Retrospective Study
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World J Gastrointest Pathophysiol. Aug 15, 2014; 5(3): 366-372
Published online Aug 15, 2014. doi: 10.4291/wjgp.v5.i3.366
Cancer stem cells in Helicobacter pylori infection and aging: Implications for gastric carcinogenesis
Edi Levi, Paula Sochacki, Nabiha Khoury, Bhaumik B Patel, Adhip PN Majumdar
Edi Levi, Paula Sochacki, Nabiha Khoury, Bhaumik B Patel, Adhip PN Majumdar, Department of Veterans Affairs, John D Dingell VA Medical Center, Wayne State University, Detroit, MI 48201, United States
Edi Levi, Pathology, Wayne State University, Detroit, MI 48201, United States
Bhaumik B Patel, Adhip PN Majumdar, Karmanos Cancer Center, Wayne State University, Detroit, MI 48201, United States
Adhip PN Majumdar, Departments of Internal Medicine, Wayne State University, Detroit, MI 48201, United States
Author contributions: Levi E and Patel BB performed the experiments and wrote the manuscript; Sochacki P and Khoury N evaluated the slides, verified the diagnoses and scored the immunohistochemical stains, they also participated in the drafting of the manuscript; Majumdar APN participated in the design, evaluation of data and writing the manuscript.
Supported by Grants to Dr. Majumdar from NIH/NIA, No. AG014343; and the Department of Veterans Affairs (VA Merit Review)
Correspondence to: Adhip PN Majumdar, PhD, DSc, Department of Veterans Affairs, John D Dingell VA Medical Center, 4646 John R, Room B-4238, Detroit, MI 48201, United States. majumdar@med.wayne.edu
Telephone: +1-313-5764460 Fax: +1-313-5761112
Received: November 2, 2013
Revised: April 3, 2014
Accepted: May 8, 2014
Published online: August 15, 2014
Abstract

AIM: To demonstrated the combined effects of aging and carcinogen treatment on cancer stem/stem-like cells (CSCs) of gastric mucosa in an animal model.

METHODS: In this study we investigated the effects of aging and Helicobacter pylori (H. pylori) inflammation as a model for inflammation induced carcinogenesis in human and rat gastric mucosa samples. In aging studies, we compared 4-mo old (young) with 22 mo (aged) old Fischer-344 rats. For human studies, gastric biopsies and resection specimens representing normal mucosa or different stages of H. pylori gastritis and gastric adenocarcinomas were used for determining the expression of stem cell markers CD166, ALDH1 and LGR5. In addition we performed immunofluorescent double labeling for B-catenin and Lgr5 in both rat and human gastric tissues to examine the status of Wnt signaling in these cells.

RESULTS: CSC markers ALDH1, LGR5, and CD166 were expressed in very low levels in normal human gastric mucosa or young rat gastric mucosa. In contrast, level of expression for all three markers significantly increased in H. pylori gastritis and gastric adenocarcinomas as well as in normal gastric mucosa in aged rats. We also observed cytoplasmic B-catenin staining in both aged rat and human H. pylori inflamed gastric mucosa, which were found to be colocalized with Lgr5 immunoreactive cells. The increased number of ALDH1, CD166 and LGR5 positive cells in H. pylori gastritis indicates that increased number of stem-like cells in gastric mucosa is an early event, and may constitute an important step in the progression to neoplasia.

CONCLUSION: Our observation of the age-related increase in cancer stem/stem-like cells in the gastric mucosa may explain the increased incidence of gastric cancer during aging. Combination of aging and H. pylori infection may have additive effects in progression to neoplasia.

Keywords: Cancer stem cells, Aging, CD166, ALDH1, LGR5, Gastric cancer, Helicobacter pylori

Core tip: In this study we demonstrated an age-related increase in cancer stem/stem-like cells (CSCs) in normal appearing gastric mucosa with activated Wnt signaling. In addition, we have shown that gastric infection by Helicobacter pylori (H. pylori) induces an increase in CSC population in the gastric mucosa. Based on our observations we believe that aging and chronic inflammation with H. pylori are two significant factors that overlap and presumably exacerbate each other in gastric carcinogenesis.