Exercise and Lung Cancer

项目摘要 临床和流行病学研究表明，运动可以降低发病率，改善 许多类型的癌症的预后;然而，运动发挥其抗癌作用的机制 其影响仍然知之甚少。大多数运动研究都是在乳腺癌中进行的;然而， 乳腺癌是肥胖相关的，胰岛素驱动的，只有弱免疫原性，很可能运动可以 在免疫原性强且与肥胖无关的癌症类型中起不同作用。一种机械的 了解运动如何减缓肿瘤生长是很重要的，因为它将为临床试验的设计提供信息。 为了根据患者的情况来确定哪种运动方案最有可能有益于特定的肿瘤类型， 临床特征，允许使用精确医学方法制定运动处方。 可以说更重要的是，这方面的研究可能会揭示肺癌的新治疗靶点， 代谢与标准治疗的组合。在本建议中，我们将研究如何行使 减缓小鼠肺癌的生长，总体假设，运动对肺癌的有益作用， 肺癌的进展是由于全身代谢相互作用的组合， 免疫系统对肿瘤我们预期运动既能减少肿瘤对葡萄糖的摄取，又能增加肿瘤对葡萄糖的摄取。 免疫细胞的葡萄糖和脂肪酸代谢，从而增强T细胞的活化，并防止疲劳。 这些假设将使用组织特异性基因敲除小鼠的补充进行测试，我们 开发用于模拟组织特异性底物代谢，以及模拟低- 高强度运动和高强度间歇训练。通过这样做，我们预计会产生新的见解， 肌肉-肿瘤-T细胞相互作用如何介导运动对免疫原性肿瘤的有益作用， 可以确定新的免疫代谢靶点，以提高运动的功效， 运动处方治疗小鼠肺癌

PROJECT SUMMARY Clinical and epidemiologic studies have demonstrated that exercise reduces the incidence and improves the prognosis of numerous types of cancer; however, the mechanisms by which exercise exerts its anti-cancer effects remain poorly understood. Most exercise studies have been performed in breast cancer; however, as breast cancer is obesity-associated, insulin-driven, and only weakly immunogenic, it is likely that exercise may work differently in cancer types that are strongly immunogenic and not associated with obesity. A mechanistic understanding of how exercise slows tumor growth is important because it will inform the design of clinical trials to determine which exercise regimens are most likely to benefit a particular tumor type based on a patient's clinical characteristics, allowing an exercise prescription to be made using precision medicine approaches. Arguably more importantly, studies in this vein may reveal new therapeutic targets for lung cancer by modulating metabolism in combination with standard-of-care treatments. In this proposal, we will examine how exercise slows lung cancer growth in mice, with the Overarching Hypothesis that the beneficial effects of exercise on lung cancer progression result from a combination of systemic metabolic interactions linking muscle to the immune system to the tumor. We anticipate that exercise both reduces tumor glucose uptake, and increases immune cell glucose and fatty acid metabolism, thereby enhancing T cell activation, and preventing exhaustion. These hypotheses will be tested using a complement of tissue-specific knockout mice, methods that we developed to model tissue-specific substrate metabolism, and multiple exercise modalities mimicking low- intensity exercise as well as high-intensity interval training. In so doing, we anticipate generating new insights into how muscle-tumor-T cell interactions mediate the beneficial effects of exercise in immunogenic tumors, and may identify new immunometabolic targets to enhance the efficacy of exercise, generating an evidence-based exercise prescription for lung cancer in mice.