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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（由申请人提供）：根据放射学成像，前列腺癌（PCa）骨转移通常归类为成骨细胞。然而，在细胞水平上，大多数患者具有骨吸收（破骨细胞生成）和骨形成（成骨细胞生成）的成分。最近，我们发现了PDGF D启动的新的蛋白酶/生长因子信号网络，对骨内PCa生长至关重要。作为潜在的同二聚体分泌，PDGF D含有N-末端CUB结构域和C-末端生长因子结构域（GFD）。CUB结构域的蛋白水解去除是生长因子结构域二聚体（PDGF D GFD-D）激活其同源受体β-PDGFR所必需的。我们证明丝氨酸蛋白酶间质蛋白酶以2步方式将潜在的PDGF D加工成其活性形式。这涉及半二聚体（PDGF D HD）的产生，半二聚体是由一个全长PDGF D链和单个GFD亚基组成的中间形式。我们的初步研究使我们假设，PCA衍生的PDGF D能够通过PDGF D HD特异性信号传导诱导破骨细胞活化（Aim 1），并通过PDGF D HD和GFD-D信号传导促进人间充质干细胞（hMSC）分化成成骨细胞（Aim 2），在骨内制备转移性小生境。关于成骨细胞生成，我们进一步假设PDGF D HD激活TGF β R/BMPR/SMAD信号级联，而PDGF D GFD-D优先激活hMSC中经典的β-PDGFR/Akt/p38信号。我们进一步假设PDGF D启动的骨重塑对于骨内PCa生长至关重要，因此PDGF D及其蛋白水解激活剂间质蛋白酶是潜在的治疗靶点（目的3）。该研究的完成将揭示PDGF D在骨重建中的新功能，这对PCa骨转移至关重要，并为基于PDGF配体特异性生物学的PDGF抑制剂的开发提供有价值的信息。