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

• 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
• 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

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.

项目摘要/摘要 定期体育锻炼或运动（EX）是预防原发性乳腺癌的有效策略。 许多研究还表明，EX显着降低了复发的风险，并提高了 乳腺癌患者表明EX在乳腺癌幸存者的长期健康中起重要作用。 迄今为止，EX和降低的复发和降低之间关系的生物学机制以及 尚未充分了解乳腺癌的生存率。我们的初步数据使用 免疫能力，同性4T1.2转移性乳腺肿瘤模型表明重量中等 稳定的小鼠导致原发性肿瘤的生长减少和转移负担。这同时与 T细胞功能的增强和髓样衍生抑制细胞的积累的减少，A 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性来减少乳腺癌患者的复发并增加乳腺癌患者的生存率 进展。在当前应用中，我们将确定干预对肿瘤的保护作用是否 生长和转移主要是由于能量平衡的变化（例如预防体重增加）或 EX（独立于体重的变化）对肿瘤结局和转移的直接影响。 BALB/C小鼠 将被随机分配到EX或久坐控制（SED）组，并可以访问跑步轮或控制 在注射5x104 4T1.2细胞（转移性肿瘤细胞系）之前，笼子分别为8周 第四乳腺。一组SED小鼠会随意（SED/AL）喂食，并且一组EX小鼠将是 重量与SED/AL组匹配。此外，一小鼠的一组将受到10％的能量限制 实现一个比SED/Al组重的ER组。第二个SED小鼠队列将是体重 与前/ER组匹配。除了量化原发性肿瘤生长和转移负担（AIM 1）之外， 我们将确定EX或WM是否改变了主机的抗肿瘤免疫环境（AIM 2）和/或 代谢和炎症环境（AIM 3）；这些介体中的哪一个与肿瘤生长有关 转移进展。迄今为止，还没有研究在相关的乳腺癌中解决这些问题 转移模型。提出的研究的结果将对Ex的机制进行关键的了解 和/或WM可以发挥二级和三级癌症预防作用，并通过 磨练特定的生物途径，并确定未来实验的靶标。键的识别 将EX和/或WM连接到减轻转移负担的机制最终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。