Pre-treatment of human umbilical cord-derived mesenchymal stem cells with interleukin-6 abolishes their growth-promoting effect on gastric cancer cells

Wang,Mei; Cai,Jie; Huang,Feng; Zhu,Mengchu; Zhang,Qiang; Yang,Tingting; Zhang,Xu; Qian,Hui; Xu,Wenrong

doi:10.3892/ijmm.2014.2019

Pre-treatment of human umbilical cord-derived mesenchymal stem cells with interleukin-6 abolishes their growth-promoting effect on gastric cancer cells

Authors:
- Mei Wang
- Jie Cai
- Feng Huang
- Mengchu Zhu
- Qiang Zhang
- Tingting Yang
- Xu Zhang
- Hui Qian
- Wenrong Xu
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Affiliations: Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, The Affiliated Hospital, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
Published online on: December 2, 2014 https://doi.org/10.3892/ijmm.2014.2019
Pages: 367-375
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

The inflammatory microenvironment contributes to cancer development and progression. Mesenchymal stem cells (MSCs), as important stromal cells, may be ‘educated’ by the inflammatory microenvironment to support the development of gastric cancer. Cytokines are a key component of cancer-related inflammation. Interleukin (IL)-6, as an inflammatory cytokine, has multiple roles in cancer. However, whether MSCs can be ‘educated’ by IL-6 to support gastric cancer remains unknown. In the present study, we focused on the phenotype and function of human umbilical cord-derived MSCs hUC‑MSCs pre-treated with IL-6 in gastric cancer. We found that the protein levels of α-smooth muscle actin (α-SMA) were upregulated, and phosphorylated nuclear factor (NF)-κB protein levels were downregulated in the hUC‑MSCs pre-treated with IL-6, as shown by western blot analysis. The levels of tumor‑promoting cytokines, including chemokine (C-C motif) ligand 5 (CCL5), platelet-derived growth factor‑BB (PDGF‑BB), monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor α(TNFα), were markedly reduced in the hUC‑MSCs following treatment with IL-6, as shown by RT-qPCR. In in vitro experiments, we co-cultured MSCs with N-methyl‑N'‑nitro‑N‑nitrosoguanidine (MNNG)‑transformed GES-1 gastric epithelial cells or SGC-7901 gastric cancer cells. Transwell and colony-forming cell assays revealed that the hUC-MSCs significantly promoted gastric cellular migration and proliferation. However, following treatment with IL-6, the hUC-MSCs had no growth-promoting effect on the gastric epithelial cells and gastric cancer cells. In in vivo experiments, we co-transplanted MSCs and SGC-7901 cells into nude mice in order to establish a nude mouse model of gastric cancer. The hUC-MSCs significantly promoted the growth gastric tumors through the promotion of cell proliferation and the inhibition of cell apoptosis. On the contrary, pre-treatment with IL-6 provided the hUC‑MSCs with the ability to inhibit cell proliferation and significantly induce cell apoptosis. Taken together, our findings indicate that pre-treatment with IL-6 significantly abolishes the ability of hUC-MSCs to promote gastric epithelial cell proliferation and migration and provide new insight into the effects of the inflammatory cytokine, IL-6, on the tumor-promoting ability of MSCs and its role in gastric cancer.

