Gastritis promotes an activated bone marrow-derived mesenchymal stem cell with a phenotype reminiscent of a cancer-promoting cell.

Abstract

BACKGROUND:

Bone marrow-derived mesenchymal stem cells (BM-MSCs) promote gastric cancer in response to gastritis. In culture, BM-MSCs are prone to mutation with continued passage but it is unknown whether a similar process occurs in vivo in response to gastritis.

AIM:

The purpose of this study was to identify the role of chronic gastritis in the transformation of BM-MSCs leading to an activated cancer-promoting phenotype.

METHODS:

Age matched C57BL/6 (BL/6) and gastrin deficient (GKO) mice were used for isolation of stomach, serum and mesenchymal stem cells (MSCs) at 3 and 6 months of age. MSC activation was assessed by growth curve analysis, fluorescence-activated cell sorting and xenograft assays. To allow for the isolation of bone marrow-derived stromal cells and assay in response to chronic gastritis, IRG/Vav-1(Cre) mice that expressed both enhanced green fluorescent protein-expressing hematopoietic cells and red fluorescent protein-expressing stromal cells were generated. In a parabiosis experiment, IRG/Vav-1(Cre) mice were paired to either an uninfected Vav-1(Cre) littermate or a BL/6 mouse inoculated with Helicobacter pylori.

RESULTS:

GKO mice displayed severe atrophic gastritis accompanied by elevated gastric tissue and circulating transforming growth factor beta (TGFβ) by 3 months of age. Compared to BM-MSCs isolated from uninflamed BL/6 mice, BM-MSCs isolated from GKO mice displayed an increased proliferative rate and elevated phosphorylated-Smad3 suggesting active TGFβ signaling. In xenograft assays, mice injected with BM-MSCs from 6-month-old GKO animals displayed tumor growth. RFP+ stromal cells were rapidly recruited to the gastric mucosa of H. pylori parabionts and exhibited changes in gene expression.

CONCLUSIONS:

Gastritis promotes the in vivo activation of BM-MSCs to a phenotype reminiscent of a cancer-promoting cell.

• Authors: Jessica M Donnelly, Amy C Engevik, Melinda Engevik, Michael A Schumacher, Chang Xiao, Li Yang, Roger T Worrell, Yana Zavros
• Journal: Digestive diseases and sciences (Dig Dis Sci) Vol. 59 Issue 3 Pg. 569-82 (Mar 2014) ISSN: 1573-2568 [Electronic] United States
• PMID: 24202649 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Gastrins
• Hedgehog Proteins
• Smad3 Protein
• Smad3 protein, mouse
• Transforming Growth Factor beta

Topics

• Animals
• Biomarkers (metabolism)
• Cell Proliferation
• Cell Transformation, Neoplastic
• Gastric Mucosa (metabolism, microbiology, pathology)
• Gastrins (deficiency)
• Gastritis, Atrophic (metabolism, microbiology, pathology)
• Hedgehog Proteins (metabolism)
• Helicobacter Infections (pathology)
• Helicobacter pylori
• Immunoblotting
• Mesenchymal Stem Cells (metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Parabiosis
• Phenotype
• Real-Time Polymerase Chain Reaction
• Smad3 Protein (metabolism)
• Transforming Growth Factor beta (metabolism)