Inserm, UMR837, Jean-Pierre Aubert Research Center, Team 5 "Mucins, epithelial differentiation and carcinogenesis", Lille, France; Université Lille Nord de France, Lille, France; Department of Digestive and Oncological Surgery, University Hospital Claude Huriez, Centre Hospitalier Régional et Universitaire de Lille, Lille, France.
Surgery. 2013 Nov;154(5):955-67. doi: 10.1016/j.surg.2013.05.029. Epub 2013 Sep 29.
The mechanisms of esophageal reflux leading to esophageal adenocarcinoma (EA) remain poorly understood. This study appraises critically an operatively induced chronic reflux rat model.
We randomized 108 Sprague-Dawley rats into 2 experimental groups; one was performing esophagoduodenal (ED) anastomosis with or without gastrectomy to induce duodeno-esophageal reflux (DER group; n = 63), and the other involved duodeno-gastro-esophageal reflux (DGER group; n = 45). Control groups included (i) Roux-en-Y esophagojejunal anastomosis, (ii) laparotomy alone, (iii) subtotal gastrectomy to induce duodenogastric reflux (DGR group), and (iv) the same procedure as in the DGER group plus proton pump inhibition (PPI group). The esophagus underwent histologic and molecular analyses.
The prevalence of Barrett's esophagus (BE), dysplasia, and EA in the experimental groups was 41%, 7%, and 11%, respectively. Histologic and molecular analyses in groups DER, DGER, and DGR suggested that BE occurred through de novo intestinal metaplasia and proximal migration of duodenal cells. No distant metastases were identified. The molecular characteristics of both BE and EA were similar to humans. BE was more common, and dysplasia and EA less frequent in the DER group when compared with the DGER group (44% vs 24% [P = .038] and 7% vs 25% [P = .012], respectively). Compared with the DGER group, carcinogenic sequence occurred less frequently in the PPI-treated group (P = .019).
Despite pathophysiologic differences with humans, the rat model of esophagoduodenostomy reproduces accurately histologic and molecular lesions in the carcinogenetic sequence of BE and allowed us to identify novel, tumor-associated proteins that may be potential biomarkers and new therapeutic targets in EA.
导致食管腺癌（EA）的食管反流机制仍知之甚少。本研究批判性评估了一种经手术诱导的慢性反流大鼠模型。
我们将 108 只 Sprague-Dawley 大鼠随机分为 2 个实验组；一组进行食管-十二指肠（ED）吻合术，同时或不进行胃切除术以诱导十二指肠胃反流（DER 组；n = 63），另一组进行十二指肠胃食管反流（DGER 组；n = 45）。对照组包括：（i）Roux-en-Y 食管空肠吻合术，（ii）单纯剖腹术，（iii）胃大部切除术以诱导十二指肠胃反流（DGR 组），和（iv）与 DGER 组相同的手术加质子泵抑制剂（PPI 组）。对食管进行组织学和分子分析。
实验组 BE、异型增生和 EA 的患病率分别为 41%、7%和 11%。DER、DGER 和 DGR 组的组织学和分子分析表明，BE 通过新生肠化生和十二指肠细胞的近端迁移发生。未发现远处转移。BE 和 EA 的分子特征与人相似。与 DGER 组相比，DER 组的 BE 更为常见，异型增生和 EA 更为少见（44% vs 24% [P =.038] 和 7% vs 25% [P =.012]）。与 DGER 组相比，PPI 治疗组致癌序列发生的频率较低（P =.019）。
尽管与人类在病理生理学上存在差异，但食管-十二指肠吻合术大鼠模型准确地再现了 BE 致癌序列中的组织学和分子病变，并使我们能够识别出可能成为 EA 潜在生物标志物和新治疗靶点的新型肿瘤相关蛋白。
