Taking AIM at Breast Cancer: Targeting Adiposity and Inflammation with Movement to Improve Prognosis in Breast Cancer Survivors

针对乳腺癌：通过运动对抗肥胖和炎症，改善乳腺癌幸存者的预后

• 批准号: 10686204
• 负责人: CHRISTINA DIELI-CONWRIGHT
• 金额: $ 61.07万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10686204
• 关键词: Abdomen; Address; Adipocytes; Adipose tissue; Adult; Aerobic Exercise; Biological Markers; Biopsy; Blood; Breast Cancer survivor; C-reactive protein; CD8-Positive T-Lymphocytes; Cancer Prognosis; Cancer Survivor; Chronic; Complex; Control Groups; Crowns; Development; Diabetes Mellitus; Disease-Free Survival; Distant; Dose; Dual-Energy X-Ray Absorptiometry; Economic Burden; Exercise; Fatty acid glycerol esters; Foundations; Guidelines; Heart Diseases; IL8 gene; Inflammation; Inflammation Mediators; Inflammatory; Insulin Resistance; Interleukin-6; Investigation; Knowledge; Lead; Least-Squares Analysis; Leptin; Leucocytic infiltrate; Link; Macrophage; Malignant Neoplasms; Measurement; Measures; Mediating; Mediator; Metabolic; Methods; Movement; Obesity; Organ; Overweight; Phase; Phase II Clinical Trials; Phase III Clinical Trials; Phenotype; Population; Postmenopause; Prognosis; Recurrence; Research; Signal Transduction; Source; Structure; Survival Rate; TNF gene; Thinness; Time; Treatment Side Effects; Work; adipokines; adiponectin; attentional control; attenuation; breast cancer progression; cancer therapy; comorbidity; cytokine; design; exercise intervention; exercise program; exercise regimen; improved; inflammatory marker; innovation; malignant breast neoplasm; mathematical model; mode of exercise; mortality; novel; prognostic; programs; resistance exercise; sarcopenic obesity; subcutaneous; systemic inflammatory response; tumor progression; tumorigenesis

Targeting chronic inflammation related to obesity with exercise has the potential to improve prognosis in obese postmenopausal breast cancer survivors. Obesity is considered a leading modifiable contributor to breast cancer mortality worldwide due to its association with increased recurrence and decreased overall survival rate. A central mechanism by which obesity stimulates cancer progression is through chronic, low-grade inflammation in adipose tissue. In particular, white adipose tissue (WAT) is a metabolically complex organ comprised of adipocytes capable of secreting adipokines and proinflammatory cytokines related to tumorigenesis. Chronic inflammation of WAT includes accumulation of adipose tissue macrophages (ATMs). Specifically, the ATM M1 phenotype, elevated with obesity, provides a rich source of cytokines, which are key mediators of obesity-associated insulin resistance. Gains in fat mass and a decline in lean mass, known as sarcopenic obesity, are observed as a treatment side effect, further contributing to the development of WAT and subsequent elevated M1 expression. Favorably, exercise-induced changes in sarcopenic obesity lead to a reduction in M1 ATMs, and increase in M2 ATMs known to protect against insulin resistance by attenuating inflammation. However it is unknown what impact this may have on cancer prognosis and what forms of exercise are most effective at reducing chronic inflammation. Our general hypothesis is that exercise designed to target chronic inflammation and associated sarcopenic obesity will improve prognosis in obese postmenopausal breast cancer survivors. We propose a Phase II RCT to compare the effects of two combined aerobic and resistance exercise interventions relative to an attention control group among early-stage obese postmenopausal breast cancer survivors who have completed primary cancer therapy. This proposal will address the following aims: 1) determine the effects of exercise on obesity-associated chronic inflammation; 2) examine the effects of exercise on sarcopenic obesity; 3) determine the effects of exercise on breast cancer prognosis and to assess whether reductions in chronic inflammation are associated with breast cancer prognosis. This study is innovative because a) we will target adipose tissue inflammatory biomarkers to improve cancer prognosis, b) derive a mathematical model that employs measureable markers of inflammation to predict prognosis, c) utilize a novel biopsy method to obtain deep subcutaneous abdominal adipose tissue to address a mechanistic prognostic question, and d) employ a unique periodized, circuit-style exercise design to reduce chronic inflammation. If the aims are achieved, findings from this study will generate new knowledge about exercise guidelines for breast cancer survivors most likely to improve prognosis. !

针对与肥胖有关的慢性炎症，有可能改善肥胖症的预后 绝经后乳腺癌幸存者。肥胖被认为是乳房的主要可修改贡献者 全球癌症死亡率由于其与复发增加和总体生存的降低相关 速度。肥胖刺激癌症进展的一种中心机制是通过慢性低级 脂肪组织中的炎症。特别是，白色脂肪组织（WAT）是一种代谢复杂的器官 由能够分泌脂肪因子和促炎性细胞因子的脂肪细胞组成 肿瘤发生。 WAT的慢性炎症包括脂肪组织巨噬细胞（ATM）的积累。 具体而言，用肥胖升高的ATM M1表型提供了丰富的细胞因子来源，这是关键 肥胖相关胰岛素抵抗的介体。脂肪质量的收益和瘦质量下降，称为 肌肉减少性肥胖是作为治疗副作用的，进一步有助于WAT的发展 随后的M1表达升高。有利的是，运动引起的肌肉减少肥胖的变化导致 减少M1 ATM，并增加已知可以通过减弱来预防胰岛素耐药性的M2 ATM 炎。但是，尚不清楚这可能对癌症预后产生什么影响以及哪种形式 运动最有效地减少慢性炎症。我们的总体假设是设计的练习 靶向慢性炎症和相关的肌肉减少肥胖将改善肥胖的预后 绝经后乳腺癌幸存者。我们提出了II期RCT，以比较两个组合的效果 早期肥胖中相对于注意力控制组的有氧和抵抗运动干预措施 完成原发性癌症治疗的绝经后乳腺癌幸存者。该提议将 解决以下目的：1）确定运动对肥胖相关慢性炎症的影响； 2） 检查运动对肌肉减少肥胖的影响； 3）确定运动对乳腺癌的影响 预后并评估慢性炎症减少是否与乳腺癌有关 预后。这项研究具有创新性，因为a）我们将靶向脂肪组织炎症生物标志物 改善癌症的预后，b）得出使用可测量的炎症标记的数学模型 为了预测预后，c）利用一种新型的活检方法来获得深层皮下腹部脂肪组织 解决一个机械预后问题，d）采用独特的周期性电路式锻炼设计 减少慢性炎症。如果实现了目标，那么这项研究的发现将产生新知识 关于乳腺癌幸存者的运动指南，最有可能改善预后。 呢