PDGF D AND PROSTATE CANCER BONE METASTASIS

PDGF D 与前列腺癌骨转移

基本信息

批准号：
7792755
负责人：
Hyeong-Reh Choi Kim
金额：
$ 31.54万
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 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7792755
关键词：
Affect Animals Biological Biological Assay Bone Growth Bone Matrix Bone Resorption Bone remodeling C-terminal Cancer Patient Cell Communication Cell Line Cell Proliferation Cell Surface Receptors Cell surface Cleaved cell Clinical Clinical Trials Complement Factor D Data Deposition Diagnostic Neoplasm Staging Event Excision Fibrin fragment D Generations Gleason Grade for Prostate Cancer Goals Growth Growth Factor Homeodomain Proteins Human In Vitro Injection of therapeutic agent LNCaP Length Ligands Lytic Malignant Epithelial Cell Malignant neoplasm of prostate Mediating Mesenchymal Metastatic Neoplasm to the Bone Modeling Molecular N-terminal Neoplasm Metastasis Organ Culture Techniques Osteoblasts Osteoclasts Osteogenesis Osteolytic PDGFRB gene Phosphorylation Platelet-Derived Growth Factor Platelet-Derived Growth Factor Receptor Platelet-Derived Growth Factor beta Receptor Principal Investigator Process Prostate carcinoma Prostatic Neoplasms Proteolytic Processing Proto-Oncogene Proteins c-sis Reaction Reading Receptor Signaling Regulation Reporting Research Role Sampling Serine Protease Signal Transduction Signal Transduction Pathway Site Specimen Stromal Cells Stromal Neoplasm Structure Structure of base of prostate Subcutaneous Injections Tertiary Protein Structure Testing Therapeutic Tumor stage Tumor-Derived Vascular Endothelial Growth Factors bone cell growth cytokine dimer extracellular in vitro Model inhibitor/antagonist matriptase monomer mouse model neoplastic cell novel osteoblast differentiation osteoclastogenesis overexpression paracrine public health relevance receptor response skeletal tibia tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): The objective of this research application is to unveil the molecular and cellular mechanisms by which prostate carcinoma-produced platelet-derived growth factor (PDGF) regulates osteoclastic bone resorption and new bone growth, creating a favorable microenvironment for metastatic deposit. Increasing evidence indicate the significance of PDGF receptor signaling, especially 2-PDGFR, in prostate cancer progression and bone metastasis. PDGF B, however, originally thought to be the sole ligand for 2-PDGFR, has rarely been found in prostate cancer clinical samples. Importantly, our recent immunohistochemical analysis of human prostate carcinoma specimens showed that increased expression of PDGF D, a newly discovered ligand for PDGF receptor-beta (2-PDGFR), is associated with increased Gleason scores and tumor stages. Whereas the classic PDGF ligands A and B are secreted as active dimers, PDGF D contains an N-terminal CUB domain and a C terminal PDGF domain which is secreted as a latent dimer. Extracellular proteolytic cleavage of the CUB domain is required for the PDGF domain to stimulate 2-PDGFR. Recently, we made a novel finding that human prostate carcinoma cells auto-activate latent PDGF D into an active growth factor domain of PDGF D utilizing the serine proteases uPA and matriptase. Consistent with previous reports that matriptase is frequently overexpressed in prostate cancer, especially in metastatic samples, our preliminary data showed increased matriptase expression in human prostate cancer. In a tibiae-injection model, PDGF D significantly enhanced tumor take and growth rate of LNCaP tumors with increased osteolytic and osteoblastic responses. Additionally, our in vitro study unveiled exciting new roles of PDGF D in the regulation of osteoclast differentiation independent of the RANKL/RANK signaling axis as well as osteoblast differentiation involving modulation of homeoprotein expression. Taken together, we hypothesize that prostate carcinoma-produced PDGF D, activated by the transmembrane serine protease matriptase, induces paracrine cell signaling in bone stromal cells, mediating tumor-stromal interactions critical for prostate carcinoma growth in the bone microenvironment. To test this hypothesis, we propose (1) To investigate matriptase-mediated proteolytic processing of PDGF D; (2) To investigate the molecular mechanisms by which PDGF D induces osteoclast and osteoblast differentiation using in vitro models of RAW264.7 and MC3T3-E1 cell lines; and (3) To investigate the roles of PDGF D and its functional regulator matriptase in bone stromal responses and prostate tumor growth in animals. Considering that 2-PDGFR as well as matriptase is highly upregulated in both bone metastases and primary prostate cancer specimens, the completion of the proposed study of interplay between PDGF D, a specific activator of 2-PDGFR, and matriptase will help us in understanding the molecular basis for prostate cancer progression. In addition, the proposed study may provide important information with therapeutic value, especially given that VEGF/PDGF inhibitors are currently in clinical trials for cancer patients. PUBLIC HEALTH RELEVANCE: Mesenchymal growth factors, produced by tumor cells, activate their cognate receptors expressed in surrounding stromal cells, mediating tumor-stromal interactions. These interactions are thought to be critical for tumor progression at both the primary and the metastatic sites. A vast majority of prostate cancer (PC) metastases occur at skeletal sites. The mechanisms underlying the marked propensity of PC to metastasize to bone are beginning to be understood. Although still debatable, it is believed that cell surface and secreted factors produced by the tumor cells induce an osteoclastic response, a critical initial step for PC growth in bones. Bone resorption by osteoclasts results in the release of growth factors and cytokines from the bone matrix, providing a favorable microenvironment for tumor cell proliferation and invasion. Bone formation follows or accompanies bone destruction, and these bone reactions eventually become extensive enough to be visible on radiographs as both sclerotic and lytic reactions. Increasing evidence suggests that platelet-derived growth factor (PDGF) mediates tumor-stromal interactions during human prostate cancer bone metastasis. The goal of this project is to investigate the molecular mechanisms by which prostate carcinoma-produced PDGF initiates bone remodeling, a critical event for tumor cell colonization to the bone. In this application, we will test our hypothesis that the tumor-associated serine proteinase, matriptase, regulates the biological activity of the newly discovered PDGF ligand, PDGF D, and that tumor-derived PDGF D regulates osteoclast differentiation as well as osteoblast proliferation/differentiation critical for tumor cell growth.

