Tetraspanin-mediated regulation of tumor cell migration and metastasis
四跨膜蛋白介导的肿瘤细胞迁移和转移的调节
基本信息
- 批准号:7997246
- 负责人:
- 金额:$ 31.28万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-12-07 至 2014-11-30
- 项目状态:已结题
- 来源:
- 关键词:ALCAM geneActivated-Leukocyte Cell Adhesion MoleculeAdhesionsAffinityBiochemicalBioinformaticsBiological AssayBlood CirculationCancer PatientCardiovascular systemCell ExtractsCell surfaceCell-Cell AdhesionCellsCessation of lifeClinicalCommunicationComplexData SetDiseaseDisease ProgressionDistantEpithelialEvaluationExtracellular MatrixGene ExpressionGeneticGoalsGuanosine Triphosphate PhosphohydrolasesHumanImageImmobilizationIn VitroIntegrinsIntercellular JunctionsInterventionInvadedKnock-outLeftLightMacromolecular ComplexesMalignant NeoplasmsMalignant neoplasm of prostateMediatingMembraneMesenchymalMetastatic Prostate CancerMetastatic toModelingMolecularMolecular ProfilingMusNeoplasm MetastasisNormal tissue morphologyOrganPTEN genePatientsPrognostic FactorProstateProteinsPublishingRecruitment ActivityRegulationRoleSignal TransductionSiteSolid NeoplasmSpecimenWorkXenograft procedurebasebonecell motilitygenetic manipulationhuman PHEMX proteinhuman diseasein vivomigrationneoplastic cellnovelpatient populationpreventpublic health relevanceresearch studytherapeutic targettumortumor progression
项目摘要
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.
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,进入局部脉管系统,并扩散到远处器官。我们最近发表了一项关于肿瘤细胞迁移的体内分析,该分析表明,通过细胞表面的tetraspanin CD151促进肿瘤细胞的不动性,可以防止肿瘤细胞内渗和随后的转移(Zijlstra et al., 2008)。进一步的生化分析发现,活化的白细胞粘附分子(Activated Leukocyte Cell Adhesion Molecule, ALCAM)是CD151在四联蛋白富集微域(TERM)中的一个新的四联蛋白伴侣。基因实验证实ALCAM是CD151介导不动所必需的。我们随后确定CD151和ALCAM形成一个内源性调节复合体,通过Rap1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作为一种锚定机制,将含有cd151的TERM招募到细胞-细胞粘附中。通过CD151或ALCAM稳定该复合物可促进不动,而破坏该复合物可促进侵袭和转移。我们建议确定CD151/ALCAM-containing TERM促进不动的分子机制,并研究该复合物在前列腺癌骨转移中的作用。本申请拟专门研究移动性调控的分子机制、控制前列腺癌转移的能力及其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在体内和体外促进肿瘤细胞不动的内源性机制。目的2将使用正交异性前列腺转移模型来研究内源性ALCAM/CD151调节复合物影响前列腺癌转移的能力。此外,ALCAM/CD151相关表达谱与患者群体中疾病进展和生存之间的相关性将在aim #3中进行研究。拟议工作的发现不仅将阐明CD151及其新发现的膜伴侣ALCAM/CD166的分子机制。它还将为肿瘤细胞固定化作为预防扩散的治疗靶点和确定治疗侵袭性疾病的潜在新的临床靶点提供重要的评估。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)
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Andries Zijlstra其他文献
Andries Zijlstra的其他文献
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{{ truncateString('Andries Zijlstra', 18)}}的其他基金
Tetraspanin-mediated regulation of tumor cell migration and metastasis
四跨膜蛋白介导的肿瘤细胞迁移和转移的调节
- 批准号:
8391265 - 财政年份:2009
- 资助金额:
$ 31.28万 - 项目类别:
Tetraspanin-mediated regulation of tumor cell migration and metastasis
四跨膜蛋白介导的肿瘤细胞迁移和转移的调节
- 批准号:
7768355 - 财政年份:2009
- 资助金额:
$ 31.28万 - 项目类别:
Tetraspanin-mediated regulation of tumor cell migration and metastasis
四跨膜蛋白介导的肿瘤细胞迁移和转移的调节
- 批准号:
8589374 - 财政年份:2009
- 资助金额:
$ 31.28万 - 项目类别:
Tetraspanin-mediated regulation of tumor cell migration and metastasis
四跨膜蛋白介导的肿瘤细胞迁移和转移的调节
- 批准号:
8196950 - 财政年份:2009
- 资助金额:
$ 31.28万 - 项目类别:
The molecular mechanisms of migration of which lead to tumor cell intravasation.
其迁移导致肿瘤细胞内渗的分子机制。
- 批准号:
7624656 - 财政年份:2007
- 资助金额:
$ 31.28万 - 项目类别:
The molecular mechanisms of migration of which lead to tumor cell intravasation.
其迁移导致肿瘤细胞内渗的分子机制。
- 批准号:
7849790 - 财政年份:2007
- 资助金额:
$ 31.28万 - 项目类别:
The molecular mechanisms of migration of which lead to tumor cell intravasation.
其迁移导致肿瘤细胞内渗的分子机制。
- 批准号:
7433729 - 财政年份:2007
- 资助金额:
$ 31.28万 - 项目类别:
The molecular mechanisms of migration of which lead to tumor cell intravasation.
其迁移导致肿瘤细胞内渗的分子机制。
- 批准号:
8076917 - 财政年份:2007
- 资助金额:
$ 31.28万 - 项目类别:
The molecular mechanisms of migration of which lead to tumor cell intravasation.
其迁移导致肿瘤细胞内渗的分子机制。
- 批准号:
7211850 - 财政年份:2007
- 资助金额:
$ 31.28万 - 项目类别:
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