The Biology of Prostate Cancer Skeletal Metastases

总体摘要 前列腺癌（PCa）的常见发生、显著衰弱和随后的致死性 骨转移使其成为主要的健康问题。在这14年中， 计划，我们已经解决了这一重要问题，在该领域产生了重大影响， 骨转移研究，包括促进概念，如肿瘤之间的串扰 以及治疗靶向微环境的重要性， 肿瘤该计划已导致超过220个赠款相关的出版物，并奠定了基础， 几个临床试验。在目前的竞争性更新中，我们进一步解决这个问题， 结合前列腺癌研究和骨生物学的领先专业知识。这本书的中心主题是 在PCa细胞和骨微环境之间存在串扰， 促进PCa转移的发生和进展。这段串话提升了 PCa细胞改变骨微环境，使其易于肿瘤生长， 化疗耐药性为了扩大这一主题，该方案密切关注 三个核心支持的四个科学项目的相互关联的假设。项目1探索 化疗诱导前列腺癌细胞融合形成多核多倍体新发现 在骨微环境中赋予化学抗性的巨癌细胞（PGCC）;项目 2检验了令人兴奋的想法，脱落酸（阿坝）诱导PCa细胞采用表型 能够以休眠和化学抗性状态存在，具有长期存活的能力， 生存和发展为明显骨转移的潜力;项目3探索了令人惊讶的 骨细胞（OCys）通过激活一种 新的生长分化因子15（GDF 15）受体，GDFN家族受体α样 前体（GFRAL），其随后促进PCa转移性侵袭和生长;项目4 研究了凋亡PCa的巨噬细胞吞噬（吞噬） 细胞在骨微环境中诱导免疫抑制信号， 促进转移性生长。这些项目将得到三个核心的支持： （行政），将协调报告，评估进展，咨询委员会的活动， 促进项目之间的互动，并提供生物统计支持;核心B（动物）将 提供小鼠模型和成像，并协助其使用，核心C（骨）将 提供骨组织学处理，解释和人类采购的专业知识 血液和骨髓样本这种调查人员、项目和核心的结合 提供了一个高度协同的计划，大于其各部分的总和，并将继续 提供前列腺癌骨转移领域的前沿研究和领导。

OVERALL ABSTRACT The common occurrence, marked debilitation and subsequent lethality of prostate cancer (PCa) skeletal metastases has made it a major health concern. In the first fourteen years of this program, we have addressed this important issue, resulting in a major impact on the field of skeletal metastasis research, including promoting concepts such as crosstalk between tumor and bone and the importance of therapeutically targeting the microenvironment, in addition to tumor. This program has resulted in over 220-grant-related publications and set groundwork for several clinical trials. In the current competitive renewal, we further attack this problem by combining leading expertise in PCa research and bone biology. The central theme of this Program is that there is crosstalk between PCa cells and the bone microenvironment that fosters the development and progression of PCa metastasis. This crosstalk promotes the ability of PCa cells to alter the bone microenvironment and render it fertile for tumor growth and chemotherapeutic resistance. To expand on this theme the Program encompasses closely interrelated hypotheses of four scientific projects supported by three cores. Project 1 explores the novel finding that chemotherapy induces fusion of PCa cells to form multinuclear polyploid giant cancer cells (PGCCs) that confer chemoresistance in the bone microenvironment; Project 2 examines the exciting idea that abscisic acid (ABA) induces PCa cells to adopt a phenotype capable of existing in a dormant and chemoresistant state, with the capacity for long-term survival and potential to develop into overt bone metastases; Project 3 explores the surprising role that osteocytes (OCys) play in promoting PCa bone metastasis through activation of a novel growth differentiation factor-15 (GDF15) receptor, GDFN family receptor alpha-like precursor (GFRAL), that subsequently promotes PCa metastatic invasion and growth; Project 4 investigates the novel hypothesis that macrophage efferocytosis (engulfment) of apoptotic PCa cells induces immunosuppressive signaling in the bone microenvironment that subsequently enhances metastatic growth. These projects will be supported by three integral cores: Core A (Administration) that will coordinate reporting, evaluation of progress, advisory board activities, facilitate interactions among the projects and provide biostatistical support; Core B (Animal) will provide mouse models and imaging and assistance with their use and Core C (Bone) will provide expertise with bone histology processing, interpretation, and procurement of human blood and bone marrow samples. This combination of investigators, projects and cores provides a highly synergistic Program that is greater than the sum of its parts and will continue to provide cutting-edge research and leadership in the field of PCa skeletal metastases.