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: 10065225
• 负责人: CHRISTINA DIELI-CONWRIGHT
• 金额: $ 59.71万
• 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/10065225
• 关键词: Abdomen; Address; Adipocytes; Adipose tissue; Adult; Aerobic Exercise; Attenuated; Biological Markers; Biopsy; Blood; Breast Cancer survivor; C-reactive protein; CD8-Positive T-Lymphocytes; Cancer Prognosis; Cancer Survivor; Chronic; Complex; Control Groups; Custom; Dental crowns; Development; Diabetes Mellitus; Dose; Dual-Energy X-Ray Absorptiometry; Economic Burden; Exercise; Fatty acid glycerol esters; Foundations; Guidelines; Heart Diseases; IL8 gene; Inflammation; Inflammatory; Insulin Resistance; Interleukin-6; Investigation; Knowledge; Lead; Leptin; Leukocytes; Link; Malignant Neoplasms; Measurement; Measures; Mediating; Mediator of activation protein; Metabolic; Methods; Movement; Obesity; Organ; Overweight; Phase; Phase II Clinical Trials; Phase III Clinical Trials; Phenotype; Population; Postmenopause; Recurrence; Research; Signal Transduction; Source; Structure; Supervision; Survival Rate; TNF gene; Thinness; Time; Treatment Side Effects; Work; adipokines; adiponectin; attentional control; attenuation; base; breast cancer progression; cancer therapy; comorbidity; cytokine; design; exercise intervention; exercise program; exercise regimen; improved; innovation; macrophage; malignant breast neoplasm; mode of exercise; mortality; novel; outcome forecast; prognostic; programs; resistance exercise; sarcopenic obesity; subcutaneous; tumor progression; tumorigenesis

PROJECT SUMMARY/ABSTRACT 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: to determine the effects of exercise on 1) obesity-associated chronic inflammation and 2) sarcopenic obesity. This study is innovative because a) we will target adipose tissue inflammatory biomarkers to improve cancer prognosis, b) utilize a novel biopsy method to obtain deep subcutaneous abdominal adipose tissue to address a mechanistic prognostic question, and c) 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.

项目摘要/摘要 针对与肥胖相关的慢性炎症，有可能改善预后 绝经后乳腺癌幸存者。肥胖被认为是领先的可修改贡献者 由于其与复发的增加和总体下降，全球乳腺癌死亡率 存活率。肥胖刺激癌症进展的一种中心机制是通过慢性 脂肪组织中的低度炎症。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细胞因子的脂肪细胞组成 与肿瘤发生有关。 WAT的慢性炎症包括脂肪组织的积累 巨噬细胞（ATM）。具体而言，ATM M1表型以肥胖升高，提供了丰富的来源 细胞因子是肥胖相关胰岛素抵抗的关键介质。脂肪质量的收益和 瘦肉质量下降，称为肌肉减少性肥胖，被视为治疗副作用，进一步 有助于WAT的发展和随后的M1表达升高。有利，运动 - 诱导的肌肉减少肥胖变化导致M1 ATM的减少，并增加已知的M2 ATM 通过减轻炎症来防止胰岛素抵抗。但是，尚不清楚这有什么影响 可能具有癌症预后，哪种运动形式最有效地减少慢性 炎。我们的总体假设是旨在针对慢性炎症和 相关的肌肉减少肥胖将改善肥胖的绝经后乳腺癌幸存者的预后。 我们提出了II期RCT，以比较两种合并有氧运动和耐药性锻炼的效果 在绝经后肥胖的早期肥胖后，相对于注意力控制组的干预措施 已经完成原发性癌症治疗的癌症幸存者。该建议将解决以下 目的：确定运动对1）肥胖相关的慢性炎症和2） 肌肉减少肥胖。这项研究具有创新性，因为a）我们将靶向脂肪组织炎症 改善癌症预后的生物标志物，b）使用一种新型活检方法获得深层皮下 腹部脂肪组织以解决机理预后问题，c）采用独特的 周期性的电路式运动设计，以减少慢性炎症。如果实现目标，发现 从这项研究中，大多数人都会为乳腺癌幸存者提供有关运动准则的新知识 可能改善预后。