Beta1 Integrins and IGF-l Receptor in Prostate Cancer

描述(申请人提供)：本实验室在当前资金周期内开展的研究，在将b1整合素表征为参与体内肿瘤进展的细胞内信号通路的新调节器方面取得了重要的里程碑。利用前列腺癌的分子和基因工程模型，我们现在已经确立了b1整合素在协调与生长因子受体(主要是胰岛素样生长因子受体-1(IGF-IR))的串扰信号、调节包括AKT和粘着斑激酶(FAK)在内的细胞质激酶的激活以及通过对抗细胞凋亡来促进肿瘤细胞存活方面的核心作用。我们发现，这些反应在前列腺癌的进展中被显著利用，在前列腺癌进展中，b1整合素指导的信号是原发肿瘤生长所必需的，促进转移扩散，并对抗肿瘤对治疗的反应，特别是电离辐射。因此，我们提出了一个统一的假设，即b1整合素在前列腺癌进展过程中协调多个细胞内信号通路的基因表达、细胞运动和细胞生存，这将构成下一个资金周期当前应用的重点。具体目标1的实验将在体外和体内剖析b1整合素在控制肿瘤细胞中的声波刺激性通路中的作用。第二个特定目标将研究b1整合素通过一种新的肿瘤细胞迁移和转移途径的促转移功能，重点是b1整合素在前列腺癌中上调的跨膜受体trop-2在前列腺癌细胞特殊的亚细胞微区中的动态重新分布。第三个特定目标将描述一种由b1整合素在前列腺癌细胞中介导的新的细胞生存机制，其核心是选择性地抑制JNK1介导的电离辐射诱导的细胞凋亡。总体而言，该应用程序结合了对体外机制途径的详细阐明，以及使用体内前列腺癌最先进的分子和遗传模型进行的验证研究。这些结果将揭示b1整合素信号在癌症进展中的重要作用的新方面，并将为前列腺癌治疗中的新的翻译方法奠定机制基础。 公共卫生相关性：本研究将阐明表面受体及其下游靶点之间协同合作的新分子网络，并将为目前针对整合素或胰岛素样生长因子受体的前列腺癌治疗方法提供新的见解。这一系列研究将为治疗晚期和转移性前列腺癌的新的翻译方法奠定广泛的机制基础。总体而言，该应用程序将来自几个研究领域的多学科最先进的方法结合到一个单一的、集成的实验平台上，该平台独特地定位于揭示前列腺癌进展的新致病机制。

DESCRIPTION (provided by applicant): Studies carried out by our laboratory during the current funding cycle, reached important milestones in the characterization of b1 integrins as novel regulators of intracellular signaling pathways participating in tumor progression in vivo. Using molecular and genetically engineered models of prostate cancer, we have now established a central role for b1 integrins in orchestrating cross-talk signaling with growth factor receptors, mostly the insulin-like growth factor receptor-1 (IGF-IR), modulating the activation of cytoplasmic kinases, including AKT and Focal Adhesion Kinase (FAK), and promoting tumor cell survival by counteracting apoptosis. We found that these responses are prominently exploited in prostate cancer progression, where b1 integrin-directed signaling is required for primary tumor growth, promotes metastatic dissemination, and antagonizes tumor response to therapy, especially ionizing radiation. Therefore, we formulated a unifying hypothesis that b1 integrins orchestrate multiple intracellular signaling pathways of gene expression, cell motility and cell survival in prostate cancer progression and this will constitute the focus of the present application for the next funding cycle. Experiments in specific aim 1 will dissect the role of b1 integrins in vitro and in vivo in the control of the sonic hedgehog pathway in tumor cells. The pro-metastatic functions of b1 integrins through a novel pathway of tumor cell migration and metastasis will be investigated in the second specific aim, with emphasis on dynamic redistribution of b1 integrins by Trop-2, a transmembrane receptor that is up-regulated in prostate cancer, in specialized subcellular microdomains of prostate cancer cells. The third specific aim will characterize a novel cell survival mechanism mediated by b1 integrins in prostate cancer cells, and centered on their selective inhibition of JNK1-mediated apoptosis in response to ionizing radiation. Overall, the application combines detailed elucidation of mechanistic pathways in vitro, with validation studies using state-of-the-art molecular and genetic models of prostate cancer in vivo. The results will uncover novel aspects of b1 integrin signaling important for cancer progression, and will establish a mechanistic foundation for novel translational approaches in prostate cancer therapy. PUBLIC HEALTH RELEVANCE: The present study will elucidate a novel molecular network of synergistic cooperation between surface receptors and their downstream targets, and it will provide new insights in the current therapeutic approaches for prostate cancer that target either integrins or the insulin-like growth factor receptor. This line of investigations will establish a broad mechanistic foundation for novel translational approaches in the treatment of advanced and metastatic prostate cancer. Overall, the application combines multidisciplinary state-of-the-art approaches from several fields of investigation into a single, integrated experimental platform, uniquely positioned to unravel novel pathogenetic mechanisms of prostate cancer progression.