2）形態的特徴と比較した早期大腸癌の発生・発育進展―遺伝子異常─文献考察

Molecular Analysis of Carcinogenesis and Metastasis in Early Colorectal Carcinomas, in Comparison with Histopathology ; Review

要旨　早期大腸癌の発生・進展に関する最近の分子病理学的文献を紹介した．その中で以下を示した．（1）早期大腸癌をSM浸潤距離と簇出を組み合わせることでリンパ節転移高危険群の抽出が可能なこと，（2）E-cadherinなどの接着関連因子の減弱が転移と相関する，またある種のサイトカインの極性の変化もまた転移と関係する，（3）T. Tn細胞から生まれた転移性細胞株との比較で両者にわずかな遺伝子異常しかないことと種々の細胞膜に存在するサイトカインらが転写活性を上げることなどがわかった，（4）平坦型癌はras遺伝子の関与が少なく，同じ傾向がLST-NGにもみられ，平坦という組織学的な共通性がK-ras遺伝子変異の頻度に反映していると考えられた，（5）大腸癌においてp53の異常はその調整遺伝子の解析からみてほとんどの癌でp53遺伝子システムが異常であることがわかった，（6）動物実験モデルでp53ホモノックアウトにおいて平坦型癌が作製できた，（7）IBD cancerにおいてER遺伝子のメチル化やDNMT-1を解析することで癌化高危険群の検出に有効であることがわかった，（8）鋸歯状病変の細分類においてSSA/Pの認識が施設によって異なることがわかった，などである．分子病理学的な知識が一般化することで日常医療に役立つ可能性を示した．

　In this article, we present recent reviews regarding the molecular analysis of carcinogenesis and metastasis in early colorectal carcinoma in comparison with histopathology. Our conclusions are as follows ;（1）When invasive SM colorectal carcinomas were divided into＜1,000μm（slight）and≧1,000μm（massive）, lymph node metastasis was found in more than 30% of massive cases with positive budding/sprouting（grade 2 and 3）,（2）The attenuated membranous expression of E-cadherin is associated with readiness for SM invasion and metastasis. Flat-type early colorectal carcinomas are more invasive than polyp types,（3）We subcloned cells that easily infiltrate in vitro by using T.Tn cells that were basically less likely to metastasize and attempted to transplant these 2 types of cells into animal models by using orthotopic transplantation. Having empirically confirmed that one cell-type metastasized, other differences were found in gene expression. On the basis of these profiles, investigations have been made into some genes from the perspective of metastatic potential. For example, the expression patterns of the gene encoding CXCR4, one of the cytokines, have been found in cancer lesions with 5-year survival rates in both esophageal and colorectal cancer,（4）A flat cancer（de novo cancer）is rarely related to K-ras genes, and defects in the p53 cancer suppressor gene and local inflammation backgrounds were considered important in a series of experiments,（5）Nagative immunohistochemical staining of p53 protein does not always reflect wild-type p53 gene in cancer cells,（6）The establishment and application of genetic diagnosis is desirable for clinical approaches for early detection and treatment, especially for screening high-risk patients who's genetic makeup may lead to ulcerative colitis-associated tumors. The analysis of the ER gene methylation and DNMT-1 is a useful marker for identifying individuals at increased risk of neoplasia among those with longstanding and extensive UC,（7）Sessile serrated adenoma/polyp（SSA/P）is known as one of the giant hyperplastic polyps and as a serrated polyp with abnormal proliferation. Definitions are : Abnormal proliferation（dysmaturation）, architectural distortion（dilation and branching extending to the crypt base）and lack of overt dysplasia. Distinct molecular abnormalities are the high frequency of DNA methylation at CpG islands and BRAF-mutations（rather than K-ras）. Analysis of molecular pathology may help us to select suitable treatment options and accurate diagnosis of colorectal carcinomas. To settle these issues further studies, based on the concepts of niches for cancer stem cells, need to be carried out.