Novel Mechanisms of Carcinoma Cell Migration

癌细胞迁移的新机制

• 批准号: 7034331
• 负责人: KATHLEEN L. O'CONNOR
• 金额: $ 26.8万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-09 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7034331
• 关键词: athymic mouse; biological signal transduction; breast neoplasms; cell migration; cell motility; chemoattractants; chemotaxis; clinical research; enzyme activity; enzyme mechanism; genetic regulation; guanosinetriphosphatases; human tissue; integrins; laboratory mouse; metastasis; neoplasm /cancer invasiveness; neoplastic cell; protein kinase A; protein structure; tissue /cell culture

DESCRIPTION (provided by applicant): The majority of breast cancer deaths are directly due to tumor dissemination through invasion and metastasis. Cell motility is a fundamental and indispensable aspect of both tumor cell invasion and metastasis. As such, cell motility is an excellent target for therapeutic intervention with the potential to decrease breast cancer patient morbidity and mortality. To better understand motility, we study integrins, which are receptors for the extracellular matrix that transduce signals that are critical for cell motility. Recently, integrins have been shown to regulate Protein Kinase A (PKA). Importantly, this regulation of PKA is critical for cell motility due to the involvement of PKA in the control of Rac and Rho GTPases. However, the mechanisms governing integrin regulation of PKA and how PKA regulates Rac and Rho are unclear. The long-term goal of this project is to understand how integrins and their control of PKA activity promote carcinoma cell invasion so that PKA activity may be properly targeted for therapeutic intervention. The objective of this proposal is to understand how pi integrin regulation of PKA activity controls Rac and Rho small GTPases in the chemotactic migration of carcinoma cells. Our first aim is to determine how pi integrins regulate PKA. Our next two aims are designed to elucidate the mechanisms by which PKA activity regulates the activities of RhoA and Racl. In our fourth aim, we will identify which PKA subunits are associated with breast cancer cell motility and dissemination using surgical samples, in vitro motility and invasion assays and animal models. With the results from this proposal, we expect to delineate the signaling molecules upstream and downstream of PKA that are required for cell migration so that we can intelligently target PKA for therapeutic intervention of late stage cancer.

描述（由申请人提供）：大多数乳腺癌死亡直接是由于肿瘤通过侵袭和转移而引起的。细胞运动性是肿瘤细胞侵袭和转移的基本和不可或缺的方面。因此，细胞运动是治疗干预措施的绝佳目标，有可能降低乳腺癌患者的发病率和死亡率。为了更好地理解运动性，我们研究整联蛋白，这些整合蛋白是传播对细胞运动至关重要的细胞外基质的受体。最近，整联蛋白已显示用于调节蛋白激酶A（PKA）。重要的是，由于PKA参与RAC和RHO GTPases，PKA的这种调节对于细胞运动至关重要。然而，尚不清楚控制PKA整联蛋白调节以及PKA调节RAC和RHO的机制尚不清楚。该项目的长期目标是了解整联蛋白及其对PKA活性的控制如何促进癌细胞侵袭，从而可以适当地针对治疗干预措施PKA活性。该建议的目的是了解PI整合素的调节PKA活性如何控制癌细胞趋化性迁移中的RAC和Rho小GTPases。我们的第一个目的是确定PI整联蛋白如何调节PKA。我们的下两个目标旨在阐明PKA活动调节RhoA和RACL活动的机制。在我们的第四个目标中，我们将确定哪些PKA亚基与乳腺癌细胞的运动性和使用手术样本，体外运动和入侵测定和动物模型有关。根据该提案的结果，我们希望在PKA的上游和下游描述细胞迁移所需的信号分子，以便我们可以智能地靶向PKA，以用于晚期癌症的治疗干预。