Variations of calorie restriction for the prevention of pancreatic cancer

预防胰腺癌的热量限制的变化

• 批准号: 7769890
• 负责人: Susan Patricia Lanza-Jacoby
• 金额: $ 17万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7769890
• 关键词: Address; Advanced Development; Age; Animal Model; Animals; Apoptosis; Atherosclerosis; Binding Proteins; Biological Markers; Body Weight; Body mass index; Breast; Caloric Restriction; Calories; Carcinoma in Situ; Cell Proliferation; Cells; Chronic; Chronic Disease; Colon; Colon Carcinoma; Computer software; Data; Development; Diagnosis; Dietary Factors; Disease; Ductal Epithelial Cell; EGFR Protein Overexpression; Early Diagnosis; Eating; Energy Intake; Epidermal Growth Factor Receptor; Evaluation; Exhibits; Female; Goals; Growth; Growth Factor; Human; Incidence; Individual; Insulin; Insulin-Like Growth Factor Binding Protein 3; Intake; Intervention; K-ras Oncogene; Laboratory Animals; Lead; Lesion; Life; Life Expectancy; Life Style; Liver; Longevity; Lung Neoplasms; Lymphoma; Malignant neoplasm of liver; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Mammary Neoplasms; Measures; Modeling; Molecular; Mononuclear; Mus; Mutation; NIH Program Announcements; Nimesulide; Nutritional Requirements; Oxidative Stress; PTGS2 gene; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Patients; Pilot Projects; Positron-Emission Tomography; Postmenopause; Premalignant; Prevention; Prevention strategy; Prostatic Neoplasms; Proteins; Rattus; Relative (related person); Reporting; Research; Risk; Risk Factors; Rodent; Serum; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Protein; Skin; Staging; Stomach; Subgroup; Survival Rate; Tissue Microarray; Transgenic Mice; Transgenic Organisms; Variant; Weight Gain; Work; base; cancer type; feeding; high risk; human FRAP1 protein; improved; inhibitor/antagonist; insulin sensitivity; leukemia; mTOR protein; malignant breast neoplasm; mouse model; neoplastic; outcome forecast; pre-clinical; prevent; protective effect; protein expression; public health relevance; pulmonary function; response; success; tumor

DESCRIPTION (provided by applicant): Pancreatic cancer progresses over many years, which offers the opportunity for early detection and prevention. Studies have identified elevated body mass index (BMI) as a risk factor for pancreatic cancer. Lower body weights resulting from calorie restriction have long been associated with extended life expectancy and reduced tumor incidence in laboratory animals. Chronic and intermittent calorie restriction have a powerful protective effect against tumor development. This proposal addresses the hypothesis that intermittent calorie restriction will prevent the development and delay progression of preneoplastic to neoplastic lesions by altering select biomarkers. The Kras; Pdx-1Cre mouse model provides an opportunity to study the efficacy of prevention strategies during the preinvasive state. The specific aims are: 1. To determine the effects of intermittent caloric restriction/refeeding and chronic restriction on the developmental progression of preneoplastic to neoplastic lesions in the K-ras; Pdx-1Cre transgenic mice relative to ad libitum fed mice. 2. Determine biomarker levels during each stage of PanIn progression to advanced lesions and whether chronic and intermittent calorie restriction modifies these biomarkers by measuring: a) serum concentrations of IGF-1 and IGFBP-3, b) the extent of proliferation and apoptosis in the pancreases from K-ras; Pdx-1Cre transgenic mice, c) IGF-1 and IGFBP-3 protein levels in pancreatic ductal cells, and d) activation of EGFR, Ras/MAPK, and PI3K/Akt signaling in pancreatic ductal cells using the cutting edge matrix assembly tissue array with AQUA software. Starting at 6-weeks mice will be assigned to: Group 1: ad libitum fed mice, Group 2: intermittent calorie restricted/refed mice fed in 2-week intervals at 50% of the ad libitum caloric intake followed by 2 weeks of ad libitum feeding; and Group 3: Chronic calorie restricted pair fed the average daily food intake that corresponds to the 4-wk restriction/refeeding interval of the intermittent calorie restricted mice. At 52 and 64 weeks of age, we will screen all the mice for the presence of a tumor by PET imaging. At 64 weeks mice in aim 1 will be sacrificed for evaluation of PanIn lesions and biomarkers. For aim 2 subgroups of mice will be sacrificed at 16 and 28 weeks of age to determine progressive changes in activation of EGFR, Ras/MAPK, PI3K/Akt, and mTOR and protein expression of IGF-1 and IGFBP-3 in pancreas by tissue array, proliferation, and serum concentrations of IGF-1 and IGFBP-3. Data obtained from this study will provide the first available information on whether calorie restriction will be of benefit for preventing pancreatic cancer and identification of biomarkers altered by this intervention. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is a deadly disease with only 5% of the patients living longer than 5 years. It is a disease with no known cure or strategy to prevent its occurrence. Thus, it is urgent to find ways to prevent this disease. Based upon the success of calorie restriction in preventing many types of cancer, this study will evaluate whether chronic and intermittent calorie restriction will prevent pancreatic cancer by targeting precancerous lesions in a relevant mouse model. Additionally, this study will identify early signaling biomarkers associated with precancerous lesion development and determine whether chronic and intermittent calorie restriction decreased the activation of Ras/MAPK/PI3K, proliferation, apoptosis in the pancreas, and circulating IGF-1.

