THE MODULATION OF THROMBOSPONDIN AND OTHER NATURALLY-OCCURRING INHIBITORS OF ANGIOGENESIS DURING TUMOR PROGRESSION

Fifteen different natural inhibitors of angiogenesis have now been ide ntified that are produced by mammalian cells and are able to block in vivo neovascularization. The majority of these are able to inhibit end othelial cell activities in vitro and all those tested have demonstrat ed significant antitumor activity. Most normal cells produce inhibitor s of neovascularization that must be downregulated before the cells ca n develop into angiogenic, malignant tumors. In several cases the prod uction of inhibitors ceases when tumor suppressor genes are inactivate d. In the BT549 human breast carcinoma cell line, the reintroduction o f a wild type p53 tumor suppressor gene resulted in the stimulation of the secretion of an inhibitor of angiogenesis, thrombospondin-1, and as a result the cells lost their angiogenic phenotype and became able to suppress angiogenesis induced by the parental tumor line. These res ults provide a new example of tumor suppressor gene control of a natur al inhibitor of angiogenesis and add support to the concept that throm bospondin loss may play an important role in the development of some h uman breast cancers.