Long-Term Helicobacter pylori Infection Switches Gastric Epithelium Reprogramming towards Cancer Stem Cell-Related Differentiation Program in Hp-Activated Gastric Fibroblast-TGFβ Dependent Manner
Open Access
- 2 October 2020
- journal article
- research article
- Published by MDPI AG in Microorganisms
- Vol. 8 (10), 1519
- https://doi.org/10.3390/microorganisms8101519
Abstract
Helicobacter pylori (Hp)-induced inflammatory reaction leads to a persistent disturbance of gastric mucosa and chronic gastritis evidenced by deregulation of tissue self-renewal and local fibrosis with the crucial role of epithelial–mesenchymal transition (EMT) in this process. As we reported before, Hp activated gastric fibroblasts into cells possessing cancer-associated fibroblast properties (CAFs), which secreted factors responsible for EMT process initiation in normal gastric epithelial RGM1 cells. Here, we showed that the long-term incubation of RGM1 cells in the presence of Hp-activated gastric fibroblast (Hp-AGF) secretome induced their shift towards plastic LGR5+/Oct4high/Sox-2high/c-Mychigh/Klf4low phenotype (l.t.EMT+RGM1 cells), while Hp-non-infected gastric fibroblast (GF) secretome prompted a permanent epithelial–myofibroblast transition (EMyoT) of RGM1 cells favoring LGR−/Oct4high/Sox2low/c-Myclow/Klf4high phenotype (l.t.EMT−RGM1 cells). TGFβ1 rich secretome from Hp-reprogrammed fibroblasts prompted phenotypic plasticity and EMT of gastric epithelium, inducing pro-neoplastic expansion of post-EMT cells in the presence of low TGFβR1 and TGFβR2 activity. In turn, TGFβR1 activity along with GF-induced TGFβR2 activation in l.t.EMT−RGM1 cells prompted their stromal phenotype. Collectively, our data show that infected and non-infected gastric fibroblast secretome induces alternative differentiation programs in gastric epithelium at least partially dependent on TGFβ signaling. Hp infection-activated fibroblasts can switch gastric epithelium microevolution towards cancer stem cell-related differentiation program that can potentially initiate gastric neoplasm.Keywords
Funding Information
- Narodowe Centrum Nauki (2018/02/X/NZ3/00276)
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