The Biology of Prostate Cancer Skeletal Metastases

描述(申请人提供)：前列腺癌骨骼病变的常见发生和严重后果促使国家癌症研究所前列腺癌进展审查小组表示，有必要研究前列腺癌骨骼转移，并需要动物模型来解决这种疾病。不幸的是，这一领域的研究活动很少。在目前的提案中，我们通过将前列腺癌研究专家与骨代谢专家结合在四个由两个核心支持的相关项目中来解决这个问题。我们的最终目标是确定导致前列腺癌骨转移的细胞和分子机制。我们计划的中心主题是骨骼微环境具有促进前列腺癌转移发展的独特特性。这些特性包括一系列因素，导致前列腺癌细胞迁移并附着在骨骼上，并增强它们在骨骼微环境中茁壮成长的能力。为了发展这一主题，我们将执行以下互动项目：项目1将探索骨髓中基质衍生因子及其受体在前列腺癌细胞上的作用，有利于细胞向骨转移的能力。项目2将发展这一主题，即蛋白酶激活受体1是前列腺癌骨转移的重要介质。项目3将研究骨形态发生蛋白对成骨细胞损伤发展的作用机制。项目4将探索甲状旁腺激素相关蛋白在转移部位成骨细胞病变发展中的作用。这些项目将通过使用几个动物模型联系在一起，包括SCID-人类和体内听骨发育。动物模型和动物相关服务将由动物核心(核心A)以高效和具有成本效益的方式提供支助。骨评估，包括组织形态计量学、密度计量学和放射成像，将由骨核(核B)提供支持。

DESCRIPTION (provided by applicant): The common occurrence and serious outcome of prostate cancer skeletal lesions has prompted the National Cancer Institute Prostate Cancer Progress Review Group to state that there is a need to study prostate cancer skeletal metastasis and a need of animal models to address this disease. Unfortunately, there is a dearth of research activity in this field. In the current proposal, we attack this problem by combining experts in prostate cancer research with bone metabolism experts in four interrelated projects supported by two cores. Our ultimate goal is to define the cellular and molecular mechanisms that lead to prostate cancer skeletal metastases. The central theme of our Program is that the bone microenvironment has unique properties that foster the development of prostate cancer metastasis. These properties include a combination of factors that cause prostate cancer cells to migrate and attach to bone and enhance their ability to thrive in the bone microenvironment. To develop this theme, we will perform the following interactive projects: Project 1 will explore the role of stromal-derived factor in the bone marrow and its receptor on the prostate cancer cells that favor the cells' ability to metastasize to bone. Project 2 will develop the theme that protease-activated receptor 1 is an important mediator of prostate cancer skeletal metastasis. Project 3 will examine the mechanisms through which bone morphogenetic proteins contribute to development of osteoblastic lesions. Project 4 will explore the role of parathyroid hormone-related protein on the development of osteoblastic lesions at the metastatic site. These projects will be tied together through use of several animal models including SCID-human and ossicle development in vivo. The animal model and animal-related services will be supported by the Animal Core (Core A) in an efficient and cost-effective manner. Bone evaluation, including histomorphometry, densitometry and radiographic imaging will be supported by a Bone Core (Core B).