Regulation of angiogenesis and tumorigenesis by signal transduction cascades: lessons from benign and malignant endothelial tumors.

Abstract

Oncogenes and tumor suppressor genes are implicated in the regulation of the angiogenic switch. Much of the data accumulated to date uses NIH 3T3 cells, which are deficient in the tumor suppressor gene p16, as models for these studies. We have used a novel system, derived by sequential introduction of a temperature-sensitive SV40 large T antigen and oncogenic H-ras, to study the angiogenic switch. The results from our studies differ from those using NIH3T3 cells, but have been confirmed by multiple other groups. The data from all of these studies suggest that there is synergy between inactivation of the p53 tumor suppressor gene and activation of the phosphoinositol-3-kinase pathway (PI-3-K), as well as synergy between inactivation of the p16 tumor suppressor gene and activation of the MAP kinase pathway. These findings suggest that there are predictable behaviors of tumors that may be assessed by the status of p53 or p16 in a biopsy, and that these predictable changes in signal transduction may be useful both prognostically and in the design of rationally based drug therapy of benign and malignant tumors.