Authors
1 Kurdistan Molecular & Cellular Research Center, Kurdistan University of Medical Sciences, Sanadaj, Iran
2 Department of Microbiology, Faculty of Medicine, Alborz University of Medical Sciences, Karaj, Iran
3 Department of Physiology, Isfahan Payamnoor University, Isfahan, Iran
Abstract
Background: Recent studies have demonstrated that during chronic Helicobacter pylori (H. pylori) infection bone marrow-derived-mesenchymal stem cells (BMD-MSCs) migrate to the gastric tissue and could be also the origin of gastric adenocarcinoma. The chemokine receptor CXCR4 through binding to its ligand stromal-derived factor (SDF-1) plays a crucial role in migration of inflammatory and stem cells. However, the possible effect of H. pylori infection on the SDF-1/CXCR4 axis has not yet been elucidated.
Materials and Methods: Gastric epithelial cell line, AGS, and BMD-MSCs were cocultured with H. pylori for 24 h. The expression of CXCR4 was examined in BMD-MSCs by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and flow cytometry, and SDF-1 expression in AGS cells was detected by qRT-PCR and enzyme-linked immunosorbent assay. Further, migration of BMD-MSCs toward SDF-1 was evaluated by chemotaxis assay.
Results: We found that coculture of H. pylori with BMD-MSCs or AGS: (i) enhanced CXCR4 expression on the cell surface of BMD-MSCs and (ii) increased SDF-1 secretion by AGS cells. Consistently, we observed that H. pylori-treated BMD-MSCs showed a higher capability to migrate toward SDF-1 gradient compared with untreated cells.
Conclusion: We found that H. pylori upregulates CXCR4 expression in BMD-MSCs and enhance their migration toward SDF-1. This study provides the first evidence that H. pylori infection may enhance BMD-MSCs migration through acting on the SDF-1/CXCR4 axis.
Keywords
1. | Jang BG, Kim WH. Molecular pathology of gastric carcinoma. Pathobiology 2011;78:302-10. |
2. | Kuipers EJ. Review article: Exploring the link between Helicobacter pylori and gastric cancer. Aliment Pharmacol Ther 1999;1:3-11. |
3. | Peek RM Jr., Fiske C, Wilson KT. Role of innate immunity in Helicobacter pylori-induced gastric malignancy. Physiol Rev 2010;90:831-58. |
4. | Yasui W, Sentani K, Motoshita J, Nakayama H. Molecular pathobiology of gastric cancer. Scand J Surg 2006;95:225-31. |
5. | Hatakeyama M. Helicobacter pylori CagA - A bacterial intruder conspiring gastric carcinogenesis. Int J Cancer 2006;119:1217-23. |
6. | Kabir S. Effect of Helicobacter pylori eradication on incidence of gastric cancer in human and animal models: Underlying biochemical and molecular events. Helicobacter 2009;14:159-71. |
7. | Farinati F, Cardin R, Cassaro M, Bortolami M, Nitti D, Tieppo C, et al. Helicobacter pylori, inflammation, oxidative damage and gastric cancer: A morphological, biological and molecular pathway. Eur J Cancer Prev 2008;17:195-200. |
8. | Houghton J, Stoicov C, Nomura S, Rogers AB, Carlson J, Li H, et al. Gastric cancer originating from bone marrow-derived cells. Science 2004;306:1568-71. |
9. | Hutchinson L, Stenstrom B, Chen D, Piperdi B, Levey S, Lyle S, et al. Human Barrett's adenocarcinoma of the esophagus, associated myofibroblasts, and endothelium can arise from bone marrow-derived cells after allogeneic stem cell transplant. Stem Cells Dev 2011;20:11-7. |
10. | Tirode F, Laud-Duval K, Prieur A, Delorme B, Charbord P, Delattre O. Mesenchymal stem cell features of Ewing tumors. Cancer Cell 2007;11:421-9. |
11. | Li HC, Stoicov C, Rogers AB, Houghton J. Stem cells and cancer: Evidence for bone marrow stem cells in epithelial cancers. World J Gastroenterol 2006;12:363-71. |
12. | Ingersoll MA, Platt AM, Potteaux S, Randolph GJ. Monocyte trafficking in acute and chronic inflammation. Trends Immunol 2011;32:470-7. |
13. | Sun L, Ye RD. Role of G protein-coupled receptors in inflammation. Acta Pharmacol Sin 2012;33:342-50. |
14. | Liekens S, Schols D, Hatse S. CXCL12-CXCR4 axis in angiogenesis, metastasis and stem cell mobilization. Curr Pharm Des 2010;16:3903-20. |
