Mitochondrial Redox Control of Metastasis

描述(由申请人提供)：癌细胞从原发肿瘤转移到远处转移部位代表了癌症进展的最致命阶段。细胞迁移和侵袭的可能性取决于多种信号通路，这些信号通路为抗癌治疗提供了新的靶点。活性氧簇(ROS)是已知的致瘤性调节因子，在许多细胞信号级联中扮演新的第二信使的角色。在许多转移性癌症类型中，ROS的内在水平升高。随着ROS环境的增加，肿瘤细胞存活和繁荣的能力表明，这些细胞已经进化到利用亚致死性ROS水平的变化来驱动促进转移的信号事件。我们的初步数据表明，线粒体来源的ROS/H_2O_2(H_2O_2)的皮摩尔亚致死性增加导致转移性癌细胞在体外和体内更具致瘤性、迁移性和侵袭性。ROS的这些变化导致了在关键磷酸酶氧化和失活之后，亲迁移信号级联的变化。此外，这些研究提出了一个新的概念，即过氧化氢是一种调节因子，本质上对支持和反对迁移的信号分子的膜定位具有相反的影响。因此，我们假设，线粒体ROS产量的亚致死性增加调节了促进迁移的信号通路的空间激活，增强了癌细胞的转移潜力。利用转移性膀胱癌模型，将通过：1)研究线粒体ROS的细胞作用部位及其在调节氧化和参与迁移信号的蛋白酪氨酸磷酸酶(PTPs)的空间分布中的作用。2)确定线粒体ROS在迁移过程中对粘着斑激酶信号转导介质的影响；以及3)评估体内转移性膀胱癌模型中细胞内ROS水平升高的后果以及该模型中抗氧化剂辅助治疗的有效性。重要的是，这些研究将确立ROS作为第二信使在调节亲迁移信号通路的空间激活中的新作用，进一步加深我们对线粒体ROS在转移进展中的作用的理解；并确定旨在抑制亲迁移信号的抗氧化剂在转移性膀胱癌中的治疗潜力。 公共卫生相关性：这项研究将进一步加深我们对调节肿瘤细胞迁移和侵袭的细胞内机制的了解。了解活性氧在这些事件中的作用将有助于开发以抗氧化剂为基础的针对转移的新型癌症治疗方法。

DESCRIPTION (provided by applicant): Movement of cancer cells from the primary tumor to distant metastatic sites represents the most lethal stage of cancer progression. The potential for a cell to migrate and invade depends on a multitude of signaling pathways, which present novel targets for anti-cancer therapies. Reactive Oxygen Species (ROS) are known modulators of tumorigenicity and act as novel second messengers in a multitude of cellular signaling cascades. Intrinsic levels of ROS are elevated in numerous metastatic cancer types. The ability of tumor cells to survive and thrive with an increased ROS milieu suggests that these have evolved to utilize changes in sublethal ROS levels to drive pro-metastatic signaling events. Our preliminary data suggest that picomolar sublethal increases in mitochondrial derived ROS/hydrogen peroxide (H2O2) lead to a more tumorigenic, migratory and invasive phenotype in metastatic cancer cells, in vitro and in vivo. These changes in ROS lead to alterations in pro-migratory signaling cascades, following oxidation and inactivation of key phosphatases. In addition, these studies present a novel concept that H2O2 is a regulatory factor that essentially has opposing effects on membrane localization of pro- and anti- migratory signaling players. We therefore hypothesize that sub lethal increases in mitochondrial ROS production regulate the spatial activation of pro-migratory signaling pathways enhancing the metastatic potential of cancer cells. Using a metastatic bladder cancer model this will be tested by: 1) Investigating the cellular site of action of mitochondrial ROS and their role in regulating oxidation and spatial distribution of Protein Tyrosine Phosphatases (PTPs) involved in migratory signaling. 2) Determining the effects of mitochondrial ROS on mediators of Focal Adhesion Kinase signaling during migration; and 3) Assessing the consequences of enhanced intracellular ROS levels in an in vivo model of metastatic bladder cancer and the effectiveness of antioxidant adjuvant therapy in this model. Importantly, these studies will establish a novel role for ROS as second messengers in regulating the spatial activation of pro-migratory signaling pathways, further our understanding of the role of mitochondrial ROS in metastatic progression; and determine the therapeutic potential of antioxidants, targeted to inhibit pro-migratory signaling, in metastatic bladder cancer. PUBLIC HEALTH RELEVANCE: This research will further our knowledge of the intracellular mechanisms that regulate migration and invasion of tumor cells. Understanding the role of reactive oxygen species in these events will aid in the development of novel antioxidant based cancer therapies targeting metastasis.