Identification of Biomarkers for Response to Chemoprevention of Colon Cancer

对遗传性肥胖小鼠的新干预研究采用了豆类饮食，测试了暴露于偶氮甲烷后对结肠癌的缓解作用。在最近完成的息肉预防试验中，以豆类为基础的饮食被选择来模拟条件，在该试验中，食用最高四分之一豆类(海军、利马、肾脏、黑色等)的人类受试者显示，晚期腺瘤的发生率降低了3倍(E.Lanza及其同事，2006,2009)。整个豆类和两种豆类成分在降低肿瘤多样性方面显示出有效性(Bobe等人，Nutr CA，2008年)。最近的研究已经确定了包括IL-6在内的炎症相关细胞因子作为豆类饮食有效性的指标(Mentor-Marcel等人，2009年)。目前的研究目的是在有效条件下确定豆类饮食的重要分子靶标以及预测生物标记物。粪便结肠细胞的非侵入性基因表达谱揭示了2到3组基因的变化表明其风险(赵等人，CA Prev res，2009)。在与NCI Frederick的小动物成像设施的合作中，我们已经用磁共振成像证明了在小鼠结肠癌发生过程中可以监测炎症、肿瘤促进和肿瘤进展的终点(Young等人Neopasia 2009)。在临床前研究中，这些可成像的标记物被用来比较短期饮食干预的效果。最近，我们与Terry Hartman及其同事(宾夕法尼亚州立大学)合作，在豆类干预喂养实验(LIFE)研究中，质疑血清生物标记物在短期控制喂养干预研究中对有息肉复发风险的男性的预测价值。豆类饮食降低了血清促炎蛋白水平，改善了血脂水平(Hartman等人，J Nutr，2010；Zhang Z等人，脂类2010)。肥胖小鼠豆生物标志物干预研究(Mentor-Marcel)证实与最近对4000名参与者息肉预防试验样本的分析一致。在这两个病例中，息肉复发(发生)风险最高的患者的血清IL-6水平升高，而在受益的编写者组中，以豆类为基础的饮食降低了IL-6水平(Bobe等人癌症研究报告2010)。

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).