an osteoblast-derived proteinase controls tumor cell survival via tgf-beta activation in the bone microenvironment一个osteoblast-derived蛋白酶控制通过鉴定及激活肿瘤细胞生存的微环境.pdfVIP

An Osteoblast-Derived Proteinase Controls Tumor Cell Survival via TGF-beta Activation in the Bone Microenvironment 1 2 1 3 1 Sophie Thiolloy , James R. Edwards , Barbara Fingleton , Daniel B. Rifkin , Lynn M. Matrisian , Conor C. Lynch4* 1 Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, United States of America, 2 Nuffield Orthopaedic Centre, University of Oxford, Oxford, United Kingdom, 3 Department of Cell Biology, New York University School of Medicine, New York, New York, United States of America, 4 Tumor Biology Department, H. Lee Moffitt Cancer Center, Tampa, Florida, United States of America Abstract Background: Breast to bone metastases frequently induce a ‘‘vicious cycle’’ in which osteoclast mediated bone resorption and proteolysis results in the release of bone matrix sequestered factors that drive tumor growth. While osteoclasts express numerous proteinases, analysis of human breast to bone metastases unexpectedly revealed that bone forming osteoblasts were consistently positive for the proteinase, MMP-2. Given the role of MMP-2 in extracellular matrix degradation and growth factor/cytokine processing, we tested whether osteoblast derived MMP-2 contributed to the vicious cycle of tumor progression in the bone microenvironment. Methodology/Principal Findings: To test our hypothesis, we utilized murine models of the osteolytic tumor-bone microenvironment in immunocompetent wild type and MMP-2 null mice. In longitudinal studies, we found that host MMP-2 significantly contributed to tumor progression in bone by protecting against apoptosis and promoting cancer cell survival (caspase-3; immunohistochemistry). Our data also indicate that host MMP-2 contribu