THE IMPACT OF EXERCISE AND CALORIC RESTRICTION ON CANCER RECURRENCE IN MICE

运动和热量限制对小鼠癌症复发的影响

• 批准号: 8072521
• 负责人: LEWIS A CHODOSH
• 金额: $ 34.67万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-24 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8072521
• 关键词: Address; Adjuvant Therapy; Affect; Animal Model; Apoptosis; Behavioral; Biological; Biological Markers; Biology; Body Weight decreased; Breast; Caloric Restriction; Cancer Biology; Cancer Etiology; Cancer Survivor; Cancer Survivorship; Cells; Clinical; Development; Diagnosis; Diet; Discipline; Down-Regulation; Doxycycline; Endocrinology; Exercise; Exercise Physiology; Fatty acid glycerol esters; Genetically Engineered Mouse; Goals; Human; Inflammation; Insulin Resistance Pathway; Insulin-Like Growth Factor I; Intervention; Intervention Studies; Knowledge; Laboratories; Link; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Mediating; Mission; Modeling; Morbidity - disease rate; Mus; Obesity; Observational Study; Oncogene Activation; Oncogenes; Outcome; Overweight; Oxidative Stress; Pathway interactions; Physical activity; Pre-Clinical Model; Process; Radiosurgery; Randomized; Recurrence; Recurrent Malignant Neoplasm; Research Design; Research Personnel; Residual Neoplasm; Residual Tumors; Risk; Role; Survivors; T-Cell Receptor-Rearrangement Excision DNA Circles; Testing; Time; Tissues; Translating; Translational Research; Tumor Angiogenesis; Weight Gain; Weight maintenance regimen; Woman; Work; adipokines; angiogenesis; base; behavior influence; cancer recurrence; cancer risk; cohort; design; dietary restriction; effective intervention; energy balance; feeding; improved; innovation; intervention effect; malignant breast neoplasm; mortality; mouse model; neoplastic cell; preclinical study; prevent; protective effect; research study; therapy development; tumor; tumor progression; tumorigenic; weight loss intervention

Understanding the biological mechanisms that underlie the anti-tumorigenic effects of calorie restriction and physical activity will likely be essential for translating laboratory advances in this field to the development of more effective strategies for preventing cancer in humans. The goal of Project 1 ofthe Penn TREC Survivor Center is to advance our understanding of the impact of energetics on breast cancer recurrence. Project 1 will use an innovative genetically engineered mouse model for breast cancer recurrence developed at Penn to determine the effects of exercise, calorie restriction, or their combination on breast cancer recurrence. Mammary tumors will be induced in oven/veight mice by the doxycycline-dependent activation of an oncogene relevant to human breast cancer in the mammary glands of mice fed a high fat diet. Regression of the resulting tumors will be induced by oncogene down-regulation to generate cohorts of mice bearing dormant residual tumor cells. Overweight mice bearing residual disease will be randomly assigned to exercise, calorie restriction, both of these interventions, or neither and followed for cancer recurrence. Biomarkers will be evaluated to explore the hypothesized relationship between energy balance and recurrence and will include markers reflecting the PI3K-Akt-mT0R pathway, insulin resistance, IGF-1, HGF, adipokines, inflammation, tumor angiogenesis and oxidative stress. To our knowledge, this study will be the first to explore the impact of exercise and calorie restriction on cancer recurrence in an animal model. The studies proposed in Project 1 build on the unique combination of strengths and expertise in cancer biology, obesity, endocrinology, and exercise physiology among researchers in the proposed Penn TREC Survivor Center. In addition, the design of this study closely parallels an analogous human trial proposed in Project 2. The assembled team of investigators will work jointly to create new experimental paradigms that integrate and move beyond discipline-specific approaches to address the role of energy balance in breast cancer recurrence. In doing so, this project will advance the mission ofthe Penn TREC Survivor center to promote transdisciplinary, translational science on energy balance and cancer survivorship.

了解卡路里限制和体力活动的抗肿瘤作用的生物学机制可能对于将该领域的实验室进展转化为更有效的预防人类癌症的策略至关重要。宾夕法尼亚TREC幸存者中心的项目1的目标是促进我们对能量学对乳腺癌复发的影响的理解。项目1将使用宾夕法尼亚大学开发的乳腺癌复发的创新基因工程小鼠模型，以确定运动，卡路里限制或其组合对乳腺癌复发的影响。 通过高脂饮食喂养的小鼠乳腺中与人乳腺癌相关的癌基因的多西环素依赖性激活，在oven/veight小鼠中诱导乳腺肿瘤。将通过癌基因下调诱导所得肿瘤的消退，以产生携带休眠残余肿瘤细胞的小鼠群。携带残留疾病的超重小鼠将被随机分配到运动、热量限制、这两种干预或都不进行，并跟踪癌症复发。 将评价生物标志物以探索能量平衡与复发之间的假设关系，并将包括反映PI 3 K-Akt-mT 0 R通路、胰岛素抵抗、IGF-1、HGF、脂肪因子、炎症、肿瘤血管生成和氧化应激的标志物。据我们所知，这项研究将是第一个在动物模型中探索运动和热量限制对癌症复发的影响。项目1中提出的研究建立在拟议的Penn TREC幸存者中心研究人员在癌症生物学，肥胖，内分泌学和运动生理学方面的优势和专业知识的独特组合之上。此外，本研究的设计与项目2中提出的类似人体试验密切相似。 集合的研究团队将共同努力，创造新的实验范式，整合并超越特定学科的方法，以解决能量平衡在乳腺癌复发中的作用。在这样做的过程中，该项目将推进宾夕法尼亚TREC幸存者中心的使命，以促进能量平衡和癌症生存的跨学科，转化科学。