Abstract
Purpose
It was presented that mesenchymal stem cells (MSCs) can be isolated from western glioma specimens. However, whether MSCs exist in glioma specimens of different ethnicities is unknown. To verify the existence of MSCs in an independent cohort, we undertook studies to isolate MSCs from a group of Korean patients. We hypothesized that cells resembling MSCs that were deemed mesenchymal stemlike cells (MSLCs) exist in an independent cohort of Korean gliomas.
Methods
We cultured fresh glioma specimens using the protocols used for culturing MSCs. The cultured cells were analyzed with fluorescence-activated cell sorting (FACS) for surface markers associated with MSCs. Cultured cells were exposed to mesenchymal differentiation conditions. To presume possible locations of MSLCs in the glioma, sections of glioma were analyzed by immunofluorescent labeling for CD105, CD31, and NG2.
Results
From nine of 31 glioma specimens, we isolated cells resembling MSCs, which were deemed Korean glioma stroma MSLCs (KGS-MSLCs). KGS-MSLCs were spindle shaped and adherent to plastic. KGS-MSLCs had similar surface markers to MSCs (CD105+, CD90+, CD73+, and CD45−). KGS-MSLCs were capable of mesenchymal differentiation and might be located around endothelial cells, pericytes, and in a disorganized perivascular area inside glioma stroma.
Conclusions
We found that cells resembling MSCs indeed exist in an independent cohort of glioma patients, as presented in western populations. We could presume that the possible location of KGS-MSLCs was in perivascular area or in glioma stroma that was a disorganized vascular niche. It might be possible that KGS-MSLCs could be one of constituent of stroma of glioma microenvironment.
Similar content being viewed by others
References
Barnholtz-Sloan JS, Sloan AE, Schwartz AG (2003) Racial differences in survival after diagnosis with primary malignant brain tumor. Cancer 98(3):603–609
Bodey B, Bodey B Jr, Siegel SE, Kaiser HE (1998) Upregulation of endoglin (CD105) expression during childhood brain tumor-related angiogenesis. Anti-angiogenic therapy. Anticancer Res 18(3A):1485–1500
Cheifetz S, Bellon T, Cales C, Vera S, Bernabeu C, Massague J, Letarte M (1992) Endoglin is a component of the transforming growth factor-beta receptor system in human endothelial cells. J Biol Chem 267(27):19027–19030
Chekenya M, Pilkington GJ (2002) NG2 precursor cells in neoplasia: functional, histogenesis and therapeutic implications for malignant brain tumours. J Neurocytol 31(6–7):507–521
Crisan M, Chen CW, Corselli M, Andriolo G, Lazzari L, Peault B (2009) Perivascular multipotent progenitor cells in human organs. Ann N Y Acad Sci 1176:118–123
da Silva ML, Chagastelles PC, Nardi NB (2006) Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J Cell Sci 119(Pt 11):2204–2213
Dirks PB (2005) Brain tumor stem cells. Biol Blood Marrow Transplant 11(2 Suppl 2):12–13
Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8(4):315–317
Ehninger D, Wang LP, Klempin F, Romer B, Kettenmann H, Kempermann G (2011) Enriched environment and physical activity reduce microglia and influence the fate of NG2 cells in the amygdala of adult mice. Cell Tissue Res 345(1):69–86
El-Haibi CP, Karnoub AE (2011) Mesenchymal stem cells in the pathogenesis and therapy of breast cancer. J Mammary Gland Biol Neoplasia 15(4):399–409
Fidler IJ, Poste G (2008) The “seed and soil” hypothesis revisited. Lancet Oncol 9(8):808
Freije WA, Castro-Vargas FE, Fang Z, Horvath S, Cloughesy T, Liau LM, Mischel PS, Nelson SF (2004) Gene expression profiling of gliomas strongly predicts survival. Cancer Res 64(18):6503–6510
Hall B, Andreeff M, Marini F (2007) The participation of mesenchymal stem cells in tumor stroma formation and their application as targeted-gene delivery vehicles. Handb Exp Pharmacol 12(180):263–283
He J, Liu Y, Zhu T, Zhu J, Dimeco F, Vescovi AL, Heth JA, Muraszko KM, Fan X, Lubman DM (2012) CD90 is identified as a candidate marker for cancer stem cells in primary high-grade gliomas using tissue microarrays. Mol Cell Proteomics 11(6):M111–010744
Hoelzinger DB, Demuth T, Berens ME (2007) Autocrine factors that sustain glioma invasion and paracrine biology in the brain microenvironment. J Natl Cancer Inst 99(21):1583–1593
Hoffman S, Propp JM, McCarthy BJ (2006) Temporal trends in incidence of primary brain tumors in the United States, 1985–1999. Neuro Oncol 8(1):27–37
Holman DW, Grzybowski DM, Mehta BC, Katz SE, Lubow M (2005) Characterization of cytoskeletal and junctional proteins expressed by cells cultured from human arachnoid granulation tissue. Cerebrospinal Fluid Res 2:9
