Helicobacter pylori-infected MSCs acquire a pro-inflammatory phenotype and induce human gastric cancer migration by promoting EMT in gastric cancer cells

Zhang,Qiang; Ding,Juan; Liu,Jinjun; Wang,Wei; Zhang,Feng; Wang,Junhe; Li,Yuyun

doi:10.3892/ol.2015.3897

Helicobacter pylori-infected MSCs acquire a pro-inflammatory phenotype and induce human gastric cancer migration by promoting EMT in gastric cancer cells

Authors:
- Qiang Zhang
- Juan Ding
- Jinjun Liu
- Wei Wang
- Feng Zhang
- Junhe Wang
- Yuyun Li
View Affiliations

Affiliations: Department of Clinical Laboratory Science, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, P.R. China, Department of Clinical Laboratory, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
Published online on: November 10, 2015 https://doi.org/10.3892/ol.2015.3897
Pages: 449-457

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Accumulating clinical and experimental evidence has suggested that Helicobacter pylori (H. pylori) infection‑associated gastric cancer (GC) is associated with high rates of mortality and serious health effects. The majority of patients succumb to H. pylori infection‑associated GC due to metastasis. Mesenchymal stem cells (MSCs), which have multipotent differentiation potential, may be recruited into the tumor‑associated stroma. MSCs are crucial components of the H. pylori infection‑associated GC microenvironment, and may be critical for GC cell migration. In this study, an MSCs/H. pylori co‑culture model was designed, and the effect of H. pylori‑infected MSCs on the migration of GC cells was evaluated using a Transwell migration assay. H. pylori‑infected MSC cytokine expression was evaluated using Luminex/ELISA. The expression of epithelial‑mesenchymal transition (EMT) markers in the GC cells treated with supernatants from H. pylori‑infected MSCs were detected by western blot analysis. The results demonstrated that the interaction between MSCs and H. pylori may induce GC cell migration, through secretion of a combination of cytokines that promote EMT in GC cells. The expression of phosphorylated forms of nuclear factor-κB (NF-κB) was observed to be increased in MSCs by H. pylori. Inhibition of NF‑κB activation by pyrrolidine dithiocarbamate blocked the effects of H. pylori‑infected MSCs on SGC‑7901 human stomach adenocarcinoma cell migration. Overall, the results of the present study suggest that H. pylori‑infected MSCs acquire a pro‑inflammatory phenotype through secretion of a combination of multiple cytokines, a number of which are NF‑κB‑dependent. These cytokines enhance H. pylori infection-associated GC cell migration by promoting EMT in GC cells. The results of the present study provide novel evidence for the modulatory effect of MSCs in the tumor microenvironment and provide insight into the significance of stromal cell involvement in GC progression.

