Metastasis represents the major cause of mortality in cancer patients. The unique ability to invade the basement membrane of epithelial barriers and migrate is believed to distinguish non-metastatic from metastatic tumor cells. According to the three step hypothesis of metastasis, adhesion, proteolysis, and motility are the key steps involved at the cellular level in the traversal of basement membrane barriers. Tumor and host cells contribute in a highly interactive process to the three steps necessary to breach epithelial barriers. Macrophages are believed necessary for enhancing the motility of tumor cells, proteolysis, and angiogenesis in the primary tumor. Significant preliminary data indicates that macrophages and carcinoma cells are locked in an obligatory dialog involving the relaying of chemotactic signals to enhance invasion and intravasation. This program builds on these results and is focused, in particular, on defining the signaling pathways from tyrosine-kinase receptors to the actin cytosketeton in carcinoma cells and macrophages and how these pathways regulate and distinguish motility in these cell types both in vitro and in vivo. This analysis will determine how the carcinoma and macrophage cell populations differ in their signaling and motility responses to growth factors found in the primary tumor and how these cell types interact to cause invasion within the primary tumor. A high level of scientific interaction and integration among the projects is a major strength of the proposed program project and this interactivity has resulted already in significant shared publications and grants. The projects cover invasion and metastasis from the basic science of signaling to the development of animal models of malignancy. The three cores support this effort by Intravital Imaging, Signaling and Motility Assays, and Animal Models development. The Intravital Imaging Core contains novel Imaging and cell collection technology that will be used to study invasion in vivo. The interdependent and multidisciplinary nature of these projects and cores makes this program project an integrated whole that is greater than the sum of its parts. This program represents a unique perspective on invasion and metastasis that has the potential for generating broad new insights into the microenvironments of the primary tumor.
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