Differences in the Regulation

Induction of angiogenesis is a critical and rate-limiting step in the progression of cancer. It is widely acknowledged that this induction requires the concomitant stimulation of pro-angiogenic and repression of anti-angiogenic proteins. It has been demonstrated that in human epithelial cells repression of the angiogenesis inhibitor Thrombospondin-1 (Tsp-1) requires stimulation of Myc in combination with hyperphysiologic levels of oncogenic Ras. This work demonstrates that in human mammary epithelial cells, repression of Tsp-1 requires the activation of Myc by a Ras-induced pathway that activates the MAPK p38. This work also demonstrates that repression of Tsp-1 in human fibroblasts requires the combined inhibition of the tumor suppressors p53 and pRb. These results suggest that the molecular requirements for the induction of angiogenesis differ significantly between carcinomas and sarcomas. Thesis Supervisor: Randolph S. Watnick Title: Assistant Professor in the Vascular Biology Program at Children's Hospital, Boston