The process of blood vessel formation, or angiogenesis, is essential in many biological processes. In the development of an embryo, blood vessels form to nourish the growing organism. During the female reproductive cycle, the uterine lining is enriched with blood vessels in preparation for pregnancy. Angiogenesis is also required for wound healing. However, in contrast to participation in normal biological processes, angiogenesis plays an important role in tumor malignancy by creating a nutrient supply for the growing neoplasm and providing vessels through which the cancer may metastasize. In fact, angiogenesis is required for the maintenance of solid tumors and is regulated by the interplay of positive and negative growth signals. According to Folkman and Ingber, there are three potential strategies by which angiogenic therapy may be developed. The first strategy is to inhibit release of angiogenic molecules by tumor cells. The second strategy is the neutralization of angiogenic molecules that have been released by the tumor cells. The third strategy is to prevent the endothelial cells from responding to the angiogenic stimulus.
Much effort has been focused on the third strategy, that of finding angiogenesis inhibitors as potential treatments of cancer. Chen et al. found that angiogenesis inhibitors are produced by malignant tumors. The inhibitors produced by these tumors are actually protein fragments. O’Reilly et al. purified the peptide angiogenesis inhibitor angiostatin, a fragment of plasminogen, from a subclone of Lewis lung carcinoma. Angiostatin is known to specifically inhibit the growth of endothelial cells and murine tumors. Also in this class is endostatin, a fragment of collagen XVIII, which was purified from a murine hemangioendothelioma and found to potently inhibit angiogenesis and tumor growth in vivo. Another class of angiogenesis inhibitors has been isolated from natural products. Squalamine, a compound originally identified as a broadspectrum antibiotic, was isolated from dogfish shark cartilage and found to have dramatic anti-angiogenic effects both in vivo and in vitro. Fumagillin, a natural product isolated from a fungal contaminant of endothelial cell culture, has been shown to be a potent inhibitor of tumor angiogenesis in mice.
One of the most potent angiogenesis inhibitors is thrombospondin-1 (TSP1), an extracellular matrix glycoprotein that up-regulates endothelial cell-surface Fas ligand, which poises cells for apoptosis to protect against pathological angiogenesis. TSP1 is transcriptionally up-regulated by wildtype p53, and mutations in p53, a frequent target in cancer, result in low TSP1 ex