Humar Bostjan, Fukuzawa Ryuji, Blair Vanessa, Dunbier Anita, More Helen, Charlton Amanda, Yang Han Kwang, Kim Woo Ho, Reeve Anthony E, Martin Iain, Guilford Parry
Cancer Genetics Laboratory, Department of Biochemistry, University of Otago, Dunedin, New Zealand.
Cancer Res. 2007 Mar 15;67(6):2480-9. doi: 10.1158/0008-5472.CAN-06-3021.
The initial development of diffuse gastric cancer (DGC) is poorly understood. The study of E-cadherin (CDH1) germ line mutation carriers predisposed to DGC provides a rare opportunity to elucidate the genetic and biological events surrounding disease initiation. Samples from various stages of hereditary and sporadic DGC were investigated to determine general mechanisms underlying early DGC development. Paraffin-embedded tissues from 13 CDH1 mutation carriers and from 10 sporadic early DGC cases were analyzed. Immunofluorescence and immunohistochemistry using differentiation, proliferation, and adhesion markers showed that DGC initiation seems to occur at the proliferative zone (the upper neck) of the gastric epithelium and correlates with absent or reduced expression of junctional proteins (beta-actin, p120, Lin-7). Slow proliferation of neoplastic cells at the upper gastric neck leads to the formation of intramucosal signet-ring cell carcinoma (SRCC) displaying differentiated features. As shown by immunolabeling, invasion from SRCC lesions beyond the gastric mucosa is associated with poor differentiation, increased proliferation, activation of the c-Src system, and an epithelial-mesenchymal transition. Our results provide a molecular description of the early development of DGC and explain the relationship between the two main DGC types, poorly differentiated carcinoma and SRCC: both share their origin, but SRCC develops following cancer cell differentiation and seems relatively indolent in its intramucosal stage.
弥漫性胃癌（DGC）的初始发展过程目前仍知之甚少。对易患DGC的E-钙黏蛋白（CDH1）种系突变携带者的研究，为阐明疾病起始周围的遗传和生物学事件提供了难得的机会。我们对遗传性和散发性DGC不同阶段的样本进行了研究，以确定DGC早期发展的一般机制。分析了来自13名CDH1突变携带者和10例散发性早期DGC病例的石蜡包埋组织。使用分化、增殖和黏附标记物进行免疫荧光和免疫组织化学分析显示，DGC的起始似乎发生在胃上皮的增殖区（上颈部），并且与连接蛋白（β-肌动蛋白、p120、Lin-7）表达缺失或减少相关。胃上颈部肿瘤细胞的缓慢增殖导致形成具有分化特征的黏膜内印戒细胞癌（SRCC）。免疫标记显示，SRCC病变从胃黏膜向外浸润与低分化、增殖增加以及c-Src系统激活和上皮-间质转化有关。我们的研究结果对DGC的早期发展进行了分子层面的描述，并解释了两种主要DGC类型，即低分化癌和SRCC之间的关系：它们起源相同，但SRCC是在癌细胞分化后发展而来，并且在其黏膜内阶段似乎相对惰性。
