Role of SDF-1/CSCR4 in bone 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。死亡率高的主要原因是恶性细胞扩散到包括骨骼在内的许多组织。由于这些事实，人们对前列腺癌的早期发现和筛查以及对导致转移的机制的更多了解越来越感兴趣。造血干细胞也是吗？回家？在胎儿生命和骨髓移植期间移植到骨骼。在这种背景下，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。这在几个方面都得到了证实，但最令人信服的是SDF-1或CXCR4基因敲除，在这些基因敲除中，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，SDF-1蛋白对人造血祖细胞具有趋化作用。我们的总体假设是，转移性CAPS也使用SDF-1/CXCR4作为定位于骨髓的途径。我们的研究将通过确定SDF-1支持CAPS细胞黏附和侵袭骨髓的机制来检验这一假说(目标1)，SDF-1的自分泌产生是否通过促进骨髓微环境中的增殖或存活而赋予CAPS选择性优势(目标2)，并通过动物模型描绘CXCR4和SDF-1是否对CAP癌与骨的归巢负责。这些研究将提供与肿瘤的分子基础有关的重要新信息？我们相信这将促进预防或最小化前列腺癌转移的新策略的开发。

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.