In addition to oncogenic mutations that act cell-autonomously, tumor cell growth depends on interactions with its microenvironment. Tumor microenvironment consists of cells of hematopoietic and mesenchymal origin, including inflammatory cells, stem and pro genitor cells, fibroblasts, endothelial cells and vascular mural cells. Tumor cell growth is known to depend on the interaction of tumor cells with such stromal cells. For example, growing tumor needs to recruit normal endothelial and vascular mural cells to form its blood vessels. In addition, tumor cells induce stromal cells to secrete factors that contribute to tumor cell growth and invasion. Stromal cell -dependent interactions represent an attractive target for cancer therapy, because normal cells are genetically stable, and would not be expected to develop resistance to therapeutic agents. The development of such therapies is hampered by the fact that the molecular mechanisms behind tumor-stroma interactions are often poorly understood. In summary, th e workplan entails development of novel advanced functional genomics instruments, technologies and methods for methods to study tumor-host interactions in cancer, and to apply these techniques to the identification of molecules and processes in normal cell s which could be targeted by novel anti-cancer therapeutic agents. In addition, we will develop targeted lentiviruses which would allow in vivo delivery of therapeutic agents into tumors. Functional validation of the discovered targets and developed delive ry systems will be performed in vivo models of murine tumor growth and dissemination. The work has significant exploitation potential, and applications for health in the understanding of the molecular mechanisms of tumor-host interactions, and in the treat ment of cancer.
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