Beta1 Integrins and IGF-l Receptor in Prostate Cancer

前列腺癌中的 Beta1 整合素和 IGF-l 受体

基本信息

批准号：
8616721
负责人：
Lucia R. Languino
金额：
$ 25.34万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8616721
关键词：
Adhesions Affect Apoptosis Apoptotic Biochemical CD29 Antigen Cancer Control Cell Death Cell Proliferation Cell Survival Cell surface Cells Complex Distant Focal Adhesion Kinase 1 Focal Adhesions Foundations Funding GLI gene Gene Expression Genetic Engineering Genetic Models Growth Factor Receptors In Vitro Insulin-Like Growth Factor Receptor Insulin-Like-Growth Factor I Receptor Integrin Signaling Pathway Integrins Investigation Ionizing radiation Laboratories MAPK8 gene Malignant Neoplasms Malignant neoplasm of prostate Mediating Metastatic Prostate Cancer Molecular Molecular Models Monomeric GTP-Binding Proteins Mus Neoplasm Metastasis Organ Pathway interactions Phosphorylation Phosphotransferases Positioning Attribute Primary Neoplasm Process Prostate Prostate Cancer therapy Proto-Oncogene Proteins c-akt Regulation Resistance Role Signal Pathway Signal Transduction Signaling Molecule Signaling Pathway Gene Sonic Hedgehog Pathway Structure Surface Survival Analysis Testing Therapeutic Xenograft Model base cell motility cell transformation in vivo insight irradiation molecular modeling multidisciplinary neoplastic cell novel prostate cancer cell prostate cancer model public health relevance receptor research study response rho trafficking transcription factor translational approach tumor tumor growth tumor progression validation studies

项目摘要

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.

描述（由申请人提供）：我们的实验室在当前资助周期内进行的研究在 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的表征方面达到了重要的里程碑。利用前列腺癌的分子和基因工程模型，我们现已确定 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)）的串扰信号传导中的核心作用，调节激活细胞质激酶，包括 AKT 和粘着斑激酶 (FAK)，并通过对抗细胞凋亡来促进肿瘤细胞存活。我们发现这些反应在前列腺癌进展中得到显着利用，其中b1整合素定向信号传导是原发性肿瘤生长所必需的，促进转移扩散，并拮抗肿瘤对治疗（尤其是电离辐射）的反应。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中协调基因表达、细胞运动和细胞存活的多个细胞内信号通路，这将构成本申请下一个资助周期的重点。具体目标 1 中的实验将剖析 b1 整合素在体外和体内在控制肿瘤细胞中的 sonic hedgehog 通路中的作用。第二个具体目标将研究 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 Trop-2（一种在前列腺中上调的跨膜受体）对 b1 整合素的动态重新分布癌症，位于前列腺癌细胞的特殊亚细胞微域中。第三个具体目标将描述前列腺癌细胞中 b1 整合素介导的新型细胞存活机制，并集中于它们对电离辐射反应中 JNK1 介导的细胞凋亡的选择性抑制。总体而言，该应用结合了体外机制途径的详细阐明以及使用前列腺癌体内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 整合素信号传导对癌症进展至关重要的新方面，并将为前列腺癌治疗的新转化方法奠定机制基础。