View Figures

View References

1	Liu GM, Zhou C, Xie C, Yang Z and Lv NH: Recent advances in research of gastric cancer stem cells. World Chinese Journal of Digestology. 7:574–579. 2012.(In Chinese).
2	Lee YY and Derakhshan MH: Environmental and lifestyle risk factors of gastric cancer. Arch Iran Med. 16:358–365. 2013.PubMed/NCBI
3	Lee KE, Khoi PN, Xia Y, Park JS, Joo YE, Kim KK, Choi SY and Jung YD: Helicobacter pylori and interleukin-8 in gastric cancer. World J Gastroenterol. 19:8192–8202. 2013. View Article : Google Scholar : PubMed/NCBI
4	Taylor MA, Parvani JG and Schiemann WP: The pathophysiology of epithelial-mesenchymal transition induced by transforming growth factor-beta in normal and malignant mammary epithelial cells. J Mammary Gland Biol Neoplasia. 15:169–190. 2010. View Article : Google Scholar : PubMed/NCBI
5	Nitta T, Mitsuhashi T, Hatanaka Y, Miyamoto M, Oba K, Tsuchikawa T, Suzuki Y, Hatanaka KC, Hirano S and Matsuno Y: Prognostic significance of epithelial-mesenchymal transition-related markers in extrahepatic cholangiocarcinoma: Comprehensive immunohistochemical study using a tissue microarray. Br J Cancer. 111:1363–1372. 2014. View Article : Google Scholar : PubMed/NCBI
6	Thiery JP, Acloque H, Huang RY and Nieto MA: Epithelial-mesenchymal transitions in development and disease. Cell. 139:871–890. 2009. View Article : Google Scholar : PubMed/NCBI
7	Kim MA, Lee HS, Lee HE, Kim JH, Yang HK and Kim WH: Prognostic importance of epithelial-mesenchymal transition-related protein expression in gastric carcinoma. Histopathology. 54:442–451. 2009. View Article : Google Scholar : PubMed/NCBI
8	Cao H, Xu W, Qian H, Zhu W, Yan Y, Zhou H, Zhang X and Xu X, Li J, Chen Z and Xu X: Mesenchymal stem cell-like cells derived from human gastric cancer tissues. Cancer Lett. 274:61–71. 2009. View Article : Google Scholar : PubMed/NCBI
9	Schäffler A and Büchler C: Concise review: Adipose tissue-derived stromal cells - basic and clinical implications for novel cell-based therapies. Stem Cells. 25:818–827. 2007. View Article : Google Scholar : PubMed/NCBI
10	Sasaki M, Abe R, Fujita Y, Ando S, Inokuma D and Shimizu H: Mesenchymal stem cells are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type. J Immunol. 180:2581–2587. 2008. View Article : Google Scholar : PubMed/NCBI
11	Spaeth E, Klopp A, Dembinski J, Andreeff M and Marini F: Inflammation and tumor microenvironments: Defining the migratory itinerary of mesenchymal stem cells. Gene Ther. 15:730–738. 2008. View Article : Google Scholar : PubMed/NCBI
12	Quante M, Tu SP, Tomita H, Gonda T, Wang SS, Takashi S, Baik GH, Shibata W, Diprete B, Betz KS, et al: Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. Cancer Cell. 19:257–272. 2011. View Article : Google Scholar : PubMed/NCBI
13	Glaire MA, El-Omar EM, Wang TC and Worthley DL: The mesenchyme in malignancy: A partner in the initiation, progression and dissemination of cancer. Pharmacol Ther. 136:131–141. 2012. View Article : Google Scholar : PubMed/NCBI
14	Taichman RS, Wang Z, Shiozawa Y, Jung Y, Song J, Balduino A, Wang J, Patel LR, Havens AM, Kucia M, et al: Prospective identification and skeletal localization of cells capable of multilineage differentiation in vivo. Stem Cells Dev. 19:1557–1570. 2010. View Article : Google Scholar : PubMed/NCBI
15	Houghton J, Stoicov C, Nomura S, Rogers AB, Carlson J, Li H, Cai X, Fox JG, Goldenring JR and Wang TC: Gastric cancer originating from bone marrow-derived cells. Science. 306:1568–1571. 2004. View Article : Google Scholar : PubMed/NCBI
16	Ferrand J, Lehours P, Schmid-Alliana A, Mégraud F and Varon C: Helicobacter pylori infection of gastrointestinal epithelial cells in vitro induces mesenchymal stem cell migration through an NF-κB-dependent pathway. PLoS One. 6:e290072011. View Article : Google Scholar : PubMed/NCBI
