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归因于肿瘤通过侵袭和转移传播。细胞运动是肿瘤细胞侵袭和转移的基本且不可或缺的方面。因此，细胞运动是治疗干预的绝佳目标，有可能降低乳腺癌患者的发病率和死亡率。为了更好地了解细胞运动性，我们研究了整合素，它是细胞外基质的受体，可转导对细胞运动至关重要的信号。最近，整合素已被证明可以调节蛋白激酶 A (PKA)。重要的是，由于 PKA 参与 Rac 和 Rho GTPases 的控制，因此 PKA 的这种调节对于细胞运动至关重要。然而，整合素调节 PKA 的机制以及 PKA 如何调节 Rac 和 Rho 尚不清楚。该项目的长期目标是了解整合素及其对 PKA 活性的控制如何促进癌细胞侵袭，以便 PKA 活性可以成为治疗干预的正确目标。本提案的目的是了解 PKA 活性的 pi 整合素调节如何控制癌细胞趋化迁移中的 Rac 和 Rho 小 GTP 酶。我们的首要目标是确定 pi 整合素如何调节 PKA。我们接下来的两个目标是阐明 PKA 活性调节 RhoA 和 Racl 活性的机制。在我们的第四个目标中，我们将使用手术样本、体外运动和侵袭测定以及动物模型来确定哪些 PKA 亚基与乳腺癌细胞运动和传播相关。根据该提案的结果，我们希望能够描绘出细胞迁移所需的 PKA 上游和下游的信号分子，以便我们能够智能地靶向 PKA 对晚期癌症进行治疗干预。