Identification of Biomarkers for Response to Chemoprevention of Colon Cancer

在遗传性肥胖小鼠中进行的新的干预研究采用了以豆类为基础的饮食，正在测试暴露于氧化偶氮甲烷后结肠癌发生的衰减。在最近完成的息肉预防试验中，选择以豆类为基础的饮食来模拟条件，其中人类受试者消耗最高四分之一的豆类（海军，利马，肾脏，黑色等）显示晚期腺瘤的发生率降低3倍（E。Lanza和同事2006，2009）。全豆和两种豆级分显示出减弱肿瘤多样性的功效（Bobe等人，Nutr Ca 2008）。最近的研究已经鉴定了包括IL-6在内的炎症相关细胞因子作为豆类饮食功效的指标（Mentor-Marcel等人Ca Prev Res 2009）。目前的研究旨在确定在功效条件下豆类饮食的功能重要分子靶标以及预测性生物标志物。粪便结肠细胞的非侵入性基因表达谱分析揭示了2至3个基因的变化指示风险（Zhao et al Ca Prev Res 2009）。与NCI Frederick的小动物成像机构合作，我们已经用磁共振成像证明，在小鼠模型中结肠癌发生期间可以监测炎症、肿瘤促进和肿瘤进展的终点（Young et al Neoplasia 2009）。这些可成像的标记物被用于在临床前研究中比较短期暴露于饮食干预的效果。最近，与Terry Hartman及其同事（宾夕法尼亚州立大学）合作，我们在豆类干预喂养实验（LIFE）研究中对有息肉复发风险的男性进行了短期控制喂养干预研究，并对血清生物标志物的预测价值进行了质疑。豆类饮食导致促炎蛋白血清水平降低，血清脂质谱改善（Hartman et al J Nutr 2010; Zhang Z et al Lipids 2010）。肥胖小鼠豆干预生物标志物研究（Mentor-Marcel）结果与最近对4000名参与者息肉预防试验样本的分析一致。在这两种情况下，血清IL-6水平升高，在那些最大的风险息肉复发（发生率）和IL-6水平被豆类饮食减弱，在LIFE研究中，高豆类低血糖指数饮食降低了血浆瘦素（Zhang等人，Eur J Clin Nutr 2011）以及在超重男性中产生体重减轻。在预防人类或小鼠结肠癌发生的条件下，用浆果（Mentor-Marcel et al Nutr Ca 2012）或类黄酮异鼠李素（Saud et al Cancer Res 2013）进行干预，揭示了潜在的预测性生物标志物。此外，还出现了令人惊讶的发现，即异鼠李素通过靶向致癌Src CSK的内源性抑制剂来发挥其化学预防活性。这些发现是第一个证明生物标志物以及可以识别那些可能从饮食干预中受益并减少结肠息肉复发的途径。

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 (Zhang et al, Eur J Clin Nutr 2011) as well as producing weight loss in overweight men. Interventions with berries (Mentor-Marcel et al Nutr Ca 2012) or the flavonoid isorhamnitin (Saud et al Cancer Res 2013) under conditions that prevent colon carcinogenesis in humans or mice revealed potentially predictive biomarkers. In addition emerged the surprising finding that isorhamnitin exerts its chemopreventive activity by targeting the endogenous inhibitor of oncogenic Src CSK. These findings are among the first to demonstrate biomarkers as well as pathways that can identify those likely to benefit from the dietary intervention with reduced colon polyp recurrence.