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Child's Nervous System

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01-03-2008 | Original Paper

Cytotoxicity of human umbilical cord blood-derived mesenchymal stem cells against human malignant glioma cells

Authors: Seok-Gu Kang, Sin Soo Jeun, Jung Yeon Lim, Seong Muk Kim, Yoon Sun Yang, Won IL Oh, Pil-Woo Huh, Chun Kun Park

Published in: Child's Nervous System | Issue 3/2008

Abstract

Background

Mesenchymal stem cells (MSCs) represent a potential useful source for cell-based glioma therapies because these cells evidence both orthodox and unorthodox plasticity and also show tropism for cancer. In this study, the authors attempted to access the cytotoxicity of human umbilical cord blood (hUCB)-derived MSCs, with or without cytokine activations against malignant glioma cells.

Materials and methods

hUCB-derived MSCs were activated by interleukin-2, interleukin-15, granulocyte macrophage colony-stimulating factor, and combinations. The hUCB-derived MSCs and activated hUCB-derived MSCs were effector cells. The cytotoxicity of the unactivated hUCB-derived MSCs and activated hUCB-derived MSCs against the target cells (human malignant glioma cells) was estimated via visual survival cell assays and transwell inserts. Phenotypic changes occurring in these hUCB-derived MSCs before and after cytokine activation were determined via flow cytometry. The secreted proteins from these effector cells were estimated via enzyme-linked immunosorbent assays.

Results

We noted a significant cytotoxicity of hUCB-derived MSCs against malignant glioma cells. In addition, the hUCB-derived MSCs activated with cytokines evidenced significantly higher cytotoxicity than that observed with unactivated hUCB-derived MSCs. Differentiated immune effectors cells from the hUCB-derived MSCs after cytokine activation were not shown to have increased in number. However, the activated hUCB-derived MSCs secreted more immune response-related proteins (interleukin 4, interferon-γ) than did the unactivated hUCB-derived MSCs.

Conclusion

The data collected herein confirm for the first time that hUCB-derived MSCs, with or without activation, evidence significant cytotoxicity against human malignant glioma cells, and the immune response-related proteins secreted in this process may perform relevant functions.

Aboody KS, Brown A, Rainov NG, Bower KA, Liu S, Yang W, Small JE, Herrlinger U, Ourednik V, Black PM, Breakefield XO, Snyder EY (2000) Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc Natl Acad Sci USA 97:12846–12851PubMedCrossRef

Anderson DJ, Gage FH, Weissman IL (2001) Can stem cells cross lineage boundaries? Nat Med 7:393–395PubMedCrossRef

Barry FP (2003) Biology and clinical applications of mesenchymal stem cells. Birth Defects Res C Embryo Today 69:250–256PubMedCrossRef

Birnbaum T, Roider J, Schankin CJ, Padovan CS, Schichor C, Goldbrunner R, Straube A (2007) Malignant gliomas actively recruit bone marrow stromal cells by secreting angiogenic cytokines. J Neuro-oncol 83:241–247CrossRef

Brazelton TR, Rossi FM, Keshet GI, Blau HM (2000) From marrow to brain: expression of neuronal phenotypes in adult mice. Science 290:1775–1779PubMedCrossRef

Brower V (2005) Search and destroy: recent research exploits adult stem cells’ attraction to cancer. J Natl Cancer Inst 97:414–416PubMedCrossRef

Desjardins A, Quinn JA, Vredenburgh JJ, Sathornsumetee S, Friedman AH, Herndon JE, McLendon RE, Provenzale JM, Rich JN, Sampson JH, Gururangan S, Dowell JM, Salvado A, Friedman HS, Reardon DA (2007) Phase II study of imatinib mesylate and hydroxyurea for recurrent grade III malignant gliomas. J Neuro-oncol 83:53–60CrossRef

Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, Grisanti S, Gianni AM (2002) Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 99:3838–3843PubMedCrossRef

Donato V, Papaleo A, Castrichino A, Banelli E, Giangaspero F, Salvati M, Delfini R (2007) Prognostic implication of clinical and pathologic features in patients with glioblastoma multiforme treated with concomitant radiation plus temozolomide. Tumori 93:248–256PubMed

10.

Ehtesham M, Kabos P, Kabosova A, Neuman T, Black KL, Yu JS (2002) The use of interleukin 12-secreting neural stem cells for the treatment of intracranial glioma. Cancer Res 62:5657–5663PubMed

11.

