The Role of Chemokines in Metastatic Prostate Cancer

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DESCRIPTION (provided by applicant): Prostate cancer (CaP) is a common neoplasm and the second leading cause of cancer deaths in American males. Despite numerous advances, once the tumors metastasize, prostate cancer is almost invariably fatal. The high mortality rate is principally due to the spread of malignant cells to many tissues including bone. Because of these facts, there is a growing interest in the early detection and screening of men for prostate cancer, and for a greater understanding of the mechanisms that lead to metastasis. Hematopoietic stem cells also 'home' to bone during fetal life and marrow transplantation. In this context, a CXC chemokine stromal-derived factor-1 (SDF-1 or CXCL12) and its receptor, CXCR4 appear to be critical molecular determinants for these events. This has been substantiated in several ways, but most convincingly with CXCL12 or CXCR4 gene knockouts, where marrow engraftment by hematopoietic cells is not observed. Moreover, osteoblasts and marrow endothelial cells express SDF-1 protein that function as a chemoattractant for human hematopoietic progenitor cells. Our overall hypothesis is that metastatic CaPs also use the CXCL12/CXCR4 as a pathway to localize to the bone marrow. Our investigations will test this hypothesis by determining the mechanisms whereby CXCL12 supports the adhesion and invasion of CaPs cells into the marrow (Aim 1), whether autocrine production of CXCL12 confers upon CaPs a selective advantage by either promoting proliferation or survival in the marrow microenvironment (Aim 2) and delineate whether CXCR4 and CXCL12 are responsible for homing of CaP carcinomas to bone using animal models. These investigations will provide important new information pertaining to the molecular basis of how tumors 'home' to bone which we believe will facilitate the development of new strategies for preventing or minimizing prostate metastasis.