Fusion of cancer stem cells and mesenchymal stem cells contributes to glioma neovascularization

Sun,Chao; Zhao,Dongliang; Dai,Xingliang; Chen,Jinsheng; Rong,Xiaoci; Wang,Haiyang; Wang,Aidong; Li,Ming; Dong,Jun; Huang,Qiang; Lan,Qing

doi:10.3892/or.2015.4135

Fusion of cancer stem cells and mesenchymal stem cells contributes to glioma neovascularization

Authors:
- Chao Sun
- Dongliang Zhao
- Xingliang Dai
- Jinsheng Chen
- Xiaoci Rong
- Haiyang Wang
- Aidong Wang
- Ming Li
- Jun Dong
- Qiang Huang
- Qing Lan
View Affiliations

Affiliations: Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, P.R. China
Published online on: July 16, 2015 https://doi.org/10.3892/or.2015.4135
Pages: 2022-2030

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

The ability of tumor cells to autonomously generate tumor vessels has received considerable attention in recent years. However, the degree of autonomy is relative. Meanwhile, the effect of bone marrow-derived mesenchymal stem cells (BMSCs) on tumor neovascularization has not been fully elucidated. The present study aimed to illuminate whether cell fusion between glioma stem cells and BMSC is involved in glioma neovascularization. BMSCs were isolated from transgenic nude mice, of which all nucleated cells express green fluorescent protein (GFP). The immunophenotype and multilineage differentiation potential of BMSC were confirmed. SU3 glioma stem/progenitor cells were transfected with red fluorescent protein (SU3-RFP cells). In a co-culture system of BMSC-GFP and SU3-RFP, RFP+/GFP+ cells were detected and isolated by dual colors using FACS. The angiogenic effect of RFP+/GFP+ cells was determined in vivo and in vitro. Flow cytometry analysis showed that BMSC expressed high levels of CD105, C44, and very low levels of CD45 and CD11b. When co-cultured with SU3-RFP, 73.8% of cells co-expressing RFP and GFP were identified as fused cells in the 5th generation. The fused cells exhibited tube formation ability in vitro and could give rise to a solid tumor and form tumor blood vessels in vivo. In the dual-color orthotopic model of transplantable xenograft glioma, yellow vessel-like structures that expressed CD105, RFP and GFP were identified as de novo-formed vessels derived from the fused cells. The yellow vessels observed in the tumor-bearing mice directly arose from the fusion of BMSCs and SU3-RFP cells. Thus, cell fusion is one of the driving factors for tumor neovascularization.