描述（由申请人提供）：本研究应用的目的是揭示分子和细胞机制，通过这种机制，前列腺癌产生的血小板衍生的生长因子（PDGF）调节了整骨骨的骨吸收和新的骨骼生长，从而创造了一种有利的微环境，以使转移性沉积物的阳性。越来越多的证据表明PDGF受体信号传导，尤其是2-PDGFR在前列腺癌进展和骨转移中的重要性。然而，PDGF B最初被认为是2-PDGFR的唯一配体，在前列腺癌临床样本中很少发现。重要的是，我们最近对人前列腺癌标本的免疫组织化学分析表明，PDGF D的表达增加，PDGF D的表达是PDGF受体β（2-PDGFR）的新发现的配体，与GLEASON分数和肿瘤阶段的增加有关。经典的PDGF配体A和B被分泌为活性二聚体，而PDGF D包含一个N末端的CUB域和C端子PDGF域，该域被分泌为潜在二聚体。 PDGF结构域需要刺激2-PDGFR的细胞外蛋白水解裂解。最近，我们提出了一个新颖的发现，即人前列腺癌细胞自动激活潜在的PDGF D进入使用丝氨酸蛋白酶UPA和基质酶的PDGF D的活性生长因子结构域。与以前的报道一致，即在前列腺癌中经常过表达基质酶，尤其是在转移性样本中，我们的初步数据显示，人类前列腺癌中的曲霉酶表达增加。在胫骨注射模型中，PDGF D显着提高了LNCAP肿瘤的肿瘤服用和生长速率，其成骨和成骨细胞反应增加。此外，我们的体外研究揭示了PDGF D在调节破骨细胞分化中的令人兴奋的新作用，而与RANKL/RANK信号轴无关，以及涉及同音蛋白表达的调节的成骨细胞分化。综上所述，我们假设前列腺癌产生的PDGF D，被跨膜丝氨酸蛋白酶基质酶激活，诱导骨基质细胞中的旁分泌细胞信号传导，介导骨微微环境中前列腺瘤生长至关重要的肿瘤 - 层相互作用。为了检验该假设，我们建议（1）研究PDGF D的雌马蛋白介导的蛋白水解加工。（2）研究了PDGF D使用RAW264.7和MC3T3-E1细胞系的体外模型诱导pDGF D诱导破骨细胞和成骨细胞分化的分子机制；（3）研究PDGF D及其功能调节蛋白曲霉酶在动物中骨基质反应和前列腺肿瘤生长中的作用。考虑到2-PDGFR以及基质酶在骨转移和原发性前列腺癌标本中都高度上调，因此在PDGF D之间完成了拟议的相互作用研究，PDGF D（2-PDGFR的特定激活剂）和Matriptase的相互作用研究将帮助我们理解前列腺癌进展的分子基础。此外，拟议的研究可能会提供具有治疗价值的重要信息，特别是考虑到目前正在针对癌症患者进行临床试验VEGF/PDGF抑制剂。公共卫生相关性：由肿瘤细胞产生的间充质生长因子激活其在周围基质细胞中表达的同源受体，从而介导肿瘤 - 基质相互作用。这些相互作用被认为对于原发性和转移性部位的肿瘤进展至关重要。绝大多数前列腺癌（PC）转移发生在骨骼部位。开始理解PC转移到骨骼的明显倾向的基础机制。尽管仍然有争议，但据认为，肿瘤细胞产生的细胞表面和分泌因子会诱导骨质碎屑反应，这是骨骼PC生长的关键初步步骤。破骨细胞的骨吸收导致骨基质中生长因子和细胞因子的释放，为肿瘤细胞增殖和侵袭提供了有利的微环境。骨形成后发生或伴随着骨骼破坏，这些骨反应最终变得足够广泛，可以在X光片上可见，因为硬化反应和裂解反应。越来越多的证据表明，血小板衍生的生长因子（PDGF）介导人前列腺癌骨转移期间的肿瘤肿瘤相互作用。该项目的目的是研究前列腺癌产生的PDGF启动骨重塑的分子机制，这是肿瘤细胞重定位的关键事件。在此应用中，我们将检验我们的假设，即肿瘤相关的丝氨酸蛋白酶（Matriptase）调节了新发现的PDGF配体的生物学活性，PDGF D，PDGF D，以及肿瘤衍生的PDGF D调节骨质细胞分化，以及骨分化的骨化细胞的生长，以获取骨细胞的生长。