The Role of Tissue Factor-Factor VIIa-PAR2 Signaling in Breast Tumor Progression

组织因子-因子 VIIa-PAR2 信号转导在乳腺肿瘤进展中的作用

• 批准号: 8120333
• 负责人: Troy Anthony McEachron
• 金额: $ 1.46万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-01-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8120333
• 关键词: Role; Tissue; Factor; VIIa; PAR2

DESCRIPTION (provided by applicant): One of the most complex and elusive events in tumor biology is metastasis. This process by which tumor cells become metastatic has been a very active area of research with extremely important clinical implications. Tissue factor (TF) is a cell surface receptor that initiates the coagulation protease cascade. Factor Vila (FVIIa) docks to TF and the TF-FVIIa complex cleaves and activates protease activated receptor-2 (PAR2) thereby inducing downstream signaling. TF-FVIIa-PAR2 signaling increases a variety of genes including those involved in metastasis. Many studies have been performed on TF-FVIIa-PAR2 signaling in a human breast tumor model. However, the detailed mechanisms concerning how TF-FVIIa- PAR2 increases tumor cell metastasis have not been revealed. The 67NR and 4T1 cell lines were derived from a single spontaneously arising mouse breast tumor. The advantage of using this breast tumor model to study TF-FVIIa-PAR2 signaling is that these cells allow for in vivo studies in a non-genetically modified immunocompetent host. We hypothesize that the increased metastatic behavior exhibited by, aggressive, as opposed to non-aggressive cancer cells is due to differential TF-FVIIa-PAR2 signaling. The specific aims of the project are: 1) analyze TF-FVIIa-PAR2 signaling in metastatic and non-metastatic breast tumor cell lines in vitro; and 2) examine the contribution of TF-FVIIa-PAR2 signaling to cell motility in a metastatic and non- metastatic breast tumor model in vivo. The overall goal of this project is to detail the precise intracellular signal transduction pathways responsible for TF-FVIIa-PAR2 induced metastasis using an in vitro and in vivo model of murine breast cancer. Cancer is a pressing public health concern. By establishing a causative role of PAR2 in metastasis I hope to provide further insight into this complex pathophysiological process. Increased understanding of the metastatic disease process will enable the scientific and medical communities to make advances in therapeutics and treatment strategies.

描述（由申请人提供）：肿瘤生物学中最复杂，最难以捉摸的事件之一是转移。肿瘤细胞变成转移性的过程一直是非常活跃的研究领域，具有极为重要的临床意义。组织因子（TF）是一种启动凝血蛋白酶级联的细胞表面受体。因子Vila（FVIIA）对TF和TF-FVIIA复合物进行裂解并激活蛋白酶激活受体-2（PAR2），从而诱导下游信号传导。 TF-FVIIA-PAR2信号传导增加了多种基因，包括参与转移的基因。在人类乳腺肿瘤模型中，已经对TF-FVIIA-PAR2信号传导进行了许多研究。但是，尚未揭示有关TF-FVIIA-PAR2如何增加肿瘤细胞转移的详细机制。 67NR和4T1细胞系源自单个自发产生的小鼠乳腺肿瘤。使用该乳腺肿瘤模型研究TF-FVIIA-PAR2信号传导的优点是，这些细胞允许在非元素修饰的免疫能力宿主中进行体内研究。我们假设侵略性与非侵袭性癌细胞所表现出的转移行为增加是由于TF-FVIIA-PAR2信号传导差异。该项目的具体目的是：1）分析体外转移性和非转移性乳腺肿瘤细胞系中的TF-FVIIA-PAR2信号传导； 2）检查体内转移性和非转移性乳腺肿瘤模型中TF-FVIIA-PAR2信号传导对细胞运动的贡献。该项目的总体目标是详细介绍使用体外和体内鼠类乳腺癌模型，导致TF-FVIIA-PAR2诱导TF-FVIIA-PAR2诱导转移的精确细胞内信号转导途径。癌症是一个紧迫的公共卫生问题。通过建立PAR2在转移中的因果作用，我希望能够进一步了解这一复杂的病理生理过程。对转移性疾病过程的更多了解将使科学和医疗社区能够在治疗和治疗策略方面取得进步。