The Biology of Prostate Cancer Skeletal Metastases

描述(申请人提供)：前列腺癌(PCa)骨转移的常见发生和严重后果已上升到公众关注的前沿，随后是NCI。在这个项目奖项的头三年里，我们已经解决了这个重要的问题，产生了50多种与赠款相关的出版物。在当前的竞争更新中，我们继续通过结合PCA研究和骨代谢方面的领先专业知识来解决这一问题。最终目标是明确围绕前列腺癌骨转移的细胞和分子机制，从而为转化为临床应用奠定基础。该计划的中心主题是，在前列腺癌细胞和骨微环境之间存在串扰，这促进了前列腺癌转移的发展和进展。这种串扰促进了PCA细胞迁移、附着和操纵骨中细胞的能力，从而增强了肿瘤改变骨微环境的能力，使其有利于肿瘤的生长。为了扩大这一主题，该方案包含了由三个核心支持的四个科学项目的密切相关的假设。项目1探索了新的概念，即与内分泌器官相似，初级PCA调节远处的骨髓，部分是通过产生CCLZ，使其有利于接收转移的PCA细胞；项目2研究了令人兴奋的想法，即PCA细胞共用骨髓中的造血干细胞(HSC)生态位；项目3探索了Wnt抑制剂Dickopff作为促进成骨细胞表型的分子开关出人意料的作用；项目4调查了新的假设，即PCA通过PTHrP调节成骨细胞和HSC，导致骨微环境中的血管生成，从而促进PCA的进展。这些项目将得到三个综合核心的支持：核心A(行政)将协调报告、评估和委员会活动，促进项目之间的互动，并提供生物统计学支持；核心B(动物)提供老鼠模型和成像并协助其使用；核心C(骨)提供骨组织学处理和解释方面的专业知识。研究人员、项目和核心的这种结合导致了一个高度协同的计划，该计划将继续提供关于前列腺癌骨转移的尖端研究。 相关性(见说明)：前列腺癌(PCa)是美国男性最常见的癌症，也是癌症相关死亡的第二大原因。当男性死于前列腺癌时，几乎总是伴随着癌症向骨骼扩散的痛苦和虚弱。我们的计划旨在了解癌症是如何扩散到骨骼并在骨骼中生长的，以便我们能够开发出预防或治疗前列腺癌扩散到骨骼的方法。

DESCRIPTION (provided by applicant): The common occurrence and serious outcome of prostate cancer (PCa) skeletal metastases has risen to the forefront of public concern and subsequently the NCI. In the first three years of this program award, we have addressed this important issue, resulting in over 50-grant-related publications. In the current competitive renewal, we continue to attack this problem by combining leading expertise in PCa research and bone metabolism. The ultimate goal is to define the cellular and molecular mechanisms that surround PCa skeletal metastases so as to set the groundwork for translation into clinical applications. The central theme of this Program is that there is crosstalk between PCa cells and the bone microenvironment that foster the development and progression of PCa metastasis. This crosstalk promotes the ability of PCa cells to migrate, attach, and manipulate the cells in bone thus enhancing the tumor's capacity to alter the bone microenvironment to render it conducive to tumor growth. To expand on this theme the Program encompasses closely interrelated hypotheses of four scientific projects supported by three cores. Project 1 explores the novel concept that the similar to an endocrine organ, the primary PCa modulates the distant bone marrow, in part through production of CCLZ, to make it conducive for receiving metastatic PCa cells; Project 2 examines the exciting idea that PCa cells co-opt the hematopoietic stem cell (HSC) niche in the bone marrow; Project 3 explores the unexpected role of the Wnt inhibitor Dickopff as a molecular switch that promotes the osteoblastic phenotype of PCa; and, Project 4 investigates the novel hypothesis that PCa, through PTHrP, modulates osteoblasts and HSCs leading to angiogenesis in the bone microenvironment that promotes PCa progression. These projects will be supported by three integral cores: Core A (Administration) that will coordinate reporting, evaluation, and committee activities, facilitate interactions among the projects and provide biostatistical support; Core B (Animal) provides mouse models and imaging and assistance with their use and Core C (Bone) provides expertise with bone histology processing and interpretation. This combination of investigators, projects and cores result in a highly synergistic Program that will continue to provide cutting-edge research on PCa bone metastases. RELEVANCE (See instructions): Prostate cancer (PCa) is the most common cancer of American men and the second leading cause of cancer-related death. When men die from PCa, it is almost always accompanied by the painful and debilitating spread of cancer to the skeleton. Our Program is directed to understand how the cancer spreads to and thrives in the skeleton so that we can develop method to prevent or treat the spread of PCa to the bone.