ELUCIDATING THE FUNCTION OF MATRIPTASE-ACTIVATED PDGF D IN BONE METASTATIC PROSTA

阐明基质酶激活的 PDGF D 在骨转移性前列腺中的功能

• 批准号: 8081817
• 负责人: Abdo Jamal Najy
• 金额: $ 5.3万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8081817
• 关键词: Adenocarcinoma; Agonist; American; Basement membrane; Binding; Biological Models; Bone Growth; Bone Pain; Cancer Etiology; Cause of Death; Cell Communication; Cells; Cessation of life; Clinical; Complement Factor D; Complex; Development; Diagnosis; Disease; Early Diagnosis; Environment; Epithelial; Epithelial Cells; Exhibits; Family; Fracture; Growth; Growth Factor; Home environment; Lead; Ligands; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metastatic Lesion; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Modality; Monitor; Neoplasm Metastasis; Osteoblasts; Osteoclasts; PC3 cell line; PDGFRB gene; Paclitaxel; Paracrine Communication; Pathway interactions; Patients; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor Receptor; Primary Neoplasm; Process; Proliferating; Proto-Oncogene Proteins c-sis; Quality of life; Recombinant Proteins; Research Design; Role; STI571; Serine Protease; Signal Transduction; Site; Stromal Cells; Structure; Survival Rate; Technology; Testing; Therapeutic; Tumor-Derived Activated Cell; bone; cancer cell; cancer diagnosis; cell growth; dimer; improved; in vivo; inhibitor/antagonist; matriptase; men; mouse model; neoplastic cell; new therapeutic target; novel; osteoclastogenesis; overexpression; receptor; response; spinal cord compression; therapeutic target; tumor; tumor progression

DESCRIPTION (provided by applicant): 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 2 (PDGFR2) has been demonstrated to be upregulated during the metastatic progression of prostate cancer. In fact the PDGFR2 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 PDGFR2 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 PDGFR2 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.

描述（申请人提供）：癌细胞转移是一个复杂的多步骤过程，需要肿瘤和周围基质之间的相互作用。原发肿瘤细胞必须能够增殖，脱离抑制性细胞-细胞连接复合物，通过底层基膜和基质迁移到附近的脉管系统，在那里这些细胞最终归巢并定植继发转移部位。前列腺癌是美国男性中诊断最多的癌症，仅2009年就估计有19.2万例，是同一群体中癌症相关死亡的第二大原因。这种腺癌在90%的病例中转移到骨，导致骨微环境破坏，引起病理性骨折和脊髓压迫，大大降低了患者的生活质量。为了使转移性前列腺癌在骨中生长，它必须分泌不同的因子，为肿瘤细胞的生长创造有利的环境。有丝分裂生长因子家族，血小板衍生生长因子（PDGF），已被证明支持成骨细胞和破骨细胞的增殖和活化。有趣的是，血小板衍生生长因子受体2 （PDGFR2）已被证明在前列腺癌转移过程中上调。事实上，PDGFR2抑制剂STI571单独使用或与紫杉醇联合使用可显著降低体内前列腺癌细胞的骨生长。该受体被其配体PDGF B和PDGF D结合并激活。我们的实验室证明，PDGF D而不是PDGF B在前列腺癌进展过程中过度表达，这表明PDGF D可能在转移部位诱导PDGFR2激活。PDGF D在上皮细胞中作为非活性二聚体表达，并被上皮特异性丝氨酸蛋白酶（基质酶）蛋白水解激活。释放的活性形式的PDGF D结合并激活其在周围基质细胞上的同源受体。目的/假设：PDGF D和PDGFR2在前列腺癌转移过程中均上调。此外，在前列腺癌骨转移过程中，PDGF - D的激活剂基质酶与PDGF - D共定位。因此，我们假设基质酶介导的PDGF成熟可能激活肿瘤细胞衍生的生长因子，导致破骨细胞和成骨细胞的激活，从而导致异常的骨反应。具体目的：(1)阐明PDGF - D和基质酶对破骨细胞信号传导和分化的影响。(2)解析PDGF - D介导的成骨细胞发生信号级联。(3)评估PDGF在体内成骨细胞和破骨细胞发生中的作用。研究设计：我们将利用不同表达PDGF - D或基质酶的低侵袭性和高侵袭性前列腺癌细胞系来监测它们对破骨细胞和成骨细胞发育的影响。此外，我们将采用重组蛋白技术来解剖PDGF - D在前列腺癌骨生长中的结构-功能，特别是观察破骨细胞和成骨细胞的发生。最后，我们将应用体内转移小鼠模型来检测PDGF - D和基质酶在转移性前列腺癌中的功能。相关性：尽管早期发现提高了前列腺癌的生存率，但许多患者在诊断时仍表现出转移性疾病。我们相信我们的发现将有助于理解PDGF-PDGFR轴在前列腺癌转移中的作用。同时，除了提高现有治疗方式的疗效外，我们还设想我们的突出贡献将导致前列腺癌的新型靶向治疗方法的发展。