Intratumor microvessel density as a prognostic factor in cancer.

In this issue, Hollingsworth et a1l present evidence that increasing intratumor microvessel density in the areas of most intense neovascularization is associated with decreasing overall and disease-free survival in patients with advanced stage ovarian cancer. Moreover, using a Cox proportional hazards model, they showed that intratumor microvessel density may be a better predictor of disease-free survival than stage, grade, and tumor type, whereas stage was the best predictor of overall survival. The authors conclude that analysis of tumor neovascularization in advanced stage ovarian cancer may be a useful prognostic marker. Clearly, for a tumor to grow, the tumor cells must not only proliferate, but benign host tissue, especially new blood vessels, must also form around the tumor cells. In 1971, Folkman proposed that tumor growth is dependent on angiogenesis.2 Furthermore, he suggested that tumor cells and blood vessels composed a highly integrated ecosystem, that endothelial cells could be switched from a resting state to one of rapid growth by a diffusible signal from tumor cells or associated inflammatory cells, and that antiangiogenesis could be an effective anticancer therapy. Indeed, now there is considerable indirect and direct evidence to show that tumor growth is angiogenesis dependent, that tumor cells can produce diffusible angiogenic regulatory molecules, and that angiogenesis antagonists can slow or prevent tumor growth. The indirect evidence is that tumors, both in vitro and in vivo, that lack access to blood vessels will grow only until passive diffusion can no longer provide adequate nutrients or allow waste products to exit into the adjacent medium.35 At equilibrium, these avascular spheroids reach sizes of only 4 mm in vitro6 and up to 2 mm in vivo.7 Additional growth and metastases do not occur unless the spheroids become vascularized.7 17 Other indirect evidence is that, in breast carcinoma, intratumor endothelial cells proliferate 45 times faster than endothelial cells in adjacent benign stroma,18 and the rate of tumor progression is associated with increased intratumor microvessel density, a morphological measure of tumor angiogenesis. 19,20 Direct evidence that tumor growth is angiogenesis dependent has been presented in several studies wherein different methods of specifically inhibiting angiogenesis (which are not cytostatic to tumor cells in vitro) clearly inhibited tumor growth in vivo.21-30 For example, a synthetic analogue of fumagillin, a naturally secreted antibiotic of Aspergillus fumigatus fresenius, inhibits endothelial proliferation in vitro and tumor-induced angiogenesis in vivo,24 and this angioinhibin (also known as AGM-1 470 or TNP-470) will suppress tumor growth with few side effects. Indeed, this drug, as well as other angiogenesis inhibitors (ie, bryostatin, thalidomide, platelet factor 4, interferon-a, carboxyaminotriazole, metalloproteinase inhibitor (BB94), and D-gluco-D-galactan sulfate (DS4152)), are now in various phases of clinical trials as chemotherapeutic agents for a variety of malignant solid tumors, leukemias, and infantile hemangiomas.2223 Also, Kim et a126 have shown that inhibition of vascular endothelial growth factor (VEGF)-induced angiogenesis suppresses tumor growth in vivo. These investigators injected human rhabdomyosarcoma, glioblastoma multiforme, or leiomyosarcoma cell lines into nude mice and found that treatment of these mice with a monoclonal antibody specific for VEGF inhibited the growth of the tumors and reduced tumor vessel density but had no effect on the growth rate of the