Role of Notch/VEGF-Receptor 3 in Breast Tumor Angiogenesis and Lymphangiogenesis

摘要

The overall objective is to define the interaction between Notch and VEGFR-3 signaling in breast cancer. We are examining a role for Notch in breast tumor vessels and attempting to block Notch and VEGFR-3 activity in breast tumors grown in mice. We proposed two aims: 1) studies of Notch/DII4 function in murine mammary tumorigenesis and 2) studies of the inhibitory effects of a Notch antagonist (Notch decoy) in a murine mammary tumor model. To study the role for notch in murine mammary tumorigenesis progress has been made in developing two new transgenic lines that will allow for conditional activation or inactivation of Notch specifically within the endothelium. In addition we have begun an assessment of mammary cancer cell growth in Notch4 mutant mice. We have also initiated experiments to test if circulating Notch antagonists can inhibit tumor growth and angiogenesis. To achieve this we have developed a system that uses injection of Notch antagonist expressing adenoviruses into immunocompromised mice. This leads to expression of the antagonist in the circulation and inhibition of tumor xenografts. We found that Notch decoy blocked tumor growth presumably by blocking tumor angiogenesis. If this approach inhibits mammary tumor growth, the ectodomains of Notch will be further pursued as candidates for breast cancer therapy.