Beta1 Integrins and IGF-l Receptor in Prostate Cancer

描述（由申请人提供）：我们实验室在当前资助周期进行的研究，在表征b1整合素作为参与体内肿瘤进展的细胞内信号通路的新型调节剂方面取得了重要里程碑。利用前列腺癌的分子和基因工程模型，我们现在已经确定了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，调节细胞质激酶（包括AKT和Focal Adhesion Kinase (FAK)）的激活以及通过对抗细胞凋亡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进展中被显著利用，其中b1整合素导向的信号传导是原发肿瘤生长所必需的，促进转移传播，并拮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整合素协调前列腺癌进展中基因表达、细胞运动和细胞存活的多种细胞内信号通路，这将构成下一个资助周期当前应用的重点。特异性目的1的实验将解剖b1整合素在体外和体内对肿瘤细胞中sonic hedgehog通路的控制作用。b1整合素通过肿瘤细胞迁移和转移的新途径的促转移功能将在第二个特定目标中进行研究，重点是b1整合素通过前列腺癌中上调的跨膜受体Trop-2在前列腺癌细胞的特定亚细胞微域中的动态再分配。第三个特定目标将描述b1整合素在前列腺癌细胞中介导的一种新的细胞存活机制，并集中于它们在电离辐射下对jnk1介导的细胞凋亡的选择性抑制。总的来说，该应用程序结合了体外机制途径的详细阐明，以及体内使用最先进的前列腺癌分子和遗传模型的验证研究。这些结果将揭示b1整合素信号在癌症进展中重要的新方面，并将为前列腺癌治疗的新转化方法建立机制基础。

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.