Murdoch Children's Research Institute, The Royal Children's Hospital , Parkville, Victoria , Australia.
Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University , Kanazawa , Japan.
Am J Physiol Gastrointest Liver Physiol. 2019 Feb 1;316(2):G251-G262. doi: 10.1152/ajpgi.00304.2018. Epub 2018 Dec 6.
Expression of the cytokine IL-11 is elevated in human Helicobacter pylori infection and progressively increases with worsening gastric pathology. Additionally, IL-11 is required for tumor development in STAT3-dependent murine models of gastric cancer (GC) and, when administered acutely, causes resolving atrophic gastritis. However, it is unclear whether locally elevated IL-11 ligand expression can, in isolation from oncogenic gp130-JAK-STAT pathway mutations, initiate GC pathogenesis. Here we developed a transgenic mouse model of stomach-specific (keratin 19 promoter) IL-11 ligand overexpression. Keratin 19 promoter-IL-11 transgenic ( K19-IL11) mice showed specific IL-11 overexpression in gastric corpus and antrum but not elsewhere in the gastrointestinal tract or in other tissues. K19-IL11 mice developed spontaneous premalignant disease of the gastric epithelium, progressing from atrophic gastritis to TFF2-positive metaplasia and severe epithelial hyperplasia, including adenoma-like lesions in a subset of older (1 yr old) animals. Although locally advanced, the hyperplastic lesions remained noninvasive. H. pylori infection in K19-IL11 mice accelerated some aspects of the premalignant phenotype. Finally, K19-IL11 mice had splenomegaly in association with elevated serum IL-11, with spleens showing an expanded myeloid compartment. Our results provide direct in vivo functional evidence that stomach-specific overexpression of IL-11, in isolation from germline gp130-JAK-STAT3 genetic drivers, is sufficient for premalignant progression. These findings have important functional implications for human GC, in which frequent IL-11 overexpression occurs in the reported absence of somatic mutations in gp130 signaling components. NEW & NOTEWORTHY We provide direct in vivo functional evidence that stomach-specific overexpression of the cytokine IL-11, in isolation from gp130-JAK-STAT3 pathway mutations, can trigger spontaneous atrophic gastritis progressing to locally advanced epithelial hyperplasia (but not dysplasia or carcinoma), which does not require, but may be accelerated by, concomitant Helicobacter pylori infection.
白细胞介素-11 (IL-11) 的表达在人类幽门螺杆菌感染中升高，并随着胃病理恶化而逐渐增加。此外，IL-11 是 STAT3 依赖性胃癌 (GC) 小鼠模型肿瘤发展所必需的，并且在急性给药时可导致萎缩性胃炎消退。然而，尚不清楚局部升高的 IL-11 配体表达是否可以在不伴有致癌 gp130-JAK-STAT 途径突变的情况下，单独引发 GC 发病机制。在这里，我们开发了一种胃特异性（角蛋白 19 启动子）IL-11 配体过表达的转基因小鼠模型。角蛋白 19 启动子-IL-11 转基因 (K19-IL11) 小鼠胃体和胃窦特异性表达 IL-11，但胃肠道其他部位或其他组织中没有表达。K19-IL11 小鼠自发发生胃上皮的癌前病变，从萎缩性胃炎进展为 TFF2 阳性化生和严重的上皮增生，包括一部分老年（1 岁）动物中出现腺瘤样病变。尽管病变局部进展，但仍为非侵袭性。K19-IL11 小鼠感染幽门螺杆菌加速了癌前表型的某些方面。最后，K19-IL11 小鼠脾肿大，同时血清 IL-11 升高，脾脏显示扩大的髓系细胞区室。我们的结果提供了直接的体内功能证据，表明胃特异性过表达 IL-11，与生殖系 gp130-JAK-STAT3 遗传驱动因素分离，足以促进癌前进展。这些发现对人类 GC 具有重要的功能意义，其中在报道的 gp130 信号传导成分无体细胞突变的情况下，经常过表达 IL-11。
