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是癌症进展中最致命的阶段。细胞迁移和入侵的潜力取决于多种信号通路，这为抗癌治疗提供了新的靶点。活性氧（ROS）是已知的致瘤性调节剂，在多种细胞信号级联反应中作为新的第二信使。在许多转移性癌症类型中，ROS的内在水平升高。肿瘤细胞在增加的ROS环境下存活和生长的能力表明，这些细胞已经进化到利用亚致死ROS水平的变化来驱动促转移信号事件。我们的初步数据表明，在体外和体内，线粒体来源的ROS/过氧化氢（H2O2）的皮摩尔亚致死增加导致转移癌细胞更具致瘤性、迁移性和侵袭性表型。在关键磷酸酶氧化和失活后，ROS的这些变化导致促迁移信号级联的改变。此外，这些研究提出了一个新的概念，即H2O2是一种调节因子，本质上对支持和反对迁移信号参与者的膜定位具有相反的作用。因此，我们假设线粒体ROS生成的亚致死增加调节了促迁移信号通路的空间激活，增强了癌细胞的转移潜力。在转移性膀胱癌模型中，将通过以下方式进行验证：1)研究线粒体ROS的细胞作用位点及其在调节参与迁移信号的蛋白酪氨酸磷酸酶（PTPs）的氧化和空间分布中的作用。2)确定线粒体ROS对迁移过程中Focal Adhesion Kinase信号介质的影响；3)评估转移性膀胱癌体内模型中细胞内ROS水平升高的影响以及抗氧化辅助治疗在该模型中的效果。重要的是，这些研究将确立ROS作为第二信使在调节促迁移信号通路的空间激活中的新作用，进一步了解线粒体ROS在转移进展中的作用；并确定靶向抑制促迁移信号的抗氧化剂在转移性膀胱癌中的治疗潜力。

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.