PDGF D and Prostate Cancer Bone Metastasis

PDGF D 与前列腺癌骨转移

基本信息

批准号：
9259918
负责人：
Hyeong-Reh Choi Kim
金额：
$ 35.43万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-01 至 2020-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9259918
关键词：
Adverse effects Biology Bone Matrix Bone Resorption Bone remodeling C-terminal Cancer Patient Cardiotoxicity Cell Differentiation process Cell surface Clinical Research Clinical Trials Complex Consensus Development Diagnostic radiologic examination Dimerization Disease Excision Fibrin fragment D Generations Growth Growth Factor Human Image Imatinib mesylate In Vitro Length Ligands MAPK14 gene Malignant neoplasm of prostate Mediating Mesenchymal Stem Cells Metaphor Metastatic Neoplasm to the Bone Molecular Monoclonal Antibodies Mus N-terminal Osteoblasts Osteoclasts Osteogenesis PDGFRB gene Patients Peptide Hydrolases Platelet-Derived Growth Factor Platelet-Derived Growth Factor Receptor Platelet-Derived Growth Factor beta Receptor Play Preparation Process Reaction Regulation Role Seeds Serine Protease Signal Transduction Soil Testing Therapeutic Transducers Tyrosine Kinase Inhibitor androgen independent prostate cancer base bone castration resistant prostate cancer dimer gastrointestinal in vivo inhibitor/antagonist irritation matriptase mouse model novel osteoblast differentiation osteoclastogenesis programs public health relevance receptor therapeutic target tumor progression

项目摘要

DESCRIPTION (provided by applicant): 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, β-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 β-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.

描述（由申请人证明）：前列腺癌（PCA）骨转移是基于放射线的一般分类为成骨细胞的。最近，我们发现了一个PDGF D- D-odease/生长因子信号网络，对于骨内PCA生长至关重要。生长因子二聚体（PDGF D GFD-D）激活同源受体所需的去除OS，我们证明了丝氨酸Protete Matriptase过程，潜在潜在的PDGF D STS活性形式以两步的方式产生。 HD）。通过PDGF D HD和GFD-D信号传导（AIM 2）进一步假设PDGF D引起的骨头重塑对于骨内PCA生长IPTase是潜在的治疗靶标（AIM 3）。基于PDGF配体特异性生物学的PDGF吸引者的开发。