic switch proposed by Folkman provided a compelling theory for the well recognized phenomenon of tumor dormancy, where tumors show prolonged growth arrest and remain as microscopic nodules, sometimes for decades before converting into rapidly progressing cancer. At the basis of this theory is the idea that diffusion of nutrients limits growth to a few cell layers, and perfusion, via sprouting of new blood vessels is required for sustained progression. Hypoxia was recognized as a potent microenvironmental stimulator of angiogenesis. Hypoxia stabilizes HIF1 alpha resulting in induced expression of VEGF, a potent vascular permeability factor and the central inducer of angiogenesis. Hypoxia, which affects genetic instability and selection for cells resistant to apoptosis, is thus also tightly linked with angiogenesis. Angiogenesis, induced by VEGF is accompanied by rapid elevation of vascular permeability. This acute effect of VEGF affects tumors in many ways. Extravasated plasma proteins result in extensive ECM remodeling to form a reactive stroma which supports Inflammation and tumor cell invasion. Elevated permeability enhances interstitial fluid pressure, limiting drug delivery. On the other hand, elevated vascular permeability provides thus far one of the most sensitive means for rapid detection and non invasive monitoring of cancer, as it results in accumulation and retention of contrast media and tumor enhancement on MRI and CT scans. Angiogenesis provides tumor cells with routes for metastatic spread to the blood circulation, and provide also the pressure gradient which drives interstitial fluid pressure and lymphatic drain and thereby facilitates colonization of sentinel lymph nodes. Despite the very strong support for the tight association of tumor progression with induction of angiogenesis, the experience with targeting angiogenesis in cancer therapy has been relatively disappointing, and antiangiogenic therapy is so far nor the magic bullet as hoped. Thus clearly it is important to study the mechanisms by which tumors escape from antiangiogenic therapy. Disclosure The author has declared no conflicts of interest.