Hamada H, Kobune M, Nakamura K, Kawano Y, Kato K, Honmou O, Houkin K, Matsunaga T, Niitsu Y (2005) Mesenchymal stem cells (MSC) as therapeutic cytoreagents for gene therapy. Cancer Sci 96:149–156PubMedCrossRef

12.

Kang SG, Ryu CH, Jeun SS, Park CK, Shin HJ, Kim JH, Kim MC, Kang JK (2004) Lymphokine activated killer cells from umbilical cord blood show higher antitumor effect against anaplastic astrocytoma cell line (U87) and medulloblastoma cell line (TE671) than lymphokine activated killer cells from peripheral blood. Child’s Nerv Syst 20:154–162CrossRef

13.

Kang SG, Jeun SS, Lim JY, Yoo DS, Huh PW, Cho KS, Kim DS, Shin HJ, Kim JH, Kim MC, Kang JK (2005) Cytotoxicity of rat marrow stromal cells against malignant glioma cells. Child’s Nerv Syst 21:528–538CrossRef

14.

Kang SG, Kim JH, Nam DH, Park K (2005) Clinical and radiological prognostic factors of anaplastic oligodendroglioma treated by combined therapy. Neurol Med-Chir 45:232–238 discussion 238–239CrossRef

15.

Kang SG, Kim JS, Park K, Kim JS, Groves MD, Nam DH (2006) Combination celecoxib and temozolomide in C6 rat glioma orthotopic model. Oncol Rep 15:7–13PubMed

16.

Kim DW, Chung YJ, Kim TG, Kim YL, Oh IH (2004) Cotransplantation of third-party mesenchymal stromal cells can alleviate single-donor predominance and increase engraftment from double cord transplantation. Blood 103:1941–1948PubMedCrossRef

17.

Kim H, Lee H, Yun Y (1998) X-Gene product of hepatitis B virus induces apoptosis in liver cells. J Biol Chem 273:381–385PubMedCrossRef

18.

Kim SK, Kim SU, Park IH, Bang JH, Aboody KS, Wang KC, Cho BK, Kim M, Menon LG, Black PM, Carroll RS (2006) Human neural stem cells target experimental intracranial medulloblastoma and deliver a therapeutic gene leading to tumor regression. Clin Cancer Res 12:5550–5556PubMedCrossRef

19.

Kimura S, Yoshino A, Katayama Y, Watanabe T, Fukushima T (2002) Growth control of C6 glioma in vivo by nerve growth factor. J Neuro-oncol 59:199–205CrossRef

20.

Krause DS, Theise ND, Collector MI, Henegariu O, Hwang S, Gardner R, Neutzel S, Sharkis SJ (2001) Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 105:369–377PubMedCrossRef

21.

Kumagai N, Fukuda K, Ishimura Y, Nishida T (2000) Synergistic induction of eotaxin expression in human keratocytes by TNF-alpha and IL-4 or IL-13. Invest Ophthalmol Vis Sci 41:1448–1453PubMed

22.

Li Y, Chen J, Chen XG, Wang L, Gautam SC, Xu YX, Katakowski M, Zhang LJ, Lu M, Janakiraman N, Chopp M (2002) Human marrow stromal cell therapy for stroke in rat: neurotrophins and functional recovery. Neurology 59:514–523PubMed

23.

Miletic H, Fischer Y, Litwak S, Giroglou T, Waerzeggers Y, Winkeler A, Li H, Himmelreich U, Lange C, Stenzel W, Deckert M, Neumann H, Jacobs AH, von Laer D (2007) Bystander killing of malignant glioma by bone marrow-derived tumor-infiltrating progenitor cells expressing a suicide gene. Mol Ther 15:1373–1381PubMedCrossRef

24.

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 65:3307–3318PubMed

25.

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 11:1155–1164PubMedCrossRef

26.

Peterson BE, Bowen WC, Patrene KD, Mars WM, Sullivan AK, Murase N, Boggs SS, Greenberger JS, Goff JP (1999) Bone marrow as a potential source of hepatic oval cells. Science 284:1168–1170CrossRef

27.

Pisati F, Belicchi M, Acerbi F, Marchesi C, Giussani C, Gavina M, Javerzat S, Hagedorn M, Carrabba G, Lucini V, Gaini SM, Bresolin N, Bello L, Bikfalvi A, Torrente Y (2007) Effect of human skin-derived stem cells on vessel architecture, tumor growth, and tumor invasion in brain tumor animal models. Cancer Res 67:3054–3063PubMedCrossRef

28.

