The Role of Capillary Morphogenesis Gene 2 in Breast Cancer Neovascularization

PUBLIC ABSTRACT

Breast cancer cannot grow easily beyond a diameter of a few millimeters since the diffusion of oxygen and nutrients into the tumor becomes increasingly difficult, thereby restricting further tumor growth. Tumors overcome this restriction by inducing angiogenesis, the sprouting of new blood vessels from existing vessels into the tumor. It is well known that angiogenesis plays an essential role in breast cancer progression by providing essential nutrients and growth factors for sustained tumor growth. Newly developed blood vessels within a tumor also provide a route for tumor cell dissemination to other parts of the body. Thus, studies into the processes that regulate blood vessel growth will further our understanding of breast cancer progression, the development of metastatic disease, and will define new targets for breast cancer therapeutics.

During my studies on breast cancer angiogenesis, I have generated preliminary data that provides the first demonstration of Capillary Morphogenesis Gene 2 (CMG2) expression on breast tumor blood vessels. I have also demonstrated that the pro-angiogenic factor VEGF induces CMG2 expression in cultured endothelial cells. These novel findings strongly implicate CMG2 as a contributing factor to human breast cancer angiogenesis. CMG2 encodes a cell surface receptor protein whose function has not yet been characterized; however, there are several lines of evidence supporting the idea that CMG2 may be a regulator of new blood vessel formation: (1) CMG2 is expressed in primary endothelial cells, (2) extracellular matrix proteins known to surround blood vessels may bind to CMG2, and (3) the CMG2 protein is closely related to Tumor Endothelial Marker 8, a protein that is specifically expressed in tumor blood vessels as compared to the blood vessels in normal tissue. Still, it remains unclear how CMG2 might function during angiogenesis. Consequently, the overall goal of the proposed research is to determine the role of CMG2 in the vasculature of breast cancer tissue.

I hypothesize that VEGF signaling in breast tumors may increase CMG2 expression in tumor-associated blood vessels. As a result, CMG2 is able to positively regulate various angiogenic responses in the blood vessels via interaction with extracellular matrix proteins. Thus, the mechanism of action of CMG2 may be essential to breast tumor vascularization, growth, and metastasis in vivo.

To test my hypothesis, I have proposed to perform a comprehensive evaluation of the expression pattern of CMG2 in various types of human breast tumors and normal mammary epithelium. It is thought that the underlying mechanisms of blood vessel formation during tumorigenesis is similar to those used during embryonic development, so I will also evaluate CMG2 function in primary human endothelial cell cultures. Proof of a role for CMG2 in tumor angiogenesis requires demonstration that inhibition of CMG2 action prevents tumor growth. Therefore, I will evaluate the ability of CMG2 antagonists to inhibit mammary tumor growth in the mouse.

This study will make contributions to the eventual effective treatment of breast cancer in three ways. First, the project will advance knowledge of the role that CMG2 plays in breast cancer vascularization and progression. Second, CMG2 may serve as a new endothelial marker for breast cancer, thereby enabling physicians to improve evaluation and classification of breast tumors. Third, CMG2 may contribute to the progression of malignant breast tumors because correlations have been found between increased tumor vascular density, tumor spread, and poor prognosis. Therefore, CMG2 may become an attractive target for the new class of therapeutics designed to inhibit angiogenesis during breast tumor formation.