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1	Whiteside TL: The tumor microenvironment and its role in promoting tumor growth. Oncogene. 27:5904–5912. 2008. View Article : Google Scholar : PubMed/NCBI
2	Candido J and Hagemann T: Cancer-related inflammation. J Clin Immunol. 33:S79–S84. 2013. View Article : Google Scholar
3	Landskron G, De la Fuente M, Thuwajit P, Thuwajit C and Hermoso MA: Chronic inflammation and cytokines in the tumor microenvironment. J Immunol Res. 2014(149185): 2014
4	Allavena P, Garlanda C, Borrello MG, Sica A and Mantovani A: Pathways connecting inflammation and cancer. Curr Opin Genet Dev. 18:3–10. 2008. View Article : Google Scholar : PubMed/NCBI
5	Yang X, Hou J, Han Z, Wang Y, Hao C, Wei L and Shi Y: One cell, multiple roles: contribution of mesenchymal stem cells to tumor development in tumor microenvironment. Cell Biosci. 3(5): 2013
6	Barcellos-de-Souza P, Gori V, Bambi F and Chiarugi P: Tumor microenvironment: bone marrow-mesenchymal stem cells as key players. Biochim Biophys Acta. 1836.321–335. 2013.
7	Cao H, Xu W, Qian H, et al: Mesenchymal stem cell-like cells derived from human gastric cancer tissues. Cancer Lett. 274:61–71. 2009. View Article : Google Scholar
8	Xu X, Zhang X, Wang S, et al: Isolation and comparison of mesenchymal stem-like cells from human gastric cancer and adjacent non-cancerous tissues. J Cancer Res Clin Oncol. 137:495–504. 2011. View Article : Google Scholar
9	Wang M, Zhao C, Shi H, et al: Deregulated microRNAs in gastric cancer tissue-derived mesenchymal stem cells: novel biomarkers and a mechanism for gastric cancer. Br J Cancer. 110:1199–1210. 2014. View Article : Google Scholar : PubMed/NCBI
10	Al-toub M, Almusa A, Almajed M, Al-Nbaheen M, Kassem M, Aldahmash A and Alajez NM: Pleiotropic effects of cancer cells’ secreted factors on human stromal mesenchymal stem cells. Stem Cell Res Ther. 4(114): 2013
11	Ren G, Liu Y, Zhao X, et al: Tumor resident mesenchymal stromal cells endow naïve stromal cells with tumor-promoting properties. Oncogene. 33:4016–4020. 2013. View Article : Google Scholar
12	Gu J, Qian H, Shen L, et al: Gastric cancer exosomes trigger differentiation of umbilical cord derived mesenchymal stem cells to carcinoma-associated fibroblasts through TGF-beta/Smad pathway. PLoS One. 7:e524652012. View Article : Google Scholar
13	Zhang Q, Wang M, Huang F, et al: 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
14	Yang T, Zhang X, Wang M, et al: Activation of mesenchymal stem cells by macrophages prompts human gastric cancer growth through NF-κB pathway. PLoS One. 9:e975692014. View Article : Google Scholar
15	Mantovani A, Allavena P, Sica A and Balkwill F: Cancer-related inflammation. Nature. 454:436–444. 2008. View Article : Google Scholar : PubMed/NCBI
16	Qi Y, Zhang M, Li H, et al: Autophagy inhibition by sustained over-production of IL-6 contributes to arsenic-induced carcinogenesis. Cancer Res. 74:3740–3752. 2014. View Article : Google Scholar : PubMed/NCBI
17	Naugler WE, Sakurai T, Kim S, Maeda S, Kim K, Elsharkawy AM and Karin M: Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science. 317:121–124. 2007. View Article : Google Scholar : PubMed/NCBI
18	Kinoshita H, Hirata Y, Nakagawa H, et al: Interleukin-6 mediates epithelial-stromal interactions and promotes gastric tumorigenesis. PLoS One. 8:e609142013. View Article : Google Scholar : PubMed/NCBI
19	Tsai KS, Yang SH, Lei YP, et al: Mesenchymal stem cells promote formation of colorectal tumors in mice. Gastroenterology. 141:1046–1056. 2011. View Article : Google Scholar : PubMed/NCBI
20	Rattigan Y, Hsu JM, Mishra PJ, Glod J and Banerjee D: Interleukin 6 mediated recruitment of mesenchymal stem cells to the hypoxic tumor milieu. Exp Cell Res. 316:3417–3424. 2010. View Article : Google Scholar : PubMed/NCBI
21	Sung SY, Liao CH, Wu HP, et al: Loss of let-7 microRNA upregulates IL-6 in bone marrow-derived mesenchymal stem cells triggering a reactive stromal response to prostate cancer. PLoS One. 8:e716372013. View Article : Google Scholar : PubMed/NCBI
22	Qiao C, Xu W, Zhu W, et al: Human mesenchymal stem cells isolated from the umbilical cord. Cell Biol Int. 32:8–15. 2008. View Article : Google Scholar
23	Studeny M, Marini FC, Dembinski JL, et al: Mesenchymal stem cells: potential precursors for tumor stroma and targeteddelivery vehicles for anticancer agents. J Natl Cancer Inst. 96:1593–1603. 2004. View Article : Google Scholar : PubMed/NCBI
24	Spaeth EL, Dembinski JL, Sasser AK, et al: Mesenchymal stem cell transition to tumor-associated fibroblasts contributes to fibrovascular network expansion and tumor progression. PLoS One. 4:e49922009. View Article : Google Scholar : PubMed/NCBI
25	Ren G, Zhao X, Wang Y, et al: CCR2-dependent recruitment of macrophages by tumor-educated mesenchymal stromal cells promotes tumor development and is mimicked by TNFα. Cell Stem Cell. 11:812–824. 2012. View Article : Google Scholar : PubMed/NCBI
26	Goldstein RH, Reagan MR, Anderson K, Kaplan DL and Rosenblatt M: Human bone marrow-derived MSCs can home to orthotopic breast cancer tumors and promote bone metastasis. Cancer Res. 70:10044–10050. 2010. View Article : Google Scholar : PubMed/NCBI
27	Brighenti E, Calabrese C, Liguori G, Giannone FA, Trerè D, Montanaro L and Derenzini M: Interleukin 6 downregulates p53 expression and activity by stimulating ribosome biogenesis: a new pathway connecting inflammation to cancer. Oncogene. Feb 17–2014. View Article : Google Scholar : PubMed/NCBI
28	Polanska UM and Orimo A: Carcinoma-associated fibroblasts: non-neoplastic tumour-promoting mesenchymal cells. J Cell Physiol. 228:1651–1657. 2013. View Article : Google Scholar : PubMed/NCBI
29	Karnoub AE, Dash AB, Vo AP, et al: Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature. 449:557–563. 2007. View Article : Google Scholar : PubMed/NCBI
30	Mi Z, Bhattacharya SD, Kim VM, Guo H, Talbot LJ and Kuo PC: Osteopontin promotes CCL5-mesenchymal stromal cell-mediated breast cancer metastasis. Carcinogenesis. 32:477–487. 2011. View Article : Google Scholar : PubMed/NCBI
31	Mitra AK, Zillhardt M, Hua Y, Tiwari P, Murmann AE, Peter ME and Lengyel E: MicroRNAs reprogram normal fibroblasts into cancer-associated fibroblasts in ovarian cancer. Cancer Discov. 2:1100–1108. 2012. View Article : Google Scholar : PubMed/NCBI
32	Guilloton F, Caron G, Ménard C, et al: Mesenchymal stromal cells orchestrate follicular lymphoma cell niche through the CCL2-dependent recruitment and polarization of monocytes. Blood. 119:2556–2567. 2012. View Article : Google Scholar : PubMed/NCBI
33	Kulbe H, Thompson R, Wilson JL, et al: The inflammatory cytokine tumor necrosis factor-alpha generates an autocrine tumor-promoting network in epithelial ovarian cancer cells. Cancer Res. 67:585–592. 2007. View Article : Google Scholar : PubMed/NCBI
34	Xue Y, Lim S, Yang Y, et al: PDGF-BB modulates hematopoiesis and tumor angiogenesis by inducing erythropoietin production in stromal cells. Nat Med. 18:100–110. 2011. View Article : Google Scholar : PubMed/NCBI
35	Karin M and Greten FR: NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol. 5:749–759. 2005. View Article : Google Scholar : PubMed/NCBI