Kang SG, Shinojima N, Hossain A, Gumin J, Yong RL, Colman H, Marini F, Andreeff M, Lang FF (2010) Isolation and perivascular localization of mesenchymal stem cells from mouse brain. Neurosurgery 67(3):711–720
Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, Richardson AL, Polyak K, Tubo R, Weinberg RA (2007) Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449(7162):557–563
Kestendjieva S, Kyurkchiev D, Tsvetkova G, Mehandjiev T, Dimitrov A, Nikolov A, Kyurkchiev S (2008) Characterization of mesenchymal stem cells isolated from the human umbilical cord. Cell Biol Int 32(7):724–732
Kim SM, Kang SG, Park NR, Mok HS, Huh YM, Lee SJ, Jeun SS, Hong YK, Park CK, Lang FF (2011) Presence of glioma stroma mesenchymal stem cells in a murine orthotopic glioma model. Childs Nerv Syst 27(6):911–922
Kong BH, Park NR, Shim JK, Kim BK, Shin HJ, Lee JH, Huh YM, Lee SJ, Kim SH, Kim EH, Park EK, Chang JH, Kim DS, Kim SH, Hong YK, Kang SG, Lang FF (2012) Isolation of glioma cancer stem cells in relation to histological grades in glioma specimens. Childs Nerv Syst. doi:10.1007/s00381-012-1964-9
Lal S, Lacroix M, Tofilon P, Fuller GN, Sawaya R, Lang FF (2000) An implantable guide-screw system for brain tumor studies in small animals. J Neurosurg 92(2):326–333
Lang FF, Amano T, Hata N, Gumin J, Aldape K, Colman H (2007) Bone marrow-derived mesenchymal stem cells are recruited to and alter the growth of human gliomas [abstract]. Neuro Oncol 9:596
Lang FF, Gumin J, Amano T, Hata N, Heimberger F, Marini F, Andreeff M, Aldape K, Sulman E, Colman H (2008) Tumor-derived mesenchymal stem cells in human gliomas: isolation and biological properties [abstract]. J Clin Oncol 26(suppl) (15S):2001
Lee CH, Jung KW, Yoo H, Park S, Lee SH (2010) Epidemiology of primary brain and central nervous system tumors in Korea. J Korean Neurosurg Soc 48(2):145–152
Lee J, Kotliarova S, Kotliarov Y, Li A, Su Q, Donin NM, Pastorino S, Purow BW, Christopher N, Zhang W, Park JK, Fine HA (2006) Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 9(5):391–403
Lennon DP, Caplan AI (2006) Isolation of human marrow-derived mesenchymal stem cells. Exp Hematol 34(11):1604–1605
Liotta LA, Kohn EC (2001) The microenvironment of the tumour–host interface. Nature 411(6835):375–379
Lopes CA, Mair WG (1974) Tubular structures in arachnoid cells. Acta Neuropathol 27(4):363–368
Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114(2):97–109
Mareschi K, Biasin E, Piacibello W, Aglietta M, Madon E, Fagioli F (2001) Isolation of human mesenchymal stem cells: bone marrow versus umbilical cord blood. Haematologica 86(10):1099–1100
Marx J (2008) Cancer biology. All in the stroma: cancer's Cosa Nostra. Science 320(5872):38–41
Mendoza M, Khanna C (2009) Revisiting the seed and soil in cancer metastasis. Int J Biochem Cell Biol 41(7):1452–1462
Murfee WL, Rehorn MR, Peirce SM, Skalak TC (2006) Perivascular cells along venules upregulate NG2 expression during microvascular remodeling. Microcirculation 13(3):261–273
Nakamizo A, Marini F, Amano T, Khan A, Studeny M, Gumin J, Chen J, Hentschel S, Vecil G, Dembinski J, Andreeff M, Lang FF (2005) Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas. Cancer Res 65(8):3307–3318
Nakamura K, Ito Y, Kawano Y, Kurozumi K, Kobune M, Tsuda H, Bizen A, Honmou O, Niitsu Y, Hamada H (2004) Antitumor effect of genetically engineered mesenchymal stem cells in a rat glioma model. Gene Ther 11(14):1155–1164
Nardi NB (2005) All the adult stem cells, where do they all come from? An external source for organ-specific stem cell pools. Med Hypotheses 64(4):811–817
Ng HK, Tse CC, Lo ST (1987) Meningiomas and arachnoid cells: an immunohistochemical study of epithelial markers. Pathology 19(3):253–257
Oi S, Matsumoto S, Choi JU, Kang JK, Wong T, Wang C, Chan TS (1990) Brain tumors diagnosed in the first year of life in five Far-Eastern countries. Statistical analysis of 307 cases. Childs Nerv Syst 6(2):79–85
Ozerdem U, Grako KA, Dahlin-Huppe K, Monosov E, Stallcup WB (2001) NG2 proteoglycan is expressed exclusively by mural cells during vascular morphogenesis. Dev Dyn 222(2):218–227
Paget S (1889) The distribution of secondary growths in cancer of the breast. Lancet 133:571–573
Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD, Misra A, Nigro JM, Colman H, Soroceanu L, Williams PM, Modrusan Z, Feuerstein BG, Aldape K (2006) Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 9(3):157–173
