Exercise and Lung Cancer

项目总结 临床和流行病学研究表明，运动可降低发病率并改善 多种癌症的预后；然而，运动发挥其抗癌作用的机制 人们对其影响仍知之甚少。大多数运动研究都是在乳腺癌中进行的；然而，正如 乳腺癌与肥胖相关，由胰岛素驱动，而且免疫原性很弱，运动可能会 对于免疫原性强且与肥胖无关的癌症类型，其作用方式有所不同。机械师 了解运动如何减缓肿瘤生长很重要，因为它将为临床试验的设计提供信息。 根据患者的情况确定哪种运动方案最有可能使特定的肿瘤类型受益 临床特征，允许使用精确的医学方法来制定运动处方。 可以说，更重要的是，这方面的研究可能揭示出通过调节 新陈代谢与标准护理治疗相结合。在这项提案中，我们将研究如何进行锻炼 减缓小鼠肺癌的生长，最主要的假设是运动对 肺癌的进展是全身代谢相互作用的结果，将肌肉连接到 免疫系统对肿瘤的影响。我们预计运动既能减少肿瘤的葡萄糖摄取，又能增加 免疫细胞葡萄糖和脂肪酸代谢，从而增强T细胞活性，防止疲劳。 这些假说将使用一组组织特异性基因敲除小鼠进行测试，方法是我们 开发用于模拟组织特定底物代谢的模型，以及模拟低密度脂蛋白的多种运动方式。 大强度运动以及高强度间歇训练。在这样做的过程中，我们期望产生新的见解 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影响，以及 可能会发现新的免疫代谢靶点，以增强运动的功效，产生循证 治疗小鼠肺癌的运动处方。

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.