View Figures

View References

1	Plate KH, Scholz A and Dumont DJ: Tumor angiogenesis and anti-angiogenic therapy in malignant gliomas revisited. Acta Neuropathol. 124:763–775. 2012. View Article : Google Scholar : PubMed/NCBI
2	Ping YF and Bian XW: Concise review: Contribution of cancer stem cells to neovascularization. Stem Cells. 29:888–894. 2011. View Article : Google Scholar : PubMed/NCBI
3	Carmeliet P and Jain RK: Molecular mechanisms and clinical applications of angiogenesis. Nature. 473:298–307. 2011. View Article : Google Scholar : PubMed/NCBI
4	Maniotis AJ, Folberg R, Hess A, Seftor EA, Gardner LM, Pe'er J, Trent JM, Meltzer PS and Hendrix MJ: Vascular channel formation by human melanoma cells in vivo and in vitro: Vasculogenic mimicry. Am J Pathol. 155:739–752. 1999. View Article : Google Scholar : PubMed/NCBI
5	El Hallani S, Boisselier B, Peglion F, Rousseau A, Colin C, Idbaih A, Marie Y, Mokhtari K, Thomas JL, Eichmann A, et al: A new alternative mechanism in glioblastoma vascularization: Tubular vasculogenic mimicry. Brain. 133:973–982. 2010. View Article : Google Scholar : PubMed/NCBI
6	Dong J, Zhao Y, Huang Q, Fei X, Diao Y, Shen Y, Xiao H, Zhang T, Lan Q and Gu X: Glioma stem/progenitor cells contribute to neovascularization via transdifferentiation. Stem Cell Rev. 7:141–152. 2011. View Article : Google Scholar
7	Zhao Y, Dong J, Huang Q, Lou M, Wang A and Lan Q: Endothelial cell transdifferentiation of human glioma stem progenitor cells in vitro. Brain Res Bull. 82:308–312. 2010. View Article : Google Scholar : PubMed/NCBI
8	Ricci-Vitiani L, Pallini R, Biffoni M, Todaro M, Invernici G, Cenci T, Maira G, Parati EA, Stassi G, Larocca LM, et al: Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature. 468:824–828. 2010. View Article : Google Scholar : PubMed/NCBI
9	Wang R, Chadalavada K, Wilshire J, Kowalik U, Hovinga KE, Geber A, Fligelman B, Leversha M, Brennan C and Tabar V: Glioblastoma stem-like cells give rise to tumour endothelium. Nature. 468:829–833. 2010. View Article : Google Scholar : PubMed/NCBI
10	Hong IS, Lee HY and Kang KS: Mesenchymal stem cells and cancer: Friends or enemies? Mutat Res. 768:98–106. 2014. View Article : Google Scholar : PubMed/NCBI
11	Dong J, Zhang Q, Huang Q, Chen H, Shen Y, Fei X, Zhang T, Diao Y, Wu Z, Qin Z, et al: Glioma stem cells involved in tumor tissue remodeling in a xenograft model. J Neurosurg. 113:249–260. 2010. View Article : Google Scholar : PubMed/NCBI
12	Huang Q, Zhang QB, Dong J, Wu YY, Shen YT, Zhao YD, Zhu YD, Diao Y, Wang AD and Lan Q: Glioma stem cells are more aggressive in recurrent tumors with malignant progression than in the primary tumor, and both can be maintained long-term in vitro. BMC Cancer. 8:3042008. View Article : Google Scholar : PubMed/NCBI
13	Dong J, Dai XL, Lu ZH, Fei XF, Chen H, Zhang QB, Zhao YD, Wang ZM, Wang AD, Lan Q, et al: Incubation and application of transgenic green fluorescent nude mice in visualization studies on glioma tissue remodeling. Chin Med J. 125:4349–4354. 2012.PubMed/NCBI
14	Wu Z, Huang Q, Shao YX, Xue ZM, Dong J, Diao Y, Wang AD and Lan Q: Transplantation of human glioma stem cells in nude mice with green fluorescent protein expression. Zhonghua Yi Xue Za Zhi. 88:2317–2320. 2008.In Chinese. PubMed/NCBI
15	Liu H, Toh WS, Lu K, MacAry PA, Kemeny DM and Cao T: A subpopulation of mesenchymal stromal cells with high osteogenic potential. J Cell Mol Med. 13:2436–2447. 2009. View Article : Google Scholar : PubMed/NCBI
16	Cheng L, Huang Z, Zhou W, Wu Q, Donnola S, Liu JK, Fang X, Sloan AE, Mao Y, Lathia JD, et al: Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell. 153:139–152. 2013. View Article : Google Scholar : PubMed/NCBI
17	Liu AY and Ouyang G: Tumor angiogenesis: A new source of pericytes. Curr Biol. 23:R565–R568. 2013. View Article : Google Scholar : PubMed/NCBI
18	Silva GV, Litovsky S, Assad JA, Sousa AL, Martin BJ, Vela D, Coulter SC, Lin J, Ober J, Vaughn WK, et al: Mesenchymal stem cells differentiate into an endothelial phenotype, enhance vascular density, and improve heart function in a canine chronic ischemia model. Circulation. 111:150–156. 2005. View Article : Google Scholar : PubMed/NCBI
