Prostate carcinoma is the second leading cause of cancer death among men in the United States with a higher risk for African-Americans, a fact attributed to disease progression and dissemination to bone. Prostate cancer bone metastasis can lead to multiple morbidities and nearly two thirds of the total cancer treatment expenditure is spent to treat its consequences such as bone pain, spinal cord compression, fractures, paralysis, etc. Despite these alarming clinical pathologies, little is known regarding the mechanism of prostate cancer metastasis to bone and its subsequent growth in bone tissue. However, it is clear that the bone specific matrix proteins, which attract and then anchor tumor cells within the bone and their tumor receptors, integrins, which mediate the adaptation of tumor cells within their new bone microenvironment, are of key importance. The overall goal of this proposal is to develop a clear understanding of the molecular mechanisms that regulate prostate tumor growth within the bone and bone lesion development. We propose to test the hypothesis that the major tumor receptor for bone matrix, ?3 integrin and its activation promotes tumor-induced bone lesion development. We have developed unique reagents (e.g. human prostate cancer cells expressing ?3 integrin in various activation states as well as cell lines with knocked down expression of ?3), established advanced imaging techniques, including Magnetic Resonance and Microcomputed Tomography (micro-CT) imaging and generated preliminary data to support this hypothesis.
Our aims are: 1. To assess the role of tumor ?3 integrin and its activation in tumor-induced bone remodeling in vivo using microcomputed Tomography. 2. To understand the mechanisms and consequences of ?3 integrin ligation by bone-specific ligands on tumor growth and tumor-induced bone remodeling. We will: a) determine whether integrin ligation by specific bone matrix proteins, including osteonectin, results in upregulation of selected growth factors;b) assess the role of these growth factors in in vivo tumor growth using specific blocking antibodies and/or lentiviral siRNA approach;c) determine the structural requirements for osteonectin to mediate these responses using recombinant protein and its fragments. 3. To determine the role of circulating platelets and platelet-secreted matrix proteins in tumor growth. We will: a) assess the growth of our prostate cancer cell lines in platelet-depleted host;b) assess the effect of platelet depletion on tumor growth in the bone;c) determine the role of platelet released osteonectin in regulation of tumor growth using osteonectin deficient mice. Our studies will define new directions for the development of therapies that target tumor growth in bone.
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