Role of SDF-1/CSCR4 in bone metastasis

SDF-1/CSCR4在骨转移中的作用

• 批准号: 6990045
• 负责人: RUSSELL S TAICHMAN
• 金额: $ 13.11万
• 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 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6990045
• 关键词: SCID mouse; autocrine; bone marrow; bone neoplasms; cell adhesion; cell adhesion molecules; cell line; cell migration; chemokine; cytokine receptors; hematopoietic stem cells; human tissue; immunocytochemistry; male; metastasis; molecular oncology; neoplasm /cancer invasiveness; prostate neoplasms; receptor expression; western blottings

DESCRIPTION (provided by applicant: Prostate cancer (CaP) is a common neoplasm and the second leading cause of cancer deaths in American males. Despite numerous advances, once the tumors metastasize, prostate cancer is almost invariably fatal. The high mortality rate is principally due to the spread of malignant cells to many tissues including bone. Because of these facts, there is a growing interest in the early detection and screening of men for prostate cancer, and for a greater understanding of the mechanisms that lead to metastasis. Hematopoietic stem cells also ?home? to bone during fetal life and marrow transplantation. In this context, a CXC chemokine stromal-derived factor-1 (SDF-1) and its receptor, CXCR4 appear to be critical molecular determinants for these events. This has been substantiated in several ways, but most convincingly with SDF-1 or CXCR4 gene knockouts, where marrow engraftment by hematopoietic cells is not observed. Moreover, osteoblasts and marrow endothelial cells express SDF-1 protein that function as a chemoattractant for human hematopoietic progenitor cells. Our overall hypothesis is that metastatic CaPs also use the SDF-1/CXCR4 as a pathway to localize to the bone marrow. Our investigations will test this hypothesis by determining the mechanisms whereby SDF-1 supports the adhesion and invasion of CaPs cells into the marrow (Aim 1), whether autocrine production of SDF-1 confers upon CaPs a selective advantage by either promoting proliferation or survival in the marrow microenvironment (Aim 2) and delineate whether CXCR4 and SDF-1 are responsible for homing of CaP carcinomas to bone using animal models. These investigations will provide important new information pertaining to the molecular basis of how tumors ?home? to bone which we believe will facilitate the development of new strategies for preventing or minimizing prostate metastasis.

描述（申请人提供：前列腺癌（CaP）是一种常见的肿瘤， 美国男性癌症死亡的第二大原因。尽管取得了许多进展，但一旦肿瘤转移，前列腺癌几乎总是致命的。高死亡率主要是由于恶性细胞扩散到包括骨骼在内的许多组织。由于这些事实，人们对男性前列腺癌的早期检测和筛查以及对导致转移的机制有更深入的了解越来越感兴趣。造血干细胞也有“家”吗？在胎儿生命和骨髓移植期间形成骨骼。在这种情况下，CXC 趋化因子基质衍生因子 1 (SDF-1) 及其受体 CXCR4 似乎是这些事件的关键分子决定因素。这已通过多种方式得到证实，但最令人信服的是 SDF-1 或 CXCR4 基因敲除，其中没有观察到造血细胞的骨髓植入。此外，成骨细胞和骨髓内皮细胞表达 SDF-1 蛋白，该蛋白可作为人类造血祖细胞的趋化剂。我们的总体假设是，转移性 CaP 也使用 SDF-1/CXCR4 作为定位至骨髓的途径。我们的研究将通过确定 SDF-1 支持 CaP 细胞粘附和侵入骨髓的机制来检验这一假设（目标 1），SDF-1 的自分泌产生是否通过促进增殖或存活而赋予 CaP 选择性优势。骨髓微环境（目​​标 2）并利用动物模型描绘 CXCR4 和 SDF-1 是否负责 CaP 癌归巢至骨。这些研究将提供有关肿瘤如何“归巢”的分子基础的重要新信息。我们相信这将有助于开发预防或减少前列腺转移的新策略。