Helicobacter pylori evolution during progression from chronic atrophic gastritis to gastric cancer and its impact on gastric stem cells
Helicobacter pylori evolution during progression from chronic atrophic gastritis to gastric cancer and its impact on gastric stem cells
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DOI：
10.1073/pnas.0800668105
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发表时间：
2008-03-18
影响因子：
11.1
通讯作者：
Gordon, Jeffrey I.
中科院分区：
文献类型：
--
作者：
Giannakis, Marios;Chen, Swaine L.;Gordon, Jeffrey I.
我们的特点是适应幽门螺杆菌很少捕获的事件在其对宿主生物学的影响的演变-从慢性萎缩性胃炎（ChAG）的胃腺癌的过渡-并确定了这些适应的影响，一个有趣的，但不好的特点之间的相互作用，这种细菌和胃上皮干细胞。细菌分离株从一个单一的人类宿主与一个单一的优势菌株之前和之后，他从ChAG进展到胃腺癌在4年的时间间隔。从两个分离株产生基因组装配草图，一个与ChAG相关，另一个与癌症相关。癌症相关菌株不太适合人类ChAG的gnotobiotic转基因小鼠模型，并且能够更好地在支持细菌附着的小鼠胃上皮祖细胞衍生细胞系（mGEP）中建立自身。基于GeneChip的mGEPs和对照小鼠胃上皮细胞系的转录组比较显示，在感染后，癌症相关菌株以不同于ChAG相关分离株的方式调节GEPs相关信号传导和代谢途径以及与人类胃癌发展相关的肿瘤抑制基因的表达。预计对GEP代谢途径的影响（其中一些已在知菌小鼠中得到证实）以及观察到的细菌转录组变化将支持该微生物与胃干细胞之间的内共生关系的各个方面。这些结果提供了关于H.幽门螺杆菌可能适应并影响干细胞生物学，以及其细胞内驻留如何有助于胃肿瘤发生。
We have characterized the adaptations of Helicobacter pylori to a rarely captured event in the evolution of its impact on host biology-the transition from chronic atrophic gastritis (ChAG) to gastric adenocarcinoma-and defined the impact of these adaptations on an intriguing but poorly characterized interaction between this bacterium and gastric epithelial stem cells. Bacterial isolates were obtained from a single human host colonized with a single dominant strain before and after his progression from ChAG to gastric adenocarcinoma during a 4-year interval. Draft genome assemblies were generated from two isolates, one ChAG-associated, the other cancer-associated. The cancer-associated strain was less fit in a gnotobiotic transgenic mouse model of human ChAG and better able to establish itself within a mouse gastric epithelial progenitor-derived cell line (mGEP) that supports bacterial attachment. GeneChip-based comparisons of the transcriptomes of mGEPs and a control mouse gastric epithelial cell line revealed that, upon infection, the cancer-associated strain regulates expression of GEP-associated signaling and metabolic pathways, and tumor suppressor genes associated with development of gastric cancer in humans, in a manner distinct from the ChAG-associated isolate. The effects on GEP metabolic pathways, some of which were confirmed in gnotobiotic mice, together with observed changes in the bacterial transcriptome are predicted to support aspects of an endosymbiosis between this microbe and gastric stem cells. These results provide insights about how H. pylori may adapt to and influence stem cell biology and how its intracellular residency could contribute to gastric tumorigenesis.