Genetic abnormality in flat type colorectal cancer

Vogelstein等人提出的结直肠癌发生的多步骤模型是基于腺瘤-癌序列；肿瘤进化过程中最重要的事件被认为是致癌基因（如ras基因突变）和胶原溶解因子的激活，肿瘤抑制基因（如p53、apc、dcc）的功能丧失和粘附分子的功能障碍。k-ras基因和cox-2的激活与肿瘤异型性和肿瘤大小的增加有关，并且被认为在结直肠癌发生的相对早期阶段参与。这些数据主要基于对息肉样腺瘤和癌症的分析。然而，我们的报告显示扁平或抑郁肿瘤没有或很少有k-ras突变，肿瘤细胞中没有cox-2过表达。这表明结直肠肿瘤的发生有一些不同的遗传途径。具有蜂窝状表面的扁平型癌可能是一种新的肿瘤，其发展途径与具有硫代或中间型表面的癌不同，可能是新发癌的候选者。在结直肠癌的免疫组化中，检测到p53蛋白的高水平存在和粘附分子表达的减少与肿瘤的侵袭性相关。组织蛋白酶D的表达增加也是易侵袭性结直肠癌的一个特征。本研究认为，遗传分析有助于形态学诊断，解剖显微镜观察结直肠肿瘤表面结构与遗传背景分析之间的相关性可能有助于评估其生长和进展。我们用实验模型证实了这些结果。

The multistep model of colorectal carcinogenesis proposed by Vogelstein et al. is based on adenoma-carcinoma sequence ; the most important events of tumor evolution are recognized to be the activation of oncogenes (i.e., ras gene mutation) and collagenolytic factors, the loss of function of tumor suppressor genes (i.e., p53, apc, dcc) and dysfunction of adhesion molecules. The activations of the k-ras genes and cox-2 are correlated with increased tumor atypia and tumor size, and are thought to be involved at a relatively early stage in colorectal carcinogenesis. These data were based mainly on the analysis of polypoid adenoma and cancer. However, our reports show that flat or depressed tumors have no or few k-ras mutation and no overexpression of cox-2 in tumor cells. These suggest that there are some different genetic pathways for the development of colorectal tumors. Flat type carcinoma with the honeycomb-like type surface might be a new carcinoma which develops via a different pathway than carcinomas with sulciform or intermediate type surface, and might be a candidate of de novo carcinogenesis. In this immunohistochemistry of colorectal carcinomas, the presence of high levels of p53 protein and the decrease of the expression of adhesion molecules are detected in correlation with tumor invasiveness. Increased expression of cathepsin D was also a feature of easily invasive colorectal carcinoma. We concluded in this study that the genetic analysis may help morphologic diagnosis and the correlation between the dissecting microscopic observation of the surface structure of colorectal tumor and the analysis of genetic background may be useful for connection with assessment of their growth and progression. We confirmed these results using experimental models.