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。这种流动性使其能够侵入邻近的正常组织，离开原始肿瘤部位，进入局部血管系统，并扩散到远处器官。我们最近发表了迁移的体内分析，其证明通过细胞表面四跨膜蛋白CD 151促进肿瘤细胞的不动性防止了内渗和随后的转移（Zijlstra et al.，2008年）。进一步的生化分析鉴定出活化的白细胞粘附分子（ALCAM）是四跨膜蛋白富集微区（TERM）中CD 151的新型四跨膜蛋白伴侣。遗传学实验证实，ALCAM是CD 151介导不动性所必需的。我们随后确定，CD 151和ALCAM形成一种内源性调节复合物，通过Rap 1激活促进整合素依赖性粘附来限制迁移。 我们目前的观察表明，ALCAM功能作为一个锚定机制，招聘含CD 151 TERM细胞-细胞粘附。该复合物通过CD 151或ALCAM的稳定促进不动性，而复合物的破坏可促进侵袭和转移。我们建议确定的分子机制，其中CD 151/ALCAM含有TERM可以促进不动性，并调查这种复杂的前列腺癌转移到骨的贡献。 本申请提出具体研究调节移动性的分子机制、其控制前列腺癌转移的能力以及其与人类疾病进展和患者存活的关系。在目标#1中，我们将确定CD 151/ALCAM在体外和体内促进肿瘤细胞不动性的内源性机制。将在目标#2中使用正交前列腺转移模型，以研究内源性ALCAM/CD 151调节复合物影响前列腺癌转移的能力。此外，ALCAM/CD 151相关表达谱与患者人群中疾病进展和生存期之间的相关性将在目标#3中进行研究。拟议工作的发现不仅将阐明CD 151及其新鉴定的膜伴侣ALCAM/CD 166的分子机制。它还将提供一个关键的评估肿瘤细胞固定作为一个治疗目标，在防止传播和识别潜在的新的临床靶点治疗侵袭性疾病。

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.