Obesity and Dietary Pathways Leading to Colon Cancer

结肠癌是美国癌症死亡的第二大原因，在肥胖人群中，发生结肠癌的风险增加2倍，这是任何肥胖相关癌症风险增加最多的人群之一。该项目的目标是证明结肠癌风险的增加与肥胖本身有关，而不是 随着膳食脂肪摄入量的增加，阐明增加的IGF 1信号传导作为肥胖相关结肠癌风险增加的介导物的作用，并进一步鉴定其在人结肠内的表达被肥胖和被改变的IGF 1信号传导改变的关键基因。该项目是基于我们的C57bl/6衍生的染色体取代小鼠品系的独特开发，当将其放置在小鼠体内时，其是肥胖敏感的或肥胖抵抗的。 高脂饮食，以及我们小组的独特发现，即由于PIK3CA（IGF1信号的早期转导子）的突变激活，在坦率的结肠癌中IGF1信号的突变激活。我们的具体研究将是：i）当这些小鼠被工程化以携带肠肿瘤诱导APC突变Min等位基因时，比较高脂肪饮食在对该饮食变得肥胖的小鼠（肥胖敏感性）与不发展肥胖的小鼠（肥胖抵抗性）中的肠肿瘤促进作用。ii）使用表达微阵列来鉴定其在肠中的表达受肥胖调节的那些小鼠基因，即其表达仅在肥胖敏感小鼠中受高脂肪饮食调节而在肥胖抵抗小鼠中不受高脂肪饮食调节的基因。为了进一步确定这些肥胖调节基因中的哪一个在来自肥胖与非肥胖人类的结肠上皮的微阵列比较中表现出改变的表达。iii）构建转基因小鼠，其中活化的突变PIK3CA基因被特异性靶向以在肠中表达。此外，通过比较携带该转基因的肥胖小鼠与非肥胖小鼠中的肿瘤发展，以确定激活的IGF 1/PIK3CA途径信号传导的肿瘤促进作用是否与肥胖的肿瘤促进作用是上位性的（在相同的途径中），或者是独立的。iv）比较来自肥胖与非肥胖的正常人结肠粘膜中IGF 1信号传导的活化 通过使用定量免疫组织化学比较这些组织中关键IGF1激活的信号分子：IGF1R、AKT和mTOR的磷酸化水平，此外，为了鉴定其在小鼠肠中的表达被增加的IGF1/PI3KCA信号传导改变的那些基因，并且为了进一步鉴定改变的基因表达的这种"IGF1信号传导特征"是否在肥胖小鼠结肠中基因表达的微阵列比较中得到证实， 与非肥胖人群的对比。

Colon cancer is the second leading cause of cancer death in the U.S., and in the obese population the risk of developing colon cancer is elevated by 2-fold, which is among the largest increases in risk seen for any obesity associated cancer. The goals of this project are to demonstrate that increased colon cancer risk is associated with obesity per se, and not with increased dietary fat intake, to elucidate the role of increased IGF1 signaling as a mediator of the obesity associated increased colon cancer risk, and to further identify key genes whose expression within the human colon is altered by obesity and by altered IGF1 signaling. This project is based on the unique development by our group of C57bl/6 derived chromosome substituted mouse strains that are either obesity sensitive or obesity resistant when placed on a high fat diet, and also on the unique finding by our group of mutational activation of IGF1 signaling in frank colon cancers due to mutational activation of PIK3CA, an early transducer of IGF1 signaling. Our specific studies will be: i) To compare the intestinal tumor promoting effects of high fat diet in mice that become obese on this diet (obesity sensitive) versus mice that do not develop obesity (obesity resistant), when these mice are engineered to carry the intestinal tumor inducing APC mutant Min allele. ii) To employ expression microarrays to identify those mouse genes whose expression in the intestine is regulated by obesity, that is genes whose expression is modulated by a high fat diet only in obesity sensitive, but not in obesity resistant mice. To further identify which of these obesity regulated genes demonstrates altered expression in a microarray comparison of colonic epithelium from obese versus non-obese humans. iii) To construct transgenic mice in which an activated mutant PIK3CA gene is specifically targeted for expression in the intestine. Further, by comparing tumor development in obese versus non-obese mice carrying this transgene, to determine whether the tumor promoting effect of activated IGF1/PIK3CA pathway signaling is epistatic with (in the same pathway with), or is independent of the tumor promoting effects of obesity. iv) To compare the activation of IGF1 signaling in normal human colon mucosa from obese versus non-obese individuals by using quantitative immunohisochemistry to compare in these tissues the levels of phosphorylation of key IGF1 activated signaling molecules: IGF1R, AKT and mTOR. Moreover, to identify those genes whose expression in the mouse intestine is altered by increased IGF1/PI3KCA signaling, and to further identify if this "IGF1 signaling signature" of altered gene expression is evidenced on microarray comparison of gene expression in the colons of obese versus non-obese humans.