Pathophysiology of tumor angiogenesis and its relevance in renal cell cancer

In many cases, solid tumors exhibit numerous and highly permeable blood vessels. For a long time, this observation drew little attention. In the early 70's, however, Folkman proposed for the first time the potential relevance of tumor angiogenesis (formation of new vessels) for tumor growth and metastasis (6). He realized that tumors up to a diameter of 1-2 mm could be nurtured with oxygen and energy simply by diffusion (prevascular phase). Further growth, however, would require newly formed blood vessels. He hypothesized that (assuming the formation of new vessels was essential for tumor growth) pharmacological inhibition of angiogenesis could be developed as a new, more specific form of tumor treatment. In recent years, several groups have investigated the pathophysiology of tumor angiogenesis. Folkman's hypothesis that tumor growth is dependent on the formation of new vessels was supported by several experiments: Implants of different tumors into an avascular cornea initially have a slow growth rate that increases exponentially after infiltration of new vessels into the tumors (9). Inversely, the growth rate of solid tumors decreases with increasing distance to the supplying capillaries (27). The onset of neovascularization at the bases of human melanomas is directly associated with tumor growth and metastasis (25). Experiments with transgenic mice have demonstrated that the transition from hyperplastic to malignant cell growth occurs parallel to the onset of angiogenesis (7). Tumor vessel density has been shown to be associated with tumor progression and the clinical course in many human tumors (e.g. of the breast, lung, colon, cervix, prostate and bladder). Aside from the basic research on the formation of new (tumor) vessels, it is the therapeutic potential of various inhibitors of angiogenesis, some of which are currently tested in clinical (phase I/II) studies, that deserves special scientific attention. This review gives an overview of the relevance of angiogenesis for tumor growth, especially for renal cancers. It also discusses the potential advantages and disadvantages of different anti-angiogenic therapeutic approaches.