nach oben

Clinical & Experimental Metastasis

Erschienen in:

01.12.2013 | Research Paper

Interleukin-6 is overexpressed and augments invasiveness of human glioma stem cells in vitro

verfasst von: Bo Qiu, Dongyong Zhang, Yong Wang, Shaowu Ou, Jun Wang, Jun Tao, Yunjie Wang

Erschienen in: Clinical & Experimental Metastasis | Ausgabe 8/2013

Einloggen, um Zugang zu erhalten

Abstract

In the present study, we carried out a series of assays to investigate the expression of interleukin-6 in glioma stem cells and its role in glioma stem cells invasion. Glioma stem cells from eight surgical glioma specimens were cultured and identified. Real-time reverse transcription polymerase chain reaction and immunoassay were used to measure and compare the expression levels of interleukin-6 in glioma stem cells and matched primary glioma cells. Subsequently, neutralizing antibody against interleukin-6 or exogenous interleukin-6 was used in a Matrigel-invasion assay and effects of interleukin-6 on glioma stem cells invasiveness was then determined. The results revealed that interleukin-6 mRNA and protein expression levels were significantly higher in glioma stem cells than in primary glioma cells from the same tumor. However, its expression levels were not apparently higher in glioma stem cells from grade IV gliomas than from grade III gliomas. In Matrigel-invasion assay, glioma stem cells invasiveness markedly decreased after interleukin-6 was blocked with neutralizing antibody, but significantly increased when exogenous interleukin-6 was added. Additionally, the similar effects of interleukin-6 were also found on primary glioma cells invasiveness. Our results suggest that glioma stem cells are likely to be the major tumor source of immunosuppressive cytokines interleukin-6 and thereby play a crucial role in determining glioma malignancy, immunosuppression and immune evasion. Furthermore, interleukin-6 can significantly augment glioma stem cells invasiveness in vitro, suggesting a potential target in future therapy for glioma stem cells rather than for their derivatives.

Bondy