Ricci-Vitiani L, Pallini R, Larocca LM, Lombardi DG, Signore M, Pierconti F, Petrucci G, Montano N, Maira G, De Maria R (2008) Mesenchymal differentiation of glioblastoma stem cells. Cell Death Differ 15(9):1491–1498
Rieske P, Golanska E, Zakrzewska M, Piaskowski S, Hulas-Bigoszewska K, Wolanczyk M, Szybka M, Witusik-Perkowska M, Jaskolski DJ, Zakrzewski K, Biernat W, Krynska B, Liberski PP (2009) Arrested neural and advanced mesenchymal differentiation of glioblastoma cells-comparative study with neural progenitors. BMC Cancer 9:54
Robertson JT, Gunter BC, Somes GW (2002) Racial differences in the incidence of gliomas: a retrospective study from Memphis, Tennessee. Br J Neurosurg 16(6):562–566
Rutka JT, Giblin JR, Balkissoon R, Wen D, Myatt CA, McCulloch JR, Rosenblum ML (1987) Characterization of fetal human brain cultures. Development of a potential model for selectively purifying human glial cells in culture. Dev Neurosci 9(3):154–173
Rutka JT, Kleppe-Hoifodt H, Emma DA, Giblin JR, Dougherty DV, McCulloch JR, De Armond SJ, Rosenblum ML (1986) Characterization of normal human brain cultures. Evidence for the outgrowth of leptomeningeal cells. Lab Invest 55(1):71–85
Shin GY, Shim JK, Lee JH, Shin HJ, Lee SJ, Huh YM, Kim EH, Park EK, Kim SH, Chang JH, Kim DS, Hong YK, Kim SH, Kang SG, Lang FF (2012) Changes in the biological characteristics of glioma cancer stem cells after serial in vivo subtransplantation. Childs Nerv Syst. doi:10.1007/s00381-012-1963-x
Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, Dirks PB (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63(18):5821–5828
Stallcup WB (2002) The NG2 proteoglycan: past insights and future prospects. J Neurocytol 31(6–7):423–435
Stallcup WB, Huang FJ (2008) A role for the NG2 proteoglycan in glioma progression. Cell Adh Migr 2(3):192–201
Stewart PA, Farrell CL, Del Maestro RF (1991) The effect of cellular microenvironment on vessels in the brain. Part 1: vessel structure in tumour, peritumour and brain from humans with malignant glioma. Int J Radiat Biol 60(1–2):125–130
Tso CL, Shintaku P, Chen J, Liu Q, Liu J, Chen Z, Yoshimoto K, Mischel PS, Cloughesy TF, Liau LM, Nelson SF (2006) Primary glioblastomas express mesenchymal stem-like properties. Mol Cancer Res 4(9):607–619
Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP, Alexe G, Lawrence M, O'Kelly M, Tamayo P, Weir BA, Gabriel S, Winckler W, Gupta S, Jakkula L, Feiler HS, Hodgson JG, James CD, Sarkaria JN, Brennan C, Kahn A, Spellman PT, Wilson RK, Speed TP, Gray JW, Meyerson M, Getz G, Perou CM, Hayes DN (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17(1):98–110
Yao Y, Kubota T, Takeuchi H, Sato K (2005) Prognostic significance of microvessel density determined by an anti-CD105/endoglin monoclonal antibody in astrocytic tumors: comparison with an anti-CD31 monoclonal antibody. Neuropathology 25(3):201–206
Yen BL, Huang HI, Chien CC, Jui HY, Ko BS, Yao M, Shun CT, Yen ML, Lee MC, Chen YC (2005) Isolation of multipotent cells from human term placenta. Stem Cells 23(1):3–9
Zannettino AC, Paton S, Arthur A, Khor F, Itescu S, Gimble JM, Gronthos S (2008) Multipotential human adipose-derived stromal stem cells exhibit a perivascular phenotype in vitro and in vivo. J Cell Physiol 214(2):413–421
Zhu L, Xiang P, Guo K, Wang A, Lu J, Tay SS, Jiang H, He BP (2012) Microglia/monocytes with NG2 expression have no phagocytic function in the cortex after LPS focal injection into the rat brain. Glia 60(9):1417–1426
Acknowledgments
This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2009–0071299 and 2010–0004506) and a grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea (1020340). The authors wish to acknowledge the financial support of the Catholic Medical Center Research Foundation made in the program year of 2010. We would also like to thank Hyun-Soo Mok for her technical support with the orthotopic glioma model and Yoon-Kyung Park for her technical support with the flow cytometry experimentation.
Conflict of interest
None.
Author information
Authors and Affiliations
Corresponding author
Additional information
Young Goo Kim and Soyoun Jeon contributed equally to this manuscript.
Rights and permissions
About this article
Cite this article
Kim, Y.G., Jeon, S., Sin, GY. et al. Existence of glioma stroma mesenchymal stemlike cells in Korean glioma specimens. Childs Nerv Syst 29, 549–563 (2013). https://doi.org/10.1007/s00381-012-1988-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00381-012-1988-1