Mitochondrial Redox Control of Metastasis

癌细胞从原发肿瘤向远处转移部位的转移最具代表性 癌症进展的致命阶段。细胞迁移和入侵的可能性取决于 大量的信号通路，为抗癌治疗提供了新的靶点。反应性 氧物种(ROS)是已知的致瘤性调节因子，并作为新的第二种 许多细胞信号中的信使级联。体内ROS水平升高 多种转移性癌症类型。肿瘤细胞存活和繁衍的能力 增加的ROS环境表明，这些细胞已经进化到利用亚致死性ROS水平的变化 以推动促进转移的信号事件。我们的初步数据显示，皮摩尔亚致死 线粒体衍生的ROS/H_2O_2(H_2O_2)增加导致更具致瘤性， 体内和体外转移性癌细胞的迁移和侵袭表型。这些变化 在ROS中导致亲迁移信号级联的改变，在氧化和 关键的磷酸酶失活。此外，这些研究提出了一个新的概念，即过氧化氢是一种 本质上对正反向膜定位有相反影响的调节因子 迁徙信号玩家。因此我们假设线粒体的亚致死性增加 ROS的产生调节促迁移信号通路的空间激活增强 癌细胞的转移潜能。使用转移性膀胱癌模型 测试：1)研究线粒体ROS在细胞内的作用部位及其在 调节蛋白酪氨酸磷酸酶(PTPs)的氧化和空间分布 迁徙信号。2)确定线粒体ROS对局灶性介质的影响 迁移过程中的黏附激酶信号；以及3)评估增强的后果 转移性膀胱癌体内细胞内ROS水平的变化及丹参的疗效 该模型中的抗氧化剂辅助治疗。重要的是，这些研究将确立一个新的角色 ROS作为第二信使调节促迁移信号的空间激活 途径，进一步了解线粒体ROS在转移进展中的作用； 并确定抗氧化剂的治疗潜力，旨在抑制亲迁移 信号，在转移性膀胱癌。

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.