Identification of Biomarkers for Response to Chemoprevention of Colon Cancer

结肠癌化学预防反应生物标志物的鉴定

• 批准号: 8349359
• 负责人: NANCY H. COLBURN
• 金额: $ 29.38万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8349359
• 关键词: Animals; Attenuated; Azoxymethane; Biological Markers; Body Weight decreased; Chemoprevention; Collaborations; Colon Carcinoma; Colonic Polyps; Diet; Dietary Intervention; Exposure to; Fabaceae; Flavonols; Gene Expression Profiling; Gene Proteins; Genes; Glycemic Index; Human; Image; Inflammation; Inflammatory; Interleukin-6; Intervention; Intervention Studies; Kidney; Leptin; Lipids; Magnetic Resonance Imaging; Malignant Neoplasms; Mentors; Molecular Target; Monitor; Mus; Neoplasms; Obese Mice; Overweight; Participant; Plasma; Polyp Prevention Trial; Polyps; Predictive Value; Proteins; Recurrence; Reducing diet; Risk; Sampling; Serum; Testing; Tumor Promotion; adenoma; attenuation; base; bean; cancer prevention; colon carcinogenesis; cytokine; feeding; human subject; improved; men; mouse model; preclinical study; protein metabolite; research study; response; tumor; tumor progression

New intervention studies in genetically obese mice employ a bean-based diet being tested for attenuation of colon carcinogenesis following exposure to azoxymethane. The bean-based diet was chosen to mimic conditions in the recently completed polyp prevention trial in which human subjects consuming the highest quartile of beans (navy, lima, kidney, black etc) showed a 3-fold reduction in ocurrence of advanced adenoma (E. Lanza and coworkers 2006, 2009). The whole beans and two bean fractions showed efficacy in attenuating tumor multiplicity (Bobe et al, Nutr Ca 2008). Recent studies have identified inflammation-associated cytokines including IL-6 as indicators of bean-diet efficacy (Mentor-Marcel et al Ca Prev Res 2009). Current studies are aimed at identifying funtionally significant molecular targets of the bean diets under conditions of efficacy as well as predictive biomarkers. Non-invasive gene expression profiling of fecal colonocytes has revealed sets of 2 to 3 genes whose changes are indicative of risk (Zhao et al Ca Prev Res 2009). In collaboration with the Small Animal Imaging facility at NCI Frederick we have demonstrated with magnetic resonance imaging that the endpoints of inflammation, tumor promotion and tumor progression can be monitored during colon carcinogenesis in a mouse model (Young et al Neoplasia 2009). These imageable markers are being used to compare the effects of short term exposure to dietary interventions in preclinical studies. Recently, in collaboration with Terry Hartman and coworkers (Penn State Univ) we have queried serum biomarkers for predictive value in short term controlled feeding intervention studies of men at risk of polyp recurrence in the Legume Intervention Feeding Experiment (LIFE) study. Serum levels of proinflammatory proteins decreased and serum lipid profiles improved in response to the bean-based diet (Hartman et al J Nutr 2010; Zhang Z et al Lipids 2010). The Obese mouse bean intervention study of biomarkers (Mentor-Marcel) turned out to agree with a recent analysis of the 4000 participant Polyp Prevention Trial samples. In both cases serum IL-6 levels were elevated in those at greatest risk of polyp recurrence (occurrence) and IL-6 levels were attenuated by the bean based diet in the complier group who benefited (Bobe et al Cancer Prev Res 2010).In the LIFE study the high legume low glycemic index diet reduces plasma leptin (Eur J Clin Nutr 2011) as well as producing weight loss in overweight men (submitted). These findings are among the first to demonstrate biomarkers that can identify those likely to benefit from the dietary intervention with reduced colon polyp recurrence.

对遗传肥胖小鼠的新干预研究采用了一种基于豆类的饮食，该饮食正在暴露于甲氧基烷后，以衰减结肠癌的衰减。在最近完成的息肉预防试验中，选择了基于豆类的饮食来模仿疾病，其中人类受试者消耗了最高的豆类豆（海军，利马，肾脏，黑色等），显示出晚期腺瘤的出现降低了3倍（E. Lanza and Cortorsers 2006，2009）。整个豆子和两个豆类部分在减弱肿瘤多重性方面显示出疗效（Bobe等，Nutr CA 2008）。最近的研究已经确定了包括IL-6在内的炎症相关的细胞因子是豆类疗效的指标（Mentor-Marcel等人CA Prev Res 2009）。当前的研究旨在在功效条件和预测生物标志物的条件下鉴定豆类饮食的娱乐性显着分子靶标。粪便结肠细胞的非侵入性基因表达分析揭示了2至3个基因的集合，其变化表明了风险（Zhao等CA Prev Res 2009）。通过与NCI Frederick的小动物成像设施合作，我们已经证明了磁共振成像，即在小鼠模型中可以监测炎症，肿瘤促进和肿瘤进展的终点（Young等人Neoplasia 2009）。这些可成像的标记被用来比较临床前研究中短期暴露于饮食干预措施的影响。最近，与特里·哈特曼（Terry Hartman）及其同事（宾夕法尼亚州立大学）合作，我们在短期受控的喂养干预研究中，在豆类干预进食实验（LIFE）研究中，在短期受控的喂养干预研究中询问血清生物标志物的预测价值。促炎蛋白的血清水平降低，血清脂质谱响应于豆类饮食（Hartman等人Jutr 2010； Zhang Z等人脂质2010）。肥胖的小鼠豆类干预研究（Mentor-Marcel）与最近对4000名参与者息肉预防试验样本进行了分析。 In both cases serum IL-6 levels were elevated in those at greatest risk of polyp recurrence (occurrence) and IL-6 levels were attenuated by the bean based diet in the complier group who benefited (Bobe et al Cancer Prev Res 2010).In the LIFE study the high legume low glycemic index diet reduces plasma leptin (Eur J Clin Nutr 2011) as well as producing weight loss in overweight men (submitted).这些发现是最早证明生物标志物的发现，这些标志物可以确定可能从饮食干预中受益的生物标志物，结肠息肉复发降低。