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    Research Grants Awarded

    VEGF as a Survival and Invasive Factor in Metastatic Breast Cancer

    Study Section:
    Postdoctoral Fellowship

    Scientific Abstract:
    Breast cancer is the most common form of cancer that affects women in the United States . Metastasis is the major cause of death in breast cancer patients. The metastatic cascade in breast cancer is dependent upon sustained angiogenesis, of which vascular endothelial growth factor (VEGF) is a primary stimulant. Expression of VEGF has been shown to be required for breast carcinoma progression and levels of VEGF correlate with severity of the disease. In addition to its role in angiogenesis, VEGF can impact tumorigenesis by other mechanisms. VEGF expressed by breast cancer cells appears to positively impact the survival of cancer cells in an autocrine fashion. Additionally, in endothelial cells, VEGF regulates expression of a number of proteolytic enzymes involved in degrading the ECM, such as matrix metalloproteinases (MMP) and urokinase plasminogen activator (uPA). VEGF also functions to recruit macrophages into the primary tumor. Tumor-associated macrophages secrete various growth factors that are essential for establishment of metastatic tumors. These data support VEGF as a target for anti-cancer therapy and also suggest that anti-VEGF strategies will reduce breast cancer metastasis by reducing tumor angiogenesis and by reducing the metastatic potential of breast cancer cells. Specific aims: 1) To evaluate the contribution of VEGF in promoting breast cancer metastasis. 2) To determine if VEGF promotes metastasis by modulating macrophage activity. Study design: Human breast carcinoma cell lines and tissues from breast cancer patients will be analyzed for the expression of members of the VEGF family of proteins and their receptors, MMPs, uPA, and monocytes/macrophage chemotactic proteins (e.g., CSF-1 and MCP-1). The expression data will be evaluated for correlation and predictive value to patient outcome. The function of VEGF as a survival factor will be determined in vitro and the effect of VEGF on the invasiveness of cancer cells will be tested in vitro and in vivo. VEGF-mediated effects on macrophages will be determined through expression studies and invasion assays in vitro. The effect of anti-VEGF therapy combined with anti-CSF-1 or MCP-1 treatment will also be determined using an orthotopic mouse model of breast cancer. The proposed study will advance our understanding of the function of VEGF in the establishment of metastatic breast cancer and could evolve to produce novel therapeutic targets for breast cancer intervention.

    Lay Abstract:
    Breast cancer is the most common form of cancer that affects women in the United States and other western societies. It is the second leading cause of cancer death for all women (after lung cancer), and the leading cause of cancer death in women between the ages of 20 and 59. At present, 63% of breast cancers are discovered at an early “localized” stage and the rate of five-year survival after treatment for early-stage breast cancer is 97%. In contrast the prognosis is poor for the 37% of breast cancer cases that are not diagnosed early. About 10% of breast cancer patients have metastatic disease at the time of diagnosis. Metastasis is the spread of cancer cells from the primary tumor to other organs and is the principle reason for breast cancer related death. Furthermore, metastasis is associated with recurrence after surgical removal of the primary tumor. Therefore therapy designed to prevent or treat metastasis will significantly improve patient survival. To develop novel therapeutic approaches, a more complete understanding of the biology of metastasis in breast cancer is required. The development, progression and spread of breast cancer are dependent upon the process of angiogenesis, which is the development of new blood vessels. Vascular endothelial growth factor (VEGF) is a protein that breast tumors and other tumors use to stimulate angiogenesis and as such VEGF is an important target for anti-cancer therapy. We and other researchers believe that VEGF does more than just promote blood vessel growth. In fact, we think VEGF promotes breast cancer metastasis by 1) keeping breast cancer cells alive, 2) increasing the migration/ movement of breast cancer cells, and 3) stimulating the recruitment of macrophages (immune cells) into the tumor. By understanding how VEGF promotes metastasis outside of it’s function as an angiogenic factor, we hope to 1) increase the effectiveness of current anti-VEGF treatments that are being used and 2) develop novel therapies to combat metastatic breast cancer.