The Role of Chemokines in Metastatic Prostate Cancer

描述（由申请人提供）： 前列腺癌（CaP）是一种常见的肿瘤，也是美国男性癌症死亡的第二大原因。尽管有许多进步，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在内的许多组织。由于这些事实，人们对前列腺癌的早期检测和筛查以及对导致转移的机制的更好理解越来越感兴趣。造血干细胞在胎儿期和骨髓移植时也是骨骼的“家园”。在这种情况下，CXC趋化因子基质衍生因子-1（SDF-1或CXCL 12）及其受体CXCR 4似乎是这些事件的关键分子决定因素。这已经在几个方面得到证实，但最令人信服的是CXCL 12或CXCR 4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，其作为人造血祖细胞的化学引诱物起作用。 我们的总体假设是转移性CaP也使用CXCL 12/CXCR 4作为定位于骨髓的途径。我们的研究将通过确定CXCL 12支持CaPs细胞粘附和侵入骨髓的机制来验证这一假设（目的1），CXCL 12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CaP选择性优势（目的2）并使用动物模型描述CXCR 4和CXCL 12是否负责CaP癌向骨的归巢。这些研究将提供重要的新信息，涉及肿瘤如何“回家”骨的分子基础，我们相信这将有助于预防或最大限度地减少前列腺转移的新策略的发展。

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 or CXCL12) and its receptor, CXCR4 appear to be critical molecular determinants for these events. This has been substantiated in several ways, but most convincingly with CXCL12 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 CXCL12/CXCR4 as a pathway to localize to the bone marrow. Our investigations will test this hypothesis by determining the mechanisms whereby CXCL12 supports the adhesion and invasion of CaPs cells into the marrow (Aim 1), whether autocrine production of CXCL12 confers upon CaPs a selective advantage by either promoting proliferation or survival in the marrow microenvironment (Aim 2) and delineate whether CXCR4 and CXCL12 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.