17	Qiao C, Xu W, Zhu W, Hu J, Qian H, Yin Q, Jiang R, Yan Y, Mao F, Yang H, et al: Human mesenchymal stem cells isolated from the umbilical cord. Cell Biol Int. 32:8–15. 2008. View Article : Google Scholar : PubMed/NCBI
18	Zhang Q, Wang M, Huang F, Yang T, Cai J, Zhang X, Zhu W, Qian H and Xu W: H. pylori infection-induced MSC differentiation into CAFs promotes epithelial-mesenchymal transition in gastric epithelial cells. Int J Mol Med. 32:1465–1473. 2013.PubMed/NCBI
19	Yang T, Zhang X, Wang M, Zhang J, Huang F, Cai J, Zhang Q, Mao F, Zhu W, Qian H and Xu W: Activation of mesenchymal stem cells by macrophages prompts human gastric cancer growth through NF-κB pathway. PLoS One. 9:e975692014. View Article : Google Scholar : PubMed/NCBI
20	Zhou H, Sheng L, Wang H, Xie H, Mu Y, Wang T and Yan J: Anti-β2GPI/β2GPI stimulates activation of THP-1 cells through TLR4/MD-2/MyD88 and NF-κB signaling pathways. Thromb Res. 132:742–749. 2013. View Article : Google Scholar : PubMed/NCBI
21	Wang M, Cai J, Huang F, Zhu M, Zhang Q, Yang T, Zhang X, Qiang H and Xu W: Pre-treatment of human umbilical cord-derived mesenchymal stem cells with interleukin-6 abolishes their growth-promoting effect on gastric cancer cells. Int J Mol Med. 35:367–375. 2015.PubMed/NCBI
22	Okabe C, Borges RL, de Almeida DC, Fanelli C, Barlette GP, Machado FG, Arias SC, Malheiros DM, Camara NO, Zatz R and Fujihara CK: NF-κB activation mediates crystal translocation and interstitial inflammation in adenine overload nephropathy. Am J Physiol Renal Physiol. 305:F155–F163. 2013. View Article : Google Scholar : PubMed/NCBI
23	Zhang J, Jiang W and Zuo Z: Pyrrolidine dithiocarbamate attenuates surgery-induced neuroinflammation and cognitive dysfunction possibly via inhibition of nuclear factor κB. Neuroscience. 261:1–10. 2014. View Article : Google Scholar : PubMed/NCBI
24	Chan J, O'Donoghue K, de la Fuente J, Roberts IA, Kumar S, Morgan JE and Fisk NM: Human fetal mesenchymal stem cells as vehicles for gene delivery. Stem Cells. 23:93–102. 2005. View Article : Google Scholar : PubMed/NCBI
25	Korkaya H, Liu S and Wicha MS: Breast cancer stem cells, cytokine networks, and the tumor microenvironment. J Clin Invest. 121:3804–3809. 2011. View Article : Google Scholar : PubMed/NCBI
26	Shinagawa K, Kitadai Y, Tanaka M, Sumida T, Kodama M and Higashi Y: Tanaka S, Yasui W and Chayama K: Mesenchymal stem cells enhance growth and metastasis of colon cancer. Int J Cancer. 127:2323–2333. 2010. View Article : Google Scholar : PubMed/NCBI
27	Yu JM, Jun ES, Bae YC and Jung JS: Mesenchymal stem cells derived from human adipose tissues favor tumor cell growth in vivo. Stem Cells Dev. 17:463–473. 2008. View Article : Google Scholar : PubMed/NCBI
28	Steeg PS: Tumor metastasis: Mechanistic insights and clinical challenges. Nat Med. 12:895–904. 2006. View Article : Google Scholar : PubMed/NCBI
29	Christiansen JJ and Rajasekaran AK: Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. Cancer Res. 66:8319–8326. 2006. View Article : Google Scholar : PubMed/NCBI
30	Kalluri R and Weinberg RA: The basics of epithelial-mesenchymal transition. J Clin Invest. 119:1420–1428. 2009. View Article : Google Scholar : PubMed/NCBI
31	Folkman J: Role of angiogenesis in tumor growth and metastasis. Semin Oncol. 29:15–18. 2002. View Article : Google Scholar : PubMed/NCBI
32	Grant CM and Kyprianou N: Epithelial mesenchymal transition (EMT) in prostate growth and tumor progression. Transl Androl Urol. 2:202–211. 2013.PubMed/NCBI
33	Christiansen JJ and Raiasekaran AK: Reassessing epithelial to mesenchymal transition as prerequisite for carcinoma invasion and metastasis. Cancer Res. 66:8319–8326. 2006. View Article : Google Scholar : PubMed/NCBI
34	Tye H and Jenkins BJ: Tying the knot between cytokine and toll-like receptor signaling in gastrointestinal tract cancers. Cancer Sci. 104:1139–1145. 2013. View Article : Google Scholar : PubMed/NCBI