19	Janeczek Portalska K, Leferink A, Groen N, Fernandes H, Moroni L, van Blitterswijk C and de Boer J: Endothelial differentiation of mesenchymal stromal cells. PloS One. 7:e468422012. View Article : Google Scholar : PubMed/NCBI
20	Huang WH, Chang MC, Tsai KS, Hung MC, Chen HL and Hung SC: Mesenchymal stem cells promote growth and angiogenesis of tumors in mice. Oncogene. 32:4343–4354. 2013. View Article : Google Scholar
21	Beckermann BM, Kallifatidis G, Groth A, Frommhold D, Apel A, Mattern J, Salnikov AV, Moldenhauer G, Wagner W, Diehlmann A, et al: VEGF expression by mesenchymal stem cells contributes to angiogenesis in pancreatic carcinoma. Br J Cancer. 99:622–631. 2008. View Article : Google Scholar : PubMed/NCBI
22	Ho IA, Toh HC, Ng WH, Teo YL, Guo CM, Hui KM and Lam PY: Human bone marrow-derived mesenchymal stem cells suppress human glioma growth through inhibition of angiogenesis. Stem Cells. 31:146–155. 2013. View Article : Google Scholar
23	Kim SM, Kang SG, Park NR, Mok HS, Huh YM, Lee SJ, Jeun SS, Hong YK, Park CK and Lang FF: Presence of glioma stroma mesenchymal stem cells in a murine orthotopic glioma model. Childs Nerv Syst. 27:911–922. 2011. View Article : Google Scholar : PubMed/NCBI
24	Kim YG, Jeon S, Sin GY, Shim JK, Kim BK, Shin HJ, Lee JH, Huh YM, Lee SJ, Kim EH, et al: Existence of glioma stroma mesenchymal stemlike cells in Korean glioma specimens. Childs Nerv Syst. 29:549–563. 2013. View Article : Google Scholar : PubMed/NCBI
25	Schichor C, Albrecht V, Korte B, Buchner A, Riesenberg R, Mysliwietz J, Paron I, Motaln H, Turnšek TL, Jürchott K, et al: Mesenchymal stem cells and glioma cells form a structural as well as a functional syncytium in vitro. Exp Neurol. 234:208–219. 2012. View Article : Google Scholar : PubMed/NCBI
26	Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D 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
27	Tropel P, Noël D, Platet N, Legrand P, Benabid AL and Berger F: Isolation and characterisation of mesenchymal stem cells from adult mouse bone marrow. Exp Cell Res. 295:395–406. 2004. View Article : Google Scholar : PubMed/NCBI
28	Dallas NA, Samuel S, Xia L, Fan F, Gray MJ, Lim SJ and Ellis LM: Endoglin (CD105): A marker of tumor vasculature and potential target for therapy. Clin Cancer Res. 14:1931–1937. 2008. View Article : Google Scholar : PubMed/NCBI
29	Bjerkvig R, Tysnes BB, Aboody KS, Najbauer J and Terzis A: Opinion: The origin of the cancer stem cell: Current controversies and new insights. Nat Rev Cancer. 5:899–904. 2005. View Article : Google Scholar : PubMed/NCBI
30	Dittmar T, Nagler C, Schwitalla S, Reith G, Niggemann B and Zänker KS: Recurrence cancer stem cells - made by cell fusion? Med Hypotheses. 73:542–547. 2009. View Article : Google Scholar : PubMed/NCBI
31	Lu X and Kang Y: Cell fusion as a hidden force in tumor progression. Cancer Res. 69:8536–8539. 2009. View Article : Google Scholar : PubMed/NCBI
32	Lu X and Kang Y: Cell fusion hypothesis of the cancer stem cell. Cell Fusion in health and Disease. Springer; pp. 129–140. 2011, View Article : Google Scholar
33	Quintana-Bustamante O, Alvarez-Barrientos A, Kofman AV, Fabregat I, Bueren JA, Theise ND and Segovia JC: Hematopoietic mobilization in mice increases the presence of bone marrow-derived hepatocytes via in vivo cell fusion. Hepatology. 43:108–116. 2006. View Article : Google Scholar
34	Suzuki K, Sun R, Origuchi M, Kanehira M, Takahata T, Itoh J, Umezawa A, Kijima H, Fukuda S and Saijo Y: Mesenchymal stromal cells promote tumor growth through the enhancement of neovascularization. Mol Med. 17:579–587. 2011. View Article : Google Scholar : PubMed/NCBI
35	Shinojima N, Hossain A, Takezaki T, Fueyo J, Gumin J, Gao F, Nwajei F, Marini FC, Andreeff M, Kuratsu J, et al: TGF-β mediates homing of bone marrow-derived human mesenchymal stem cells to glioma stem cells. Cancer Res. 73:2333–2344. 2013. View Article : Google Scholar : PubMed/NCBI
36	Fonsatti E, Nicolay HJ, Altomonte M, Covre A and Maio M: Targeting cancer vasculature via endoglin/CD105: A novel antibody-based diagnostic and therapeutic strategy in solid tumours. Cardiovasc Res. 86:12–19. 2010. View Article : Google Scholar
37	Warrington K, Hillarby MC, Li C, Letarte M and Kumar S: Functional role of CD105 in TGF-beta1 signalling in murine and human endothelial cells. Anticancer Res. 25:1851–1864. 2005.PubMed/NCBI