Mechanisms underlying the protective effect of exercise and weight maintenance on metastatic progression in breast cancer

项目摘要/摘要 有规律的体育活动或锻炼(EX)是预防乳腺癌的有效策略。 大量研究还表明，EX显著降低了复发的风险，并提高了患者的生存率 乳腺癌患者提示EX在乳腺癌幸存者的长期健康中起着重要作用。 到目前为止，EX与减少复发和 提高乳腺癌的存活率还不是很清楚。我们的初步数据使用 免疫活性的同基因4T1.2转移性乳腺肿瘤模型显示体重适中 稳定的小鼠可以减少原发肿瘤的生长和转移负担。这与 T细胞功能的增强和髓系来源的抑制细胞积聚的减少 免疫抑制细胞在肿瘤转移过程中起重要作用。因此，EX和/或体重维护(WM)可以 通过预防或延缓转移减少乳腺癌患者的复发和提高存活率 进步。在目前的应用中，我们将确定我们的干预对肿瘤的保护作用 生长和转移在很大程度上是由于能量平衡的变化(例如防止体重增加)或 EX对肿瘤转归和转移的直接影响(与体重变化无关)。BALB/c小鼠 将被随机分配到EX组或久坐对照组(SED)，并给予方向盘或对照组 在将5X104 4T1.2细胞(一种转移性肿瘤细胞系)注射到 第四个乳腺。一组SED小鼠将被随意喂养(SED/AL)，一组EX小鼠将被 体重与SED/AL组相匹配。此外，一组前老鼠将受到10%的能量限制，以 实现比SED/AL组更轻的EX/ER组。第二批SED小鼠的体重将 与前/急诊室组匹配。除了量化原发肿瘤生长和转移负担(目标1)外， 我们将确定EX或WM是否改变了宿主的亲肿瘤和抗肿瘤免疫环境(目标2)，和/或 代谢和炎症环境(目标3)；这些介质中的哪些与肿瘤生长和 转移的进展。到目前为止，还没有关于相关乳腺癌的这些问题的研究。 转移模型。所提出的研究结果将为我们提供关键的洞察力，以了解 和/或西医可能正在发挥预防第二和第三癌症的作用，并通过以下方式推动该领域的发展 钻研特定的生物途径，并为未来的实验确定目标。密钥的标识 将EX和/或WM与减少转移负担联系起来的机制最终可能使我们能够设计出更多 有效的预防和治疗策略，包括运动和减肥干预。

PROJECT SUMMARY/ABSTRACT Regular physical activity or exercise (EX) is an effective strategy for primary breast cancer prevention. Numerous studies also indicate that EX significantly decreases the risk of recurrence, and improves survival in breast cancer patients suggesting an important role for EX in the long-term health of breast cancer survivors. To date, the biological mechanism(s) underlying the relationship between EX and reduced recurrence and improved survival from breast cancer are not well understood. Our preliminary data using the immunocompetent, syngeneic 4T1.2 metastatic mammary tumor model indicate that moderate EX in weight stable mice results in reduced primary tumor growth and metastatic burden. This occurs concurrently with an augmentation of T cell function and a reduction in the accumulation of myeloid derived suppressor cells, an immune suppressive cell important in the metastatic process. Thus, EX and/or weight maintenance (WM) may reduce recurrence and increase survival in breast cancer patients by preventing or delaying metastatic progression. In the current application, we will determine if the protective effect of our intervention on tumor growth and metastases is due largely to changes in energy balance (e.g. the prevention of weight gain) or to direct effect of EX (independent of changes in body weight) on tumor outcomes and metastases. BALB/c mice will be randomized to EX or sedentary control (SED) groups and given access to running wheel or control cages, respectively, for 8 weeks prior to the injection of 5X104 4T1.2 cells, a metastatic tumor cell line, into the 4th mammary gland. One cohort of SED mice will be fed ad libitum (SED/AL) and a cohort of EX mice will be weight matched to the SED/AL group. Additionally, one cohort of EX mice will be energy-restricted by 10% to achieve an EX/ER group that weighs less than the SED/AL group. A second cohort of SED mice will be weight matched to the EX/ER group. In addition to quantifying primary tumor growth and metastatic burden (Aim 1), we will determine if EX or WM alters the pro- vs. anti-tumor immune environment of the host (Aim 2), and/or the metabolic and inflammatory milieu (Aim 3); and which of these mediators are related to tumor growth and metastatic progression. To date, no studies have addressed these questions in a relevant breast cancer metastases model. Results from the studies proposed will shed critical insight on the mechanisms by which EX and/or WM may be exerting a secondary and tertiary cancer preventive effect, and move the field forward by honing in on specific biological pathways, and identify targets for future experiments. Identification of key mechanisms linking EX and/or WM to reduced metastatic burden may ultimately enable us to design more effective preventative and therapeutic strategies that include exercise and weight maintenance interventions.