15. | Zlotnik A, Burkhardt AM, Homey B. Homeostatic chemokine receptors and organ-specific metastasis. Nat Rev Immunol 2011;11:597-606. |
16. | Zlotnik A. New insights on the role of CXCR4 in cancer metastasis. J Pathol 2008;215:211-3. |
17. | Duda DG, Kozin SV, Kirkpatrick ND, Xu L, Fukumura D, Jain RK. CXCL12 (SDF1α-CXCR4/CXCR7 pathway inhibition: An emerging sensitizer for anticancer therapies? Clin Cancer Res 2011;17:2074-80. |
18. | Liu H, Liu S, Li Y, Wang X, Xue W, Ge G, et al. The role of SDF-1-CXCR4/CXCR7 axis in the therapeutic effects of hypoxia-preconditioned mesenchymal stem cells for renal ischemia/reperfusion injury. PLoS One 2012;7:e34608. |
19. | Cronin PA, Wang JH, Redmond HP. Hypoxia increases the metastatic ability of breast cancer cells via upregulation of CXCR4. BMC Cancer 2010;10:225. |
20. | Lazennec G, Richmond A. Chemokines and chemokine receptors: New insights into cancer-related inflammation. Trends Mol Med 2010;16:133-44. |
21. | Zhao C, Lu X, Bu X, Zhang N, Wang W. Involvement of tumor necrosis factor-α in the upregulation of CXCR4 expression in gastric cancer induced by Helicobacter pylori. BMC Cancer 2010;10:1471-2407. |
22. | Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 2008;3:1101-8. |
23. | Jalili A, Shirvaikar N, Marquez-Curtis L, Qiu Y, Korol C, Lee H, et al. Fifth complement cascade protein (C5) cleavage fragments disrupt the SDF-1/CXCR4 axis: further evidence that innate immunity orchestrates the mobilization of hematopoietic stem/progenitor cells. Exp Hematol 2010;38:321-32. |
24. | Son BR, Marquez-Curtis LA, Kucia M, Wysoczynski M, Turner AR, Ratajczak J, et al. Migration of bone marrow and cord blood mesenchymal stem cells in vitro is regulated by stromal-derived factor-1-CXCR4 and hepatocyte growth factor-c-met axes and involves matrix metalloproteinases. Stem Cells 2006;24:1254-64. |
25. | Iwasa S, Yanagawa T, Fan J, Katoh R. Expression of CXCR4 and its ligand SDF-1 in intestinal-type gastric cancer is associated with lymph node and liver metastasis. Anticancer Res 2009;29:4751-8. |
26. | Peled A, Grabovsky V, Habler L, Sandbank J, Arenzana-Seisdedos F, Petit I, et al. The chemokine SDF-1 stimulates integrin-mediated arrest of CD34(+) cells on vascular endothelium under shear flow. J Clin Invest 1999;104:1199-211. |
27. | Xia XM, Wang FY, Xu WA, Wang ZK, Liu J, Lu YK, et al. CXCR4 antagonist AMD3100 attenuates colonic damage in mice with experimental colitis. World J Gastroenterol 2010;16:2873-80. |
28. | Dotan I, Werner L, Vigodman S, Weiss S, Brazowski E, Maharshak N, et al. CXCL12 is a constitutive and inflammatory chemokine in the intestinal immune system. Inflamm Bowel Dis 2010;16:583-92. |
29. | Shibata W, Ariyama H, Westphalen CB, Worthley DL, Muthupalani S, Asfaha S, et al. Stromal cell-derived factor-1 overexpression induces gastric dysplasia through expansion of stromal myofibroblasts and epithelial progenitors. Gut 2013;62:192-200. |
30. | Ferrand J, Lehours P, Schmid-Alliana A, Mégraud F, Varon C. Helicobacter pylori infection of gastrointestinal epithelial cells in vitro induces mesenchymal stem cell migration through an NF- K B-dependent pathway. PLoS One 2011;6:e29007. |
31. | Summers C, Rankin SM, Condliffe AM, Singh N, Peters AM, Chilvers ER. Neutrophil kinetics in health and disease. Trends Immunol 2010;31:318-24. |
32. | Petit I, Szyper-Kravitz M, Nagler A, Lahav M, Peled A, Habler L, et al. G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nat Immunol 2002;3:687-94. |
33. | Avital I, Moreira A, Downey RJ. The origin of epithelial neoplasms after allogeneic stem cell transplantation. Haematologica 2006;91:ELT07; author reply ELT06. |
34. | Okumura T, Wang SS, Takaishi S, Tu SP, Ng V, Ericksen RE, et al. Identification of a bone marrow-derived mesenchymal progenitor cell subset that can contribute to the gastric epithelium. Lab Invest 2009;89:1410-22. |
35. | Hu C, Yong X, Li C, Lü M, Liu D, Chen L, et al. CXCL12/CXCR4 axis promotes mesenchymal stem cell mobilization to burn wounds and contributes to wound repair. J Surg Res 2013;183:427-34. |