Molecular Mechanisms of Prostate Cancer Induced Bone Remodeling

前列腺癌诱导骨重塑的分子机制

• 批准号: 8201091
• 负责人: Bethany Amber Kerr
• 金额: $ 5.39万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8201091
• 关键词: American Association of Cancer Research; Androgens; Architecture; Blood Platelets; Bone Resorption; Bone neoplasms; Bone remodeling; Cancer Patient; Cell Differentiation process; Cell Proliferation; Cell physiology; Cessation of life; Communication; Conditioned Culture Media; Data; Development; Diagnosis; Distant Metastasis; Early Diagnosis; Elements; Environment; Extracellular Matrix Proteins; Goals; Histology; Immunocompetent; In Vitro; Incidence; Investigation; Knockout Mice; Lead; Lesion; Link; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Modeling; Molecular; Mus; Neoplasm Metastasis; Oncogenic; Osteoblasts; Osteoclasts; Osteogenesis; Pain; Patient Care; Patients; Preparation; Prevalence; Prevention; Primary Neoplasm; Proteins; Quality of life; Research; Research Priority; Role; Screening for Prostate Cancer; Signal Transduction; Source; Structure; Survival Rate; Thrombospondin 1; Transforming Growth Factors; United States; Work; bone; bone cell; bone turnover; improved; in vivo; insight; male; mouse model; neoplastic cell; public health relevance; response; skeletal; therapy development; tomography; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): The metastasis of prostate cancer to bone is responsible for decreased patient survival, increased pain and mobility difficulties, and decreased quality of life for patients. Despite the serious consequences of bone metastasis, the mechanisms of bone lesion development remain poorly understood. In patients, primary tumors stimulate abnormal bone formation and turnover without visible metastases. In concert, our preliminary data demonstrates that primary prostate cancer tumor growth stimulates bone formation. Thus, there is evidence that prostate cancer can induce changes in bone remodeling prior to the development of metastases. We hypothesize that proteins involved in tumor growth may also stimulate bone turnover and that these proteins may be delivered to the bone environment by circulating platelets. Therefore, we plan to undertake a careful and systematic investigation into the mechanisms of communication between primary tumor growth and bone remodeling. To accomplish this goal we will complete the following specific aims: 1) Investigate the role of platelets in tumor signaling to bone. 2) Elucidate the role of TSP-1 regulating tumor growth on bone turnover. 3) Study the role of TGF-21 activation in TSP-1 controlled bone turnover. In aim 1, we will use an oncogenic, immunocompetent mouse model to study the initiation of bone metastasis in androgen-independent, aggressive, metastatic prostate cancer. We will deplete or infuse mice with platelets in the presence of tumors and assess the consequences on bone structure by microcomputed tomography and histology. In addition, we will use platelet releasates from mice with and without tumors in vitro to study changes in osteoblast and osteoclast proliferation and differentiation. In aim 2, to determine the mechanism of platelet effects on bone, we will focus on TSP-1, a protein known to control tumor growth that is highly expressed in platelets. We will modulate the levels of TSP-1 in the presence and absence of tumor conditioned media or platelet releasate from tumor-bearing mice and determine the effects on bone cell proliferation and differentiation. The role of TSP-1 in vivo will be determined using TSP-1 null mice by injecting tumors and assessing the effects on bone structure. In the final aim 3, we will use our established models to study the role of TSP-1 activation of TGF-21 in tumor growth and bone remodeling in preparation for metastases. These data will provide insights to cross-talk between tumors and bone prior to metastasis. Further, our proposed research will produce pathophysiologically relevant data on the molecular mechanisms of prostate cancer induced bone remodeling. PUBLIC HEALTH RELEVANCE: Our study will investigate the mechanism of pre-metastatic communication between primary tumors and bone. The results of this investigation will identify new targets for the prevention and treatment of prostate cancer bone metastasis. In addition, these targets could be used for the screening of prostate cancer metastasis. These improvements in patient care will result in improved diagnosis, treatment, and quality of life for prostate cancer patients with bone metastases.

描述（由申请方提供）：前列腺癌骨转移导致患者生存率降低、疼痛和移动困难增加以及患者生活质量下降。尽管骨转移的严重后果，骨病变发展的机制仍然知之甚少。在患者中，原发性肿瘤刺激异常的骨形成和转换，而没有可见的转移。同时，我们的初步数据表明，原发性前列腺癌肿瘤生长刺激骨形成。因此，有证据表明前列腺癌可以在转移发生之前诱导骨重建的变化。我们假设参与肿瘤生长的蛋白质也可能刺激骨转换，这些蛋白质可能通过循环血小板传递到骨环境。因此，我们计划对原发性肿瘤生长和骨重建之间的通讯机制进行仔细和系统的研究。为了实现这一目标，我们将完成以下具体目标：1）研究血小板在肿瘤骨信号传导中的作用。2)阐明TSP-1调节肿瘤生长对骨转换的作用。3)研究TGF-21活化在TSP-1控制的骨转换中的作用。在目标1中，我们将使用一种致癌的、免疫活性的小鼠模型来研究雄激素非依赖性、侵袭性、转移性前列腺癌骨转移的起始。我们将在肿瘤存在的情况下耗尽或注入血小板，并通过微计算机断层扫描和组织学评估对骨结构的影响。此外，我们将在体外使用有和无肿瘤小鼠的血小板释放物来研究成骨细胞和破骨细胞增殖和分化的变化。在目标2中，为了确定血小板对骨的作用机制，我们将关注TSP-1，一种已知在血小板中高度表达的控制肿瘤生长的蛋白质。我们将在存在和不存在肿瘤条件培养基或来自荷瘤小鼠的血小板释放物的情况下调节TSP-1的水平，并确定对骨细胞增殖和分化的影响。TSP-1在体内的作用将使用TSP-1缺失小鼠通过注射肿瘤和评估对骨结构的影响来确定。在最终的目标3中，我们将使用我们建立的模型来研究TSP-1激活TGF-21在肿瘤生长和骨重建中的作用，为转移做准备。这些数据将为转移前肿瘤和骨之间的串扰提供见解。此外，我们提出的研究将产生前列腺癌诱导骨重建的分子机制的病理生理学相关数据。 公共卫生相关性：我们的研究将探讨原发性肿瘤和骨之间转移前通讯的机制。本研究的结果将为前列腺癌骨转移的预防和治疗确定新的靶点。此外，这些靶点可用于前列腺癌转移的筛查。患者护理的这些改善将改善前列腺癌骨转移患者的诊断、治疗和生活质量。