Metastasis represents the major cause of mortality in, cancer patients. According to most current models of metastasis, interactions between tumor cells and the stromal microenvironment involving adhesion, proteolysis, growth factor and cytokine secretion and chemotaxis are key events at the cellular level driving the traversal of basement membrane barriers, migration and intravasation. Until recently, however, the technology has not existed to observe and manipulate these events at the cellular and molecular levels in vivo. The interdisciplinary projects and specialized cores of this program project, some with unique technologies, have provided the opportunity to investigate these events at the molecular and cellular levels in vivo. During the previous funding period the members of this program have demonstrated that macrophages are necessary for enhancing the motility and invasion of tumor cells in primary mammary tumors of rats and mice. We have shown how tumor cells and host macrophages both contribute, in a highly interactive process, to the intercellular signaling necessary for tumor cell motility, invasion, intravasation and metastasis. We have discovered the signaling pathways in macrophages and tumor cells that contribute to the signaling, motility and chemotaxis behaviors that generate the invasive phenotype and identified an invasion signature that uniquely defines invasive tumor cells in rat and mouse mammary tumors. In this competing continuation application we propose to extend and broaden the new insights derived during the previous funding period: 1) to identify the various subpopulations of macrophages present in primary tumors and metastatic tumors, and how they differentially affect angiogenesis, intravasation and extravasation;2) to define, at the molecular level, the specific colony stimulating factor (CSF1) and erbB family phosphotyrosine-associated pathways that regulate growth factor production, chemotaxis, intravasation and metastasis;3) to identify additional cytokines, growth factors, and stromal cells involved in initiating the paracrine loop between macrophages and tumor cells and the cellular sources of these cytokines and growth factors;4) investigate chemotaxis and motility pathways in tumor cells and macrophages that determine cell polarity and migration efficiency at the molecular level;5) extend the invasion signature discovered in rats and mice to human breast tumors by adapting the technology developed during the previous funding period to human cell line-derived tumors and human tumors from patients transplanted into mouse hosts;and 6) evaluate biomarkers derived from the human and mouse invasion signatures for their ability to define landmarks involved in invasion and intravasation in human breast tumors and predict the outcome of the disease.
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