Prostate cancer (PCa) bone metastases are generally categorized as osteoblastic, based on radiographic imaging. However, on a cellular level, most patients have components of both bone resorption (osteoclastogenesis) and bone formation (osteoblastogenesis). Recently, we uncovered a PDGF D-initiated, novel protease/growth factor signaling network, critical for intraosseous PCa growth. Secreted as a latent homodimer, PDGF D contains a N-terminal CUB domain and a C-terminal growth factor domain (GFD). The proteolytic removal of the CUB domain is required for the growth factor domain dimer (PDGF D GFD-D) to activate its cognate receptor, ?-PDGFR. We demonstrated that the serine protease matriptase processes latent PDGF D into its active form in a 2-step manner. This involves the generation of a hemidimer (PDGF D HD), an intermediate form consisting of one full-length PDGF D chain and a single GFD subunit. Our preliminary studies have led us to hypothesize that PCa-derived PDGF D is capable of preparing a metastatic niche within the bone by inducing osteoclast activation via PDGF D HD-specific signaling (Aim 1), and by promoting human mesenchymal stem cell (hMSC) differentiation into osteoblasts through both PDGF D HD and GFD-D signaling (Aim 2). With regard to osteoblastogenesis, we further postulate that PDGF D HD activates the TGF?R/BMPR/SMAD signaling cascade, while PDGF D GFD-D preferentially activates the classic ?-PDGFR/Akt/p38 signaling in hMSCs. We further hypothesize that PDGF D-initiated bone remodeling is critical for intraosseous PCa growth, and thus PDGF D and its proteolytic activator matriptase are potential therapeutic targets (Aim 3). Completion of the proposed study will uncover novel functions of PDGF D in bone remodeling critical for PCa bone metastasis and provide valuable information for the development of PDGF inhibitors based on PDGF ligand-specific biology.
As there is wide consensus on the importance of PDGF receptor ? (?-PDGFR) signaling in PCa progression and bone metastasis, this receptor remains a target in PCa in new clinical trials. However, clinical trials with tyrosine kinase inhibitors suh as imatinib mesylate have been largely unsuccessful in PCa patients due to side effects such as irritation in gastrointestinal track and cardiotoxicity. Based on our novel finding that PDGF D (a ligand for ?-PDGFR) is a powerful regulator of metastatic niches in the bone microenvironment, we propose to investigate the molecular mechanisms by which PDGF D regulates bone remodeling for intraosseous PCa growth and to identify druggable targets based on PDGF ligand-specific biology.