描述(申请人提供)：胰腺癌经过多年的发展，这为早期发现和预防提供了机会。研究发现，体重指数(BMI)升高是胰腺癌的一个危险因素。长期以来，在实验动物中，限制卡路里导致的体重较低一直与延长预期寿命和降低肿瘤发病率有关。慢性和间歇性的热量限制对肿瘤的发展有很强的保护作用。这项建议解决了这样的假设，即间歇性热量限制将通过改变选定的生物标记物来防止癌前病变的发展和延缓肿瘤病变的进展。Kras；PDX-1Cre小鼠模型为研究入侵前状态下预防策略的有效性提供了机会。具体目的是：1.确定间歇性热量限制/再喂养和慢性限制对K-ras；pDX-1Cre转基因小鼠癌前病变向肿瘤病变发展的影响。2.通过测量：a)血清中IGF-1和IGFBP-3的浓度，b)K-ras和PDX-1Cre转基因小鼠胰腺的增殖和凋亡程度，c)胰腺导管细胞中IGF-1和IGFBP-3的蛋白水平，以及d)使用AQUA软件的尖端矩阵组装组织阵列激活胰腺导管细胞中的EGFR、Ras/MAPK和PI3K/Akt信号，确定在Panin进展到晚期病变的每个阶段的生物标志物水平以及慢性和间歇性热量限制是否改变了这些生物标志物。从6周开始，小鼠将被分配到：第1组：随意喂养小鼠；第2组：间歇性卡路里限制/再喂养小鼠，每隔2周以自由卡路里摄入量的50%喂养一次，然后自由喂养2周；以及第3组：慢性卡路里限制对饲喂相当于间歇卡路里限制小鼠4周限制/再喂养间隔的平均每日食物摄入量。在52周龄和出生时，我们将通过正电子发射计算机断层扫描对所有小鼠进行肿瘤筛查。在周，AIM 1中的小鼠将被处死以评估Panin损伤和生物标志物。目的：分别于16周龄和28周龄处死两组小鼠，通过组织芯片、细胞增殖和血清IGF-1、IGFBP-3浓度的变化来确定胰腺组织中EGFR、RAS/MAPK、PI3K/Akt的活性以及IGF-1和IGFBP-3的mTOR和蛋白表达的进行性变化。从这项研究中获得的数据将提供关于限制卡路里是否对预防胰腺癌有益的第一批可用信息，并识别由这种干预措施改变的生物标记物。公共卫生相关性：胰腺癌是一种致命的疾病，只有5%的患者存活超过5年。这是一种没有已知的治疗方法或策略来防止其发生的疾病。因此，迫切需要找到预防这种疾病的方法。基于卡路里限制在预防多种癌症方面的成功，这项研究将评估慢性和间歇性卡路里限制是否可以通过在相关小鼠模型中靶向癌前病变来预防胰腺癌。此外，这项研究将确定与癌前病变发展相关的早期信号生物标记物，并确定慢性和间歇性热量限制是否降低了RAS/MAPK/PI3K的激活、胰腺的增殖、凋亡和循环IGF-1。

项目成果

Calorie restriction delays the progression of lesions to pancreatic cancer in the LSL-KrasG12D; Pdx-1/Cre mouse model of pancreatic cancer.

热量限制延缓了 LSL-KrasG12D 中胰腺癌病变的进展；

• DOI: 10.1177/1535370213493727
• 发表时间: 2013
• 期刊: Experimental biology and medicine (Maywood, N.J.)
• 作者: Lanza-Jacoby,Susan;Yan,Guang;Radice,Glenn;LePhong,Christopher;Baliff,Jeffrey;Hess,Rachael
• 通讯作者: Hess,Rachael