Sanchez-Ramos JR (2002) Neural cells derived from adult bone marrow and umbilical cord blood. J Neurosci Res 69:880–893PubMedCrossRef

29.

Scheda A, Finjap JK, Tuettenberg J, Brockmann MA, Hochhaus A, Hofheinz R, Lohr F, Wenz F (2007) Efficacy of different regimens of adjuvant radiochemotherapy for treatment of glioblastoma. Tumori 93:31–36PubMed

30.

Schichor C, Birnbaum T, Etminan N, Schnell O, Grau S, Miebach S, Aboody K, Padovan C, Straube A, Tonn JC, Goldbrunner R (2006) Vascular endothelial growth factor A contributes to glioma-induced migration of human marrow stromal cells (hMSC). Exp Neurol 199:301–310PubMedCrossRef

31.

Shah GD, Silver JS, Rosenfeld SS, Gavrilovic IT, Abrey LE, Lassman AB (2007) Myelosuppression in patients benefiting from imatinib with hydroxyurea for recurrent malignant gliomas. J Neuro-oncol DOI 10.1007/s11060-007-9408-1

32.

Short B, Brouard N, Occhiodoro-Scott T, Ramakrishnan A, Simmons PJ (2003) Mesenchymal stem cells. Arch Med Res 34:565–571PubMedCrossRef

33.

Solves P, Moraga R, Saucedo E, Perales A, Soler MA, Larrea L, Mirabet V, Planelles D, Carbonell-Uberos F, Monleon J, Planells T, Guillen M, Andres A, Franco E (2003) Comparison between two strategies for umbilical cord blood collection. Bone Marrow Transplant 31:269–273PubMedCrossRef

34.

Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Eng J Med 352:987–996CrossRef

35.

Wang JC, Doedens M, Dick JE (1997) Primitive human hematopoietic cells are enriched in cord blood compared with adult bone marrow or mobilized peripheral blood as measured by the quantitative in vivo SCID-repopulating cell assay. Blood 89:3919–3924PubMed

36.

Wen PY, Yung WK, Lamborn KR, Dahia PL, Wang Y, Peng B, Abrey LE, Raizer J, Cloughesy TF, Fink K, Gilbert M, Chang S, Junck L, Schiff D, Lieberman F, Fine HA, Mehta M, Robins HI, DeAngelis LM, Groves MD, Puduvalli VK, Levin V, Conrad C, Maher EA, Aldape K, Hayes M, Letvak L, Egorin MJ, Capdeville R, Kaplan R, Murgo AJ, Stiles C, Prados MD (2006) Phase I/II study of imatinib mesylate for recurrent malignant gliomas: North American Brain Tumor Consortium Study 99-08. Clin Cancer Res 12:4899–4907PubMedCrossRef

37.

Williams B, Allan DJ (1996) Combination of SCF, IL-6, IL-3, and GM-CSF increases the mitotic index in short term bone marrow cultures from acute promyelocytic leukemia (APL) patients. Cancer Genet Cytogenet 91:77–81PubMedCrossRef

38.

Woodbury D, Reynolds K, Black IB (2002) Adult bone marrow stromal stem cells express germline, ectodermal, endodermal, and mesodermal genes prior to neurogenesis. J Neurosci Res 69:908–917PubMedCrossRef

39.

Yang SE, Ha CW, Jung M, Jin HJ, Lee M, Song H, Choi S, Oh W, Yang YS (2004) Mesenchymal stem/progenitor cells developed in cultures from UC blood. Cytotherapy 6:476–486PubMedCrossRef

Title: Cytotoxicity of human umbilical cord blood-derived mesenchymal stem cells against human malignant glioma cells
Authors: Seok-Gu Kang
Sin Soo Jeun
Jung Yeon Lim
Seong Muk Kim
Yoon Sun Yang
Won IL Oh
Pil-Woo Huh
Chun Kun Park
Publication date: 01-03-2008
Publisher: Springer-Verlag
Published in: Child's Nervous System / Issue 3/2008
Print ISSN: 0256-7040
Electronic ISSN: 1433-0350
DOI: https://doi.org/10.1007/s00381-007-0515-2

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Cytotoxicity of human umbilical cord blood-derived mesenchymal stem cells against human malignant glioma cells

Abstract

Background

Materials and methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Materials and methods

Results

Conclusion

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