Tetraspanin-mediated regulation of tumor cell migration and metastasis

描述(由申请人提供)：为了发生癌症转移，肿瘤细胞必须能够自我动员。这种移动性允许它侵入邻近的正常组织，离开原来的肿瘤部位，进入局部血管系统，并扩散到远处的器官。我们最近发表了一项体内迁移分析，该分析表明，通过细胞表面Tetraspanin CD151促进肿瘤细胞的固定可以防止血管内和随后的转移(Zijlstra等人，2008年)。进一步的生化分析表明，激活的白细胞黏附分子(ALCAM)是在TERM中与CD151结合的一种新的TERM。遗传学实验证实，CD151需要alcam来调节不动。我们随后确定CD151和alcam形成内源性调节复合体，通过激活Rap1促进整合素依赖的黏附来限制迁移。我们目前的观察表明，alcam作为一种锚定机制，招募了含有CD151的术语到细胞间的粘连。通过CD151或alcam稳定该复合体可促进不动，而破坏该复合体可促进侵袭和转移。我们建议确定CD151/alcam所含Term促进不动的分子机制，并研究该复合体在前列腺癌骨转移中的作用。这项应用建议专门研究调节移动性的分子机制，它控制前列腺癌转移的能力，以及它与人类疾病进展和患者生存的关系。在目标1中，我们将确定CD151/alcam在体外和体内促进肿瘤细胞静止的内源性机制。在AIM#2中，将使用正交异性前列腺癌转移模型来研究内源性alcam/CD151调节复合体影响前列腺癌转移的能力。此外，目标3将研究患者群体中与alcam/CD151相关的表达谱和疾病进展与生存的相关性。拟议的工作结果不仅将有助于阐明CD151及其新发现的膜伙伴alcam/CD166的分子机制。它还将对肿瘤细胞固定化作为防止扩散和确定潜在的侵袭性疾病治疗的新临床靶点的治疗目标进行关键评估。 公共卫生相关性：与癌症相关的死亡主要是因为肿瘤细胞通过循环系统从起源部位扩散到远处的重要器官。为了到达远处的器官，肿瘤细胞必须动员起来，进入循环。拟议工作的总体目标是开发分子干预机制，以固定肿瘤细胞并防止癌症患者的肿瘤细胞转移。

DESCRIPTION (provided by applicant): In order for cancer metastasis to occur, a tumor cell must be able to mobilize itself. This mobility allows it to invade adjacent normal tissue, leave the original tumor site, enter local vasculature, and disseminate to distant organs. We have recently published an in vivo analysis of migration which demonstrates that promoting the immobility of tumor cells through the cell surface tetraspanin CD151 prevents intravasation and subsequent metastasis (Zijlstra et al., 2008). Further biochemical analysis identified Activated Leukocyte Cell Adhesion Molecule (ALCAM) as a novel tetraspanin partner of CD151 in tetraspanin enriched microdomains (TERM). Genetic experiment confirmed that ALCAM is required for CD151 to mediate immobility. We have subsequently determined that CD151 and ALCAM form an endogenous regulatory complex that limits migration by promoting integrin-dependent adhesion via Rap1 activation. Our current observations suggest that ALCAM functions as an anchoring mechanism that recruits CD151-containing TERM to cell-cell adhesions. Stabilization of this complex via CD151 or ALCAM promotes immobility while disruption of the complex can promote invasion and metastasis. We propose to determine the molecular mechanism by which CD151/ALCAM-containing TERM can promote immobility and to investigate the contribution of this complex to metastasis of prostate cancer to the bone. This application proposes to specifically investigate the molecular mechanism by which mobility is regulated, its ability to control prostate cancer metastasis, and its relation to human disease progression and patient survival. In aim #1 we will determine the endogenous mechanism by which CD151/ALCAM promote tumor cell immobility in vitro and in vivo. Orthotropic prostate metastasis models will be used in aim #2 to investigate the ability of the endogenous ALCAM/CD151 regulatory complex to influence prostate cancer metastasis. Furthermore, the correlation between ALCAM/CD151 related expression profiles and disease progression with survival within patient populations will be investigated in aim #3 The findings of the proposed work will not only shed light on the molecular mechanism of CD151 and its newly identified membrane partner ALCAM/CD166. It will also provide a critical evaluation of tumor cell immobilization as a therapeutic target in preventing dissemination and identifying potentially novel clinical targets for the treatment of invasive disease. PUBLIC HEALTH RELEVANCE: Cancer related deaths occur primarily because tumor cells spread from the site of origin to distant vital organs using the circulatory system. In order to reach a distant organ, tumor cells have to mobilize themselves and enter the circulation. The overall goal of proposed work is to develop mechanisms of molecular intervention which immobilizes tumor cells and prevent tumor cell metastasis in cancer patients.