The Biology of Prostate Cancer Skeletal Metastases

描述（由申请人提供）：前列腺癌（PCa）骨转移的常见发生率和严重结局已成为公众关注的焦点，随后成为NCI关注的焦点。在这个计划奖的前三年，我们已经解决了这个重要的问题，导致超过50赠款相关的出版物。在目前的竞争性更新中，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个问题。最终目标是确定PCa骨转移的细胞和分子机制，从而为临床应用奠定基础。该计划的中心主题是PCa细胞与促进PCa转移发展和进展的骨微环境之间存在串扰。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，使其有利于肿瘤生长。为了扩展这一主题，该计划包括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，原发性PCa调节远端骨髓，部分通过产生CCLZ，使其有利于接受转移性PCa细胞;项目2研究了令人兴奋的想法，即PCa细胞在骨髓中占据造血干细胞（HSC）的小生境;项目3探索了Wnt抑制剂Dickopff作为促进PCa成骨表型的分子开关的意想不到的作用;项目4研究了新的假说，即前列腺癌通过PTHrP调节成骨细胞和HSC，导致骨微环境中的血管生成，从而促进前列腺癌的进展。这些项目将得到三个核心的支持：核心A（管理），将协调报告、评估和委员会活动，促进项目之间的互动，并提供生物统计支持;核心B（动物）提供小鼠模型和成像，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。这种研究者、项目和核心的结合导致了一个高度协同的项目，该项目将继续提供关于PCa骨转移的前沿研究。

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.