Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Gut. 2012 Mar;61(3):344-53. doi: 10.1136/gutjnl-2011-300050. Epub 2011 Aug 24.
Gastric cancer is the second most frequent cause of death from cancer in the world, diffuse-type gastric cancer (DGC) exhibiting a poor prognosis. Germline mutations of CDH1, encoding E-cadherin, have been reported in hereditary DGC, and genetic and/or epigenetic alterations of CDH1 are frequently detected in sporadic DGC. Genetic alterations of TP53 are also frequently found in DGC. To examine the synergistic effect of the loss of E-cadherin and p53 on gastric carcinogenesis, a mouse line was established in which E-cadherin and p53 are specifically inactivated in the stomach parietal cell lineage.
Atp4b-Cre mice were crossed with Cdh1(loxP/loxP) and Trp53(loxP/loxP) mice, and the gastric phenotype of Atp4b-Cre(+);Cdh1(loxP/loxP);Trp53(loxP/loxP) double conditional knockout (DCKO) mice was examined.
Non-polarised E-cadherin-negative parietal cells and proton pump-negative atypical foci were observed in DCKO mice. Intramucosal cancers and invasive cancers composed of poorly differentiated carcinoma cells and signet ring cells, histologically very similar to those in humans, were found from 6 to 9 months, respectively. Fatal DGC developed at 100% penetrance within a year, frequently metastasised to lymph nodes, and had tumourigenic activity in immunodeficient mice. Gene expression profiles of DGC in DCKO mice also resembled those of human DGC, and mesenchymal markers and epithelial-mesenchymal transition-related genes were highly expressed in mouse DGC as in human DGC.
This mouse line is the first genetically engineered mouse model of DGC and is very useful for clarifying the mechanism underlying gastric carcinogenesis, and provides a new approach to the treatment and prevention of DGC.
胃癌是全球癌症死亡的第二大常见原因，弥漫型胃癌（DGC）预后较差。CDH1 基因胚系突变已在遗传性 DGC 中报道，而 CDH1 的遗传和/或表观遗传改变在散发性 DGC 中经常检测到。TP53 的基因改变也经常在 DGC 中发现。为了研究 E-钙黏蛋白和 p53 缺失对胃癌发生的协同作用，建立了一种在胃壁细胞谱系中特异性失活 E-钙黏蛋白和 p53 的小鼠系。
将 Atp4b-Cre 小鼠与 Cdh1(loxP/loxP)和 Trp53(loxP/loxP)小鼠杂交，检查 Atp4b-Cre(+);Cdh1(loxP/loxP);Trp53(loxP/loxP)双条件敲除（DCKO）小鼠的胃表型。
在 DCKO 小鼠中观察到非极化的 E-钙黏蛋白阴性壁细胞和质子泵阴性非典型灶。从 6 到 9 个月，分别发现了黏膜内癌和侵袭性癌，由分化差的癌细胞和印戒细胞组成，组织学上与人类非常相似。在一年内，100%的 DGC 发生致命性，经常转移到淋巴结，并在免疫缺陷小鼠中具有致瘤活性。DCKO 小鼠的 DGC 基因表达谱也与人类 DGC 相似，间质标志物和上皮-间质转化相关基因在小鼠 DGC 中的表达与人类 DGC 相似。
这种小鼠系是首个弥漫型胃癌的基因工程小鼠模型，非常有助于阐明胃癌发生的机制，并为弥漫型胃癌的治疗和预防提供了新的途径。
