The Biology of Prostate Cancer Skeletal Metastases

前列腺癌骨骼转移的生物学

• 批准号: 8854463
• 负责人: Evan T Keller
• 金额: $ 151.94万
• 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 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8854463
• 关键词: Accounting; Address; Adopted; American; Animal Model; Animals; Apoptotic; Award; Biology; Bone Marrow; Cancer Etiology; Cancer Patient; Cessation of life; Clinical; Clinical Trials; Collection; Complication; Critiques; Development; Distant; EGF gene; Elements; Evaluation Reports; Fertilization; Fostering; Foundations; Funding; Goals; Grant; Growth; Health; Healthcare; Hematopoietic stem cells; Histology; Image; Knowledge; Laboratories; Leadership; Life; Malignant Neoplasms; Malignant neoplasm of prostate; Marrow; Measurement; Mediator of activation protein; Metabolic; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Methods; Molecular; Neoplasm Circulating Cells; Neoplasm Metastasis; Outcome; Pain; Pathologist; Pathway interactions; Patients; Phagocytosis; Phenotype; Primary Neoplasm; Process; Prognostic Marker; Prostate; Proteins; Publications; Pyruvate Kinase; Research; Research Personnel; Resources; Role; Sampling; Second Primary Cancers; Seeds; Serum; Services; Skeleton; Soil; Tissue Procurements; Tissues; Translations; Tumor-Derived; Work; anticancer research; base; biobank; bone; bone imaging; clinical application; combat; design; epithelial to mesenchymal transition; insight; mTOR protein; macrophage; male health; meetings; men; milk fat globule; mouse model; neoplastic cell; novel; novel therapeutics; pre-clinical; preference; prevent; programs; prospective; prostate cancer cell; skeletal; stem cell niche; therapeutic target; transcription factor; translational study; tumor; tumor growth; tumor microenvironment

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 nine years of this program award, we have addressed this important issue, resulting in over 135-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 ultimate goal is to define the cellular and molecular mechanisms that surround PCa skeletal metastases to facilitate translation into clinical application. 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. 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 ability of tumor-associated macrophages (TAMs) to induce PCa cells to undergo epithelial to mesenchymal transition (EMT) is a key mediator of bone metastasis; Project 2 examines the exciting idea that the hematopoietic stem cell (HSC) niche induces disseminated tumor cells (DTCs) to adopt a primitive, phenotype capable of existing in a chemoresistant/dormant state, with the capacity for long-term survival and potential to develop into overt bone metastases; Project 3 explores the surprising role of primary PCa microvesicles in inducing a metabolic state in the distant marrow microenvironment that favors PCa growth; and Project 4 investigates the novel hypothesis that bone marrow macrophages support PCa growth in bone via phagocytosis/efferocytosis of apoptotic tumor cells. These projects will be supported by three integral cores: Core A (Administration) that will coordinate reporting, evaluation, and advisor 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, interpretation, and procurement of bone marrow elements. This combination of investigators, projects and cores result in a highly synergistic Program that will continue to provide cutting-edge research and leadership in the field of PCa 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。在该项目的前九年中，我们已经解决了这个重要问题，导致超过135篇与资助相关的出版物，并为几项临床试验奠定了基础。在目前的竞争性更新中，我们通过结合PCa研究和骨生物学的领先专业知识进一步解决这个问题。最终目标是确定PCa骨转移周围的细胞和分子机制，以促进转化为临床应用。该计划的中心主题是PCa细胞与骨微环境之间存在串扰，促进PCa转移的发展和进展。这种串扰促进了PCa细胞改变骨微环境并使其对肿瘤生长具有肥沃性的能力。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探讨了肿瘤相关巨噬细胞（TAMs）诱导PCa细胞进行上皮间质转化（EMT）的能力是骨转移的关键介质的新概念;项目2研究了令人兴奋的想法，即造血干细胞（HSC）小生境诱导播散性肿瘤细胞（DTC）采用能够以化疗耐药/休眠状态存在的原始表型，具有长期存活的能力和发展成明显骨转移的潜力;项目3探索了原发性PCa微泡在诱导有利于PCa生长的远端骨髓微环境中的代谢状态中的令人惊讶的作用;项目4研究了新的假设，即骨髓巨噬细胞通过吞噬/吞噬凋亡肿瘤细胞来支持骨中的PCa生长。这些项目将得到三个核心的支持：核心A（管理），将协调报告、评估和顾问活动，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、解释和骨髓成分采购方面的专业知识。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，该项目将继续在PCa骨转移领域提供前沿研究和领导地位。