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Bone Marrow-Derived Stem Cells in Pathogenesis ofHelicobacter Pylori-Associated Gastric Cancer

Yaghoobi, Mohammad1

Clinical and Translational Gastroenterology: September 2015 - Volume 6 - Issue 9 - p e110
doi: 10.1038/ctg.2015.35
Translational Medicine: Bench to Bedside
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Bone marrow-derived stem cells (BMSCs) are now believed to be the progenitors in the development of gastric cancer in patients with chronic infection withHelicobacter pylori. However, the mechanism of recruitment and malignant transformation of these cells has not been completely understood. Here I will discuss selected findings on how BMSCs compromise local immunity and skip local defense mechanisms in order to undergo malignant transformation. In addition, the role of C-X-C chemokine receptor type 4 through binding to its ligand stromal-derived factor in migration of BMSCs in mouse model of gastric cancer will be looked at. These findings are important in understanding the pathogenesis ofH. pylori-associated gastric cancer and to develop new diagnostic and therapeutic modalities.

1Division of Gastroenterology, McMaster University, Hamilton, Ontario, Canada

Correspondence: M Yaghoobi, MD, MSc, AFS, FRCPC, Division of Gastroenterology, McMaster University Medical Center, 1280 Main Street West, Rm-3V3, Hamilton, Ontario L8S 4K1, Canada. E-mail: yaghoob@mcmaster.ca

published online 10 September 2015

Helicobacter pylori is the most common infection worldwide and nearly half of world population is infected with this microorganism. Multiple cohort studies and meta-analyses clearly showed a link between this infection and risk of gastric cancer.1 On the basis of this evidence, World Health Organization classified H. pylori as level I carcinogen in 1994.2 It had long been believed that chronic infection ends in transformation of epithelial cells to premalignant cells due to hyperproliferation and mitotic error, causing metaplasia, dysplasia and eventually adenocarcinoma. However, recent studies have shown that the nature of this transformation might not be the same as what was previously believed. Recent developments in understanding the carcinogenesis of gastric cancer showed that bone marrow-derived stem cells (BMSCs), which are recruited in the course of chronic infection with H. pylori, rather than somatic epithelial cells, may gain clonal advantage and undergo stepwise transformation to malignant cells.3, 4 This theory could also explain the currently believed heterogeneity among tumor cells as one could expect monoclonal tumor cells if they originated from one somatic cell. However, the mechanism of recruitment of these cells and their transformation to premalignant and malignant cells has not been well scrutinized.

In a promising in vivo and in vitro study by Lin and colleagues, the authors inoculated 50 female mice with H. pylori.5 After 10 months, male-donor BMSCs were transplanted to the sub-serousal area of stomach tissue in the case group (n=25). The control group (n=25) only received culture media with no BMSCs. At 3 and 28 days, BMSCs migrated to the muscular layer and mucosal layer, respectively. The investigators then extracted splenic mononuclear cells at 52 weeks and showed higher level of IL-10 secreting CD4+ T cells in cases as compared to controls. In their in vitro experiment, they measured candidate cytokines in four different media environment, all containing splenic monocular and gastric epithelial cells, as follow: no added cell (control); BMSCs; ultrasonic crushing of H. pylori; and ultrasonic crushing of H. pylori and BMSCs. They showed a higher quantity of IL-10 and tumor growth factor-β1 (TGF-β1) as well as IL-10 secreting T cells and CD4+ CD25+ Foxp3+ T (Treg) cells in splenic mononuclear cells in the media containing H. pylori and BMSCs as compared to the media with only H. pylori or BMSCc.

In another interesting in vitro study, Fakhari and colleagues tried to understand the role of C-X-C chemokine receptor type 4 (CXCR4) through binding to its ligand stromal-derived factor (SDF-1) in migration of BMSCs in mouse model of gastric cancer.6 SDF-1 and its receptor, CXCR4, have an important role in retention and engraftment of hematopoietic stem cells within the bone marrow.7 The investigators first isolated and cultured vacA+H. pylori. Gastric epithelial cell line, human gastric adenocarcinoma cell line, and BMSC cell line were concurrently cultured with H. pylori for 24 h. The expression of CXCR4 was measured by quantitative reverse transcription polymerase chain reaction and flow cytometry. SDF-1 expression in human gastric adenocarcinoma cells was detected by quantitative reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay. Migration of BMSCs toward SDF-1 was evaluated by chemotaxis assay. The investigators found that the CXCR4 is expressed in BMSCs and showed that H. pylori infection significantly upregulated its expression (3.6-fold; P<0.035). The migration of H. pylori-treated BMSC toward SDF-1 gradient was significantly higher than untreated cells (1.8-fold; P<0.03). They showed that H. pylori infection increases CXCR4 expression in BMSCs and provides a better response to SDF-1 gradient. In addition, H. pylori infection enhanced SDF-1 secretion by gastric epithelial cells, indicating that H. pylori infection increases the communication between gastric epithelial cells and BMSCs through acting on the SDF-1/CXCR4 axis.

The study by Lin et al. showed that BMSCs, which are recruited to the site of the chronic H. pylori infection, act both locally and systematically to compromise cancer immunosurveillance system. This could explain how these cells skip local immunity during malignant transformation. It also carries a potentially important clinical implication. Currently, transplant of BMSCs is considered as an experimental treatment in some post-organ transplant patients to induce immunosuppression. On the basis of the findings of this study, malignancy could be a hypothetical risk in such treatments, given these cells might theoretically end up in the epithelium of other organs including stomach and predispose to malignant transformation mainly in the presence of H. pylori infection.

The study by Fakhari et al showed that chronic infection by H. pylori causes overexpression of SDF-1 in gastric epithelial cells. This may explain the affinity of gastric epithelium, which possesses a high level of CXCR4 in response to H. pylori infection, for BMSCs. This knowledge maybe used in developing diagnostic methods, including new biomarkers involved in this pathway, to detect H. pylori-associated gastric cancer or potentially other types of cancer. However, it is premature to conclude the future application of the current data as animal and human studies are required to confirm similar results in an in vivo environment. Then clinical studies are needed to show if the blockage of the SDF-1/CXCR4 pathway would inhibit tumor growth or metastasis and/or could cause regression of cancer. It should also be noted that there are likely other unexplored molecular pathways involved in the recruitment of BMSCs into the gastric epithelium given this is a new entity in scrutinizing the carcinogenesis of H. pylori.

On the other hand, these findings could be also used in developing new chemotherapeutic agents targeting new receptors. It is currently believed that BMSCs are the origin of the tumor cells explaining the polyclonal nature of cancer cells as discussed before. The absence of homogeneous cell population in tumor tissue explains the lack of complete response to current chemotherapeutic agents since they are targeting a particular pathway, which may not exist in all tumor cells. Targeting BMSCs could potentially stop their further differentiation into tumor cells and the growth of the tumor and therefore prevent metastatic disease and/or relapse of the primary tumor.

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CONFLICT OF INTEREST

Guarantorof the article: Mohammad Yaghoobi, MD, MSc, AFS, FRCPC.

Financial support: None.

Potential competing interests:None.

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© 2015 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology