Kristina M. Dameron

As normal cells progress toward malignancy, they must switch to an angiogenic phenotype to attract the nourishing vasculature that they depend on for their growth. In cultured fibroblasts from Li-Fraumeni patients, this switch was found to coincide with loss of the wild-type allele of the p53 tumor suppressor gene and to be the result of reduced expression of thrombospondin-1 (TSP-1), a potent inhibitor of angiogenesis. Transfection assays revealed that p53 can stimulate the endogenous TSP-1 gene and positively regulate TSP-1 promoter sequences. These data indicate that, in fibroblasts, wild-type p53 inhibits angiogenesis through regulation of TSP-1 synthesis.

The proteins encoded by most human tumor suppressor genes are transcription factors or components of signal transduction pathways (Levine 1993). These tumor suppressors impose their antineoplastic phenotype on cells by modulating the expression of other genes. It is the proteins encoded by these suppressor-regulated genes, acting as effector molecules for the suppressor genes, that directly alter the cell or its environment in such a way as to make progression toward malignancy less likely. For example, it is the p53-regulated p21 protein that actually implements the p53-induced cell-cycle block by binding to and inhibiting cyclin/cdk complexes (El-Deiry et al. 1993). We have sought effector proteins that implement phenotypes induced by tumor suppressor genes by studying secreted molecules that regulate new blood vessel growth (neovascularization or angiogenesis), reasoning that they may provide insight into suppressor gene action and simultaneously serve as a starting point for the development of nongenotoxic anticancer therapies.