The Metastatic Cascade: Macrophages Lead the Way

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DESCRIPTION (provided by applicant): Breast Cancer is the most common malignancy in women, accounting for approximately 28% of all cancers affecting US women. Approximately 230,480 new cases of invasive breast cancer along with 54,010 new cases of non-invasive (in situ) breast cancer and 39,520 breast cancer deaths are expected to occur among US women in 2011. Recent clinical data indicated significant improvement in overall survival in women with local disease but no change in this parameter when women have metastatic disease. This depressing statistic shows that the current armamentarium of therapeutics is inadequate and indicates the metastatic tumor cells are resistant to cytotoxic drugs as well as targeted biologics This indicates the need for new approaches to the treatment of metastatic disease and it is this aspect of breast cancer biology that the current application is focused upon. The metastatic cascade has many steps. Firstly the tumor cells need to leave the primary site and travel through the lymph to the blood or to directly enter the blood. Data shows that there can be large numbers of circulating tumor cells in humans but despite this load only one or a few metastases occur. Thus the steps of extravasation, survival and establishment at distant sites are thought to be major barriers to the formation of metastases. Clearly the genetic/epigenetic changes in the tumor cells define their ability to be metastatic and their trophism to particular tissues. However, the microenvironment of the target site also plays a significant role in this process and determines the fate of the tumor cells. These data strongly suggest that targeting the microenvironment could be of significant value in therapy. Our preliminary studies have shown that macrophages promote tumor cell extravasation, survival and persistent growth in bone and lung, the primary sites of breast cancer metastasis. In addition the PI has recently defined several macrophage-tumor cell-signaling pathways that result in the enhancement of metastasis. These pathways involve the ligands, CCL2, vascular endothelial derived growth factor (VEGF) and colony stimulating factor-1 (CSF-1) and their respective receptors. It is the intent of this application to define the mechanisms behind these pro-metastatic functions of macrophages in the two metastatic sites bone and lung. To do this there are three specific aims: Aim 1: The mechanistic basis for macrophage enhancement of metastatic seeding in the lung. Aim 2: Mechanistic Basis of CSF-1R Promotion of Persistent Growth Aim 3: Define the role of mononuclear phagocytes in bone marrow metastasis. Our strategies are innovative and novel because we are defining important microenvironmental controls of metastatic seeding and subsequent growth. Our focus upon macrophages is because they have been shown to have important roles in this process. Definition of these mechanism behind these actions will potentially allow novel therapeutics to be devised that pull away the microenvironmental support for metastatic cells and which should enhance the chemotherapeutic and biological agents currently in use.