The Biology of Prostate Cancer Skeletal Metastases

前列腺癌骨骼转移的生物学

• 批准号: 10427243
• 负责人: Evan T Keller
• 金额: $ 145.12万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-05 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10427243
• 关键词: Abscisic Acid; Address; Adopted; Animal Model; Animals; Apoptotic; Biological Assay; Biology; Biometry; Blood; Bone Marrow; Bone Tissue; Cells; Cessation of life; Chemoresistance; Clinical Trials; Development; Ensure; Environment; Evaluation; Experimental Animal Model; Family; Fostering; GDF15 gene; Grant; Growth; Health; Histology; Human; Hypoxia; Image; Immunosuppression; Incidence; Injections; Leadership; Malignant Neoplasms; Malignant neoplasm of prostate; Measurement; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Methods; Modeling; Mus; Neoplasm Metastasis; Osteocytes; Pain; Patient Care; Phenotype; Play; Polyploidy; Predisposition; Publications; Reporting; Research; Research Personnel; Resistance; Resource Sharing; Role; Running; Sampling; Signal Transduction; Skeleton; Stress; Sum; advanced prostate cancer; anticancer research; bone; bone cell; cancer cell; chemotherapy; experience; macrophage; men; mouse model; multidisciplinary; neoplastic cell; new therapeutic target; novel; prevent; programs; prostate cancer cell; prostate cancer metastasis; prostate cancer progression; receptor; therapeutic target; therapy resistant; tumor; tumor growth; tumorigenesis

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.

总体抽象 常见的发生，明显的衰弱和随后的前列腺癌（PCA）的致命性（PCA） 骨骼转移使其成为主要的健康问题。在此的前十四年 程序，我们已经解决了这个重要问题，从而对现场产生了重大影响 骨骼转移研究，包括促进诸如肿瘤之间串扰之类的概念 骨骼以及治疗靶向微环境的重要性，除了 瘤。该计划导致了220多个赠款相关的出版物，并为 几项临床试验。在当前的竞争续约中，我们通过 结合PCA研究和骨生物学领域的主要专业知识。这个中心主题 程序是PCA细胞和骨微环境之间存在串扰 促进PCA转移的发展和发展。这个串扰促进了能力 PCA细胞改变骨微环境并使肿瘤生长和 化学治疗性抗性。为了扩展此主题，程序密切包含 由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 化学疗法诱导PCA细胞融合形成多核多倍体的新发现发现 在骨微环境中赋予化学抗性的巨型癌细胞（PGCC）；项目 2研究了脱节酸（ABA）诱导PCA细胞采用表型的令人兴奋的想法 能够处于休眠和化学抗性状态，具有长期的能力 生存和发展为明显的骨转移的潜力；项目3探讨了令人惊讶的 骨细胞（OCY）在促进PCA骨转移中扮演的作用 新型生长分化因子15（GDF15）受体，GDFN家族受体α样 前体（GFRAL），随后促进PCA转移性侵袭和生长；项目4 研究了凋亡PCA的巨噬细胞传播（吞噬）的新假设 细胞在骨微环境中诱导免疫抑制信号传导，随后 增强转移性生长。这些项目将得到三个积分核的支持：核心A （管理）将协调报告，进度评估，顾问委员会活动， 促进项目之间的互动并提供生物统计支持；核心（动物）将 提供鼠标模型，成像和帮助，并使用其使用和核心C（骨）将 提供人类骨组织学处理，解释和采购的专业知识 血液和骨髓样品。调查人员，项目和核心的结合 提供了一个高度协同的程序，该程序大于其部分的总和，并将继续 在PCA骨骼转移领域提供尖端的研究和领导。