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内进行的研究在表征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达到了重要的里程碑。使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））的串扰信号传导、调节细胞质激酶（包括AKT和粘着斑激酶（FAK））的活化以及通过对抗凋亡促进肿瘤细胞存活中的核心作用。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性肿瘤生长所需的，促进转移性传播，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整联蛋白协调前列腺癌进展中基因表达、细胞运动性和细胞存活的多种细胞内信号传导途径，这将构成本申请下一个资助周期的焦点。具体目标1中的实验将剖析b1整联蛋白在肿瘤细胞中的音刺猬途径的控制中在体外和体内的作用。在第二个具体目标中，将研究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，重点是在前列腺癌细胞的专门亚细胞微区中通过Trop-2（一种在前列腺癌中上调的跨膜受体）对b1整合素的动态再分布。第三个具体的目标将表征一种新的细胞存活机制介导的b1整合素在前列腺癌细胞中，并集中在其选择性抑制JNK 1介导的细胞凋亡在电离辐射。总的来说，该申请结合了体外机制途径的详细阐明，以及使用最先进的前列腺癌体内分子和遗传模型的验证研究。这些结果将揭示b1整合素信号传导对癌症进展的重要性，并将为前列腺癌治疗中的新翻译方法建立机制基础。

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.