Role of premalignant lesion and its significance in the promotion/progssion stage of colon carcinogenesis in Apc min mice.

众所周知，Apc min小鼠主要在小肠中发生肠肿瘤，但结肠中的数量较少。在以前的研究中，我们已经确定了一些微腺瘤的存在下，在结肠中的Apc min小鼠，并表明Apc的杂合性丢失被发现在大多数这样的微腺瘤。这些发现表明Apc洛缺失是微腺瘤发生的原因，但对结肠肿瘤的发生并不充分。为了确定参与癌发生的促进/进展阶段的改变，我们进行了突变分析，并检查了Apc min小鼠结肠肿瘤中蛋白质表达的变化。在该模型中，未检测到人类结肠癌中常见的基因改变，如K-ras、p53和B-raf基因突变或微卫星不稳定性，表明该模型的肿瘤发生过程与大多数人类癌症不同。然而，许多癌症相关蛋白的表达模式，如PLK 1，Aurora A，细胞周期蛋白D1，Smad 4和MGMT，这些蛋白通过免疫染色鉴定，与人类结肠癌中的表达模式相似，表明小鼠和人类之间改变的表达相似。进一步的分析正在使用转基因小鼠模型，结合Apc min等位基因进行。

It is well known that Apc min mice develop intestinal tumors predominantly in the small intestine, but less number in the colon. In previous studies, we have identified the presence of a number of microadenomas in the colon of Apc min mice and showed that loss of heterozygosity of Apc is found in most of such microadenomas. These findings suggest that Apc LOH is responsible for microadenoma development, but is not sufficient for colon tumorigenesis. In order to identify alterations involved in promotion/progression stages of the carcinogenesis, we have performed mutational analysis and examined changes of protein expression in the colon tumors of Apc min mice. None of genetic alterations which are frequently found in human colon cancers, such as K-ras, p53 and B-raf gene mutations or microsatellite instability is not detectable at colon tumors in this model, suggesting that tumorigenesis process of this model is different from that of most human cancers. However, patterns of expression of many cancer-related proteins, such as PLK1, Aurora A, cyclin D1, Smad4, and MGMT which are identified by immunostainings are similar to those in human colon cancers, indicating the similarity of altered expressions between mice and humans. Further analyses are going on using genetically modified mouse models, combined with Apc min allele.