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

运动和体重维持对乳腺癌转移进展的保护作用的机制

基本信息

批准号：
9321998
负责人：
Connie J Rogers
金额：
$ 17.1万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9321998
关键词：
4T1 Address Adult Adverse effects Aerobic Exercise Antigens Biological Biological Response Modifiers Body Weight Breast Cancer Model Breast Cancer Patient Breast Cancer Prevention Breast Cancer survivor Breast Cancer therapy Breast cancer metastasis CCL2 gene CD4 Positive T Lymphocytes CSF3 gene Cell Proliferation Cell physiology Cells Clinical Research Control Groups Data Disease Environment Equilibrium Exercise Fatigue Flow Cytometry Future Gene Expression Glucose Granulocyte-Macrophage Colony-Stimulating Factor Health Human IGFBP3 gene Immune Immune response Immunocompetent Inbred BALB C Mice Inflammation Mediators Inflammatory Injection of therapeutic agent Insulin Insulin-Like Growth Factor I Interferons Interleukin-1 Interleukin-6 Intervention Leptin Link Malignant Neoplasms Mammary gland Measures Mediating Mediator of activation protein Metabolic Modeling Moderate Exercise Mus Myelogenous Natural Immunity Neoplasm Metastasis Outcome Pathway interactions Physical Exercise Physical activity Plasma Pre-Clinical Model Prevention Preventive Primary Neoplasm Production Quality of life Randomized Randomized Controlled Trials Recurrence Risk Role Running Suppressor-Effector T-Lymphocytes T-Lymphocyte TNF gene Therapeutic Time Tumor Cell Line Vascular Endothelial Growth Factors Weight Woman adaptive immunity adiponectin breast cancer survival cohort cost design energy balance exercise intervention exercise training experimental study group intervention immune function implantation improved inflammatory milieu insight malignant breast neoplasm metabolomics metastatic process preclinical study prevent protective effect response sedentary tool tumor tumor growth weight gain prevention weight maintenance

项目摘要

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.

项目概要/摘要定期体力活动或锻炼 (EX) 是预防乳腺癌的有效策略。大量研究还表明 EX 显着降低了复发风险，并提高了患者的生存率乳腺癌患者表明 EX 在乳腺癌幸存者的长期健康中发挥着重要作用。迄今为止，EX 与减少复发和减少复发之间关系的生物学机制乳腺癌生存率的提高尚不清楚。我们的初步数据使用免疫活性强的同基因 4T1.2 转移性乳腺肿瘤模型表明 EX 体重适中稳定的小鼠可减少原发性肿瘤的生长和转移负担。这与以下情况同时发生：增强 T 细胞功能并减少骨髓源性抑制细胞的积累，免疫抑制细胞在转移过程中很重要。因此，EX 和/或体重维持 (WM) 可能通过预防或延迟转移来减少乳腺癌患者的复发并提高生存率进展。在当前的应用中，我们将确定我们的干预措施是否对肿瘤有保护作用生长和转移主要是由于能量平衡的变化（例如防止体重增加）或 EX（与体重变化无关）对肿瘤结果和转移的直接影响。 BALB/c小鼠将被随机分配到 EX 或久坐控制 (SED) 组，并有权使用跑步轮或控制组在将 5X104 4T1.2 细胞（一种转移性肿瘤细胞系）注射到笼中之前，分别将其放置 8 周。第四乳腺。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 EX 小鼠的能量将受到 10% 的限制，实现 EX/ER 组的重量小于 SED/AL 组。第二组 SED 小鼠的体重与 EX/ER 组匹配。除了量化原发肿瘤生长和转移负担（目标 1）之外，我们将确定 EX 或 WM 是否改变宿主的亲肿瘤免疫环境与抗肿瘤免疫环境（目标 2），和/或代谢和炎症环境（目标 3）；这些介质中哪些与肿瘤生长有关转移进展。迄今为止，还没有研究在相关乳腺癌中解决这些问题转移模型。所提出的研究结果将为 EX 的机制提供重要的见解和/或 WM 可能发挥二级和三级癌症预防作用，并通过以下方式推动该领域向前发展：专注于特定的生物途径，并确定未来实验的目标。钥匙识别将 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更多有效的预防和治疗策略，包括运动和体重维持干预措施。