Principal Investigator: ABDO JAMAL NAJY
Abstract: ABSTRACT Elucidating the function of Matriptase-activated PDGF D in bone metastatic prostate cancer Abdo Najy Background: Cancer cell metastasis is an intricate multistep process requiring interplay between the tumor and the surrounding stroma. The primary tumor cells must be able to proliferate, disengage from the inhibitory cell-cell junctional complex, migrate through the underlying basement membrane and matrix to gain access to nearby vasculature where these cells eventually home in and colonize secondary metastatic sites. Prostate cancer is the most diagnosed cancer in American men responsible for an estimated 192,000 cases in 2009 alone and it is the second leading cause of cancer-related death within the same group. This adenocarcinoma metastasizes to the bone in 90% of cases resulting in the disruption of the bone microenvironment and causing pathological bone fractures and spinal cord compressions drastically reducing the quality of life of patients. In order for metastatic prostate cancer to grow in the bone, it must secrete different factors creating a favorable environment for tumor cell growth. A family of mitogenic growth factors, platelet-derived growth factors (PDGF), have been shown to support osteoblast and osteoclast proliferation and activation. Interestingly, the platelet-derived growth factor receptor Beta (PDGFRBeta) has been demonstrated to be upregulated during the metastatic progression of prostate cancer. In fact the PDGFRBeta inhibitor, STI571, alone or in combination with paclitaxel significantly reduced osseous growth of prostate cancer cells in vivo. This receptor is bound and activated by its ligands, PDGF B and PDGF D. Our lab demonstrated that PDGF D, and not PDGF B, is overexpressed during prostate cancer progression suggesting that PDGF D may induce PDGFRBeta activation at the metastatic site. PDGF D is expressed in epithelial cells as an inactive dimer and is proteolytically activated by the epithelial specific serine protease, matriptase. The released active form of PDGF D binds to and activates its cognate receptor on surrounding stromal cells. Objective/Hypothesis: Both PDGF D and PDGFRBeta are upregulated within prostate cancer metastasis. Furthermore, the activator of PDGF D, matriptase, co-localizes with PDGF D during prostate cancer bone metastasis. Therefore, we hypothesize that matriptase mediated maturation of PDGF D may activate the tumor cell derived growth factor resulting in the activation of osteoclasts and osteoblasts leading to an aberrant osseous response. Specific Aims: (1) Elucidate the effects of PDGF D and matriptase on osteoclast signaling and differentiation. (2) Dissect the PDGF D mediated signaling cascade in osteoblastogenesis. (3) Assess the role of PDGF D in osteoblastogenesis and osteoclastogenesis in vivo. Study Design: We will utilize minimally aggressive and highly invasive prostate cancer cell lines differentially expressing PDGF D or matriptase to monitor their influence on osteoclast and osteoblast development. Furthermore, we will employ recombinant protein technology to dissect the structure-function of PDGF D in prostate cancer bone growth, specifically looking at osteoclast- and osteoblastogenesis. Finally, we will apply in vivo metastasis mouse models to examine the function of PDGF D and matriptase in metastatic prostate cancer. Relevance: Although early detection has improved prostate cancer survival rate, many patients still exhibit metastatic disease at diagnosis. We believe our findings will contribute greatly toward understanding the role of the PDGF-PDGFR axis in prostate cancer metastasis. Concomitantly, we envision our salient contributions leading to the development of novel and targeted therapeutics for prostate cancer in addition to improving the efficacy of existing treatment modalities.
Funding Period: 2010-06-01 - 2013-05-31
more information: NIH RePORT