Integrin α4 is involved in the regulation of glioma-induced motility of bone marrow mesenchymal stem cells

Ma,Jiang-Chun; Cheng,Peng; Hu,Yi; Xue,Yi-Xue; Liu,Yun-Hui

doi:10.3892/or.2015.4012

Integrin α4 is involved in the regulation of glioma-induced motility of bone marrow mesenchymal stem cells

Authors:
- Jiang-Chun Ma
- Peng Cheng
- Yi Hu
- Yi-Xue Xue
- Yun-Hui Liu
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Affiliations: Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China, Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China, Neurobiology, College of Basic Medicine, China Medical University, Shenyang, Liaoning 110001, P.R. China
Published online on: May 28, 2015 https://doi.org/10.3892/or.2015.4012
Pages: 779-786

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Abstract

Bone marrow mesenchymal stem cells (BMSCs) have the ability of migrating towards glioma tissue. However, this migratory behavior remains to be elucidated. The aim of this study was to define the role of integrin α4 in the motility of BMSCs towards glioma. The role of integrin α4 in the migration of BMSCs towards glioma was evaluated using an in vitro migration assay with the application of a specific integrin α4‑blocking antibody. The effect of glioma conditioned medium (CM) on the integrin α4 expression level of BMSCs was assessed by RT-PCR, immunocytochemistry and western blot analysis. BAY11-7082, LY294002, SB203580, PD98059 and SP600125 were used to investigate the role of NF-κB, PI3K, p38 MAPK, MEK and JNK in the above process. In addition, the role of NF-κB in the tropism of BMSCs towards glioma was also evaluated using the in vitro model. The migration of BMSCs towards glioma CM was attenuated by blocking integrin α4. The stimulation of glioma CM increased integrin α4 expression of BMSCs. Furthermore, the inhibition of NF-κB and PI3K decreased the glioma-induced integrin α4 upregulation on BMSCs. Inhibition of NF-κB decreased the number of migrating BMSCs towards gliomas. Glioma cells induced the migration of BMSCs by promoting the expression of integrin α4. NF-κB and PI3K contributed to the signal transduction of this process. Similar to PI3K, NF-κB is associated with the regulation of BMSCs migration toward glioma. Thus, these results may be useful to elucidate the mechanism involved in the glioma-induced migration of BMSCs.

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1	Olar A and Aldape KD: Using the molecular classification of glioblastoma to inform personalized treatment. J Pathol. 232:165–177. 2014. View Article : Google Scholar :
2	Jones TS and Holland EC: Standard of care therapy for malignant glioma and its effect on tumor and stromal cells. Oncogene. 31:1995–2006. 2012. View Article : Google Scholar
3	Wen PY and Kesari S: Malignant gliomas in adults. N Engl J Med. 359:492–507. 2008. View Article : Google Scholar : PubMed/NCBI
4	Sasportas LS, Kasmieh R, Wakimoto H, Hingtgen S, van de Water JA, Mohapatra G, Figueiredo JL, Martuza RL, Weissleder R and Shah K: Assessment of therapeutic efficacy and fate of engineered human mesenchymal stem cells for cancer therapy. Proc Natl Acad Sci USA. 106:4822–4827. 2009. View Article : Google Scholar : PubMed/NCBI
5	Murphy AM and Rabkin SD: Current status of gene therapy for brain tumors. Transl Res. 161:339–354. 2013. View Article : Google Scholar :
6	Bexell D, Svensson A and Bengzon J: Stem cell-based therapy for malignant glioma. Cancer Treat Rev. 39:358–365. 2013. View Article : Google Scholar
7	Bexell D, Gunnarsson S, Tormin A, Darabi A, Gisselsson D, Roybon L, Scheding S and Bengzon J: Bone marrow multipotent mesenchymal stroma cells act as pericyte-like migratory vehicles in experimental gliomas. Mol Ther. 17:183–190. 2009. View Article : Google Scholar
8	Kim SM, Woo JS, Jeong CH, Ryu CH, Lim JY and Jeun SS: Effective combination therapy for malignant glioma with TRAIL-secreting mesenchymal stem cells and lipoxygenase inhibitor MK886. Cancer Res. 72:4807–4817. 2012. View Article : Google Scholar : PubMed/NCBI
9	Nakamizo A, Marini F, Amano T, Khan A, Studeny M, Gumin J, Chen J, Hentschel S, Vecil G, Dembinski J, et al: Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas. Cancer Res. 65:3307–3318. 2005.PubMed/NCBI
10	Cheng M and Qin G: Progenitor cell mobilization and recruitment: SDF-1, CXCR4, α4-integrin, and c-kit. Prog Mol Biol Transl Sci. 111:243–264. 2012. View Article : Google Scholar
11	Haanstra KG, Hofman SO, Lopes Estêvão DM, Blezer EL, Bauer J, Yang LL, Wyant T, Csizmadia V, ‘t Hart BA and Fedyk ER: Antagonizing the α4β1 integrin, but not α4β7, inhibits leukocytic infiltration of the central nervous system in rhesus monkey experimental autoimmune encephalomyelitis. J Immunol. 190:1961–1973. 2013. View Article : Google Scholar : PubMed/NCBI
12	Takeichi T, Mocevicius P, Deduchovas O, Salnikova O, Castro-Santa E, Büchler MW, Schmidt J and Ryschich E: αL β2 integrin is indispensable for CD8⁺ T-cell recruitment in experimental pancreatic and hepatocellular cancer. Int J Cancer. 130:2067–2076. 2012. View Article : Google Scholar
13	Couture P, Paradis-Massie J, Oualha N and Thibault G: Adhesion and transcellular migration of neutrophils and B lymphocytes on fibroblasts. Exp Cell Res. 315:2192–2206. 2009. View Article : Google Scholar : PubMed/NCBI
14	Engelhardt B: Molecular mechanisms involved in T cell migration across the blood-brain barrier. J Neural Transm. 113:477–485. 2006. View Article : Google Scholar : PubMed/NCBI
15	Klemke M, Weschenfelder T, Konstandin MH and Samstag Y: High affinity interaction of integrin alpha4beta1 (VLA-4) and vascular cell adhesion molecule 1 (VCAM-1) enhances migration of human melanoma cells across activated endothelial cell layers. J Cell Physiol. 212:368–374. 2007. View Article : Google Scholar : PubMed/NCBI
16	Hu Y, Cheng P, Xue YX and Liu YH: Glioma cells promote the expression of vascular cell adhesion molecule-1 on bone marrow-derived mesenchymal stem cells: a possible mechanism for their tropism toward gliomas. J Mol Neurosci. 48:127–135. 2012. View Article : Google Scholar : PubMed/NCBI
17	Ilina O and Friedl P: Mechanisms of collective cell migration at a glance. J Cell Sci. 122:3203–3208. 2009. View Article : Google Scholar : PubMed/NCBI
18	Hu Y, Cheng P, Ma JC, Xue YX and Liu YH: Platelet-derived growth factor BB mediates the glioma-induced migration of bone marrow-derived mesenchymal stem cells by promoting the expression of vascular cell adhesion molecule-1 through the PI3K, P38 MAPK and NF-κB pathways. Oncol Rep. 30:2755–2764. 2013.PubMed/NCBI
19	Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop Dj and Horwitz E: Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 8:315–317. 2006. View Article : Google Scholar : PubMed/NCBI
20	Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S and Marshak DR: Multilineage potential of adult human mesenchymal stem cells. Science. 284:143–147. 1999. View Article : Google Scholar : PubMed/NCBI
21	Nora CC, Camassola M, Bellagamba B, Ikuta N, Christoff AP, Meirelles LS, Ayres R, Margis R and Nardi NB: Molecular analysis of the differentiation potential of murine mesenchymal stem cells from tissues of endodermal or mesodermal origin. Stem Cells Dev. 21:1761–1768. 2012. View Article : Google Scholar
22	Birnbaum T, Roider J, Schankin CJ, Padovan CS, Schichor C, Goldbrunner R and Straube A: Malignant gliomas actively recruit bone marrow stromal cells by secreting angiogenic cytokines. J Neurooncol. 83:241–247. 2007. View Article : Google Scholar : PubMed/NCBI
23	Umesh A, Thompson MA, Chini EN, Yip KP and Sham JS: Integrin ligands mobilize Ca2⁺ from ryanodine receptor-gated stores and lysosome-related acidic organelles in pulmonary arterial smooth muscle cells. J Biol Chem. 281:34312–34323. 2006. View Article : Google Scholar : PubMed/NCBI
24	Nishiya N, Kiosses WB, Han J and Ginsberg MH: An α4 integrin-paxillin-Arf-GAP complex restricts Rac activation to the leading edge of migrating cells. Nat Cell Biol. 7:343–352. 2005. View Article : Google Scholar : PubMed/NCBI
25	Garmy-Susini B, Avraamides CJ, Desgrosellier JS, Schmid MC, Foubert P, Ellies LG, Lowy AM, Blair SL, Vandenberg SR, Datnow B, et al: PI3Kα activates integrin α4β1 to establish a metastatic niche in lymph nodes. Proc Natl Acad Sci USA. 110:9042–9047. 2013. View Article : Google Scholar
26	James WG, Bullard DC and Hickey MJ: Critical role of the α4 integrin/VCAM-1 pathway in cerebral leukocyte trafficking in lupus-prone MRL/fas(lpr) mice. J Immunol. 170:520–527. 2003. View Article : Google Scholar
27	Bernhart E, Damm S, Wintersperger A, DeVaney T, Zimmer A, Raynham T, Ireson C and Sattler W: Protein kinase D2 regulates migration and invasion of U87MG glioblastoma cells in vitro. Exp Cell Res. 319:2037–2048. 2013. View Article : Google Scholar : PubMed/NCBI
28	Wang YB, Hu Y, Li Z, Wang P, Xue YX, Yao YL, Yu B and Liu YH: Artemether combined with shRNA interference of vascular cell adhesion molecule-1 significantly inhibited the malignant biological behavior of human glioma cells. PLoS One. 8:e608342013. View Article : Google Scholar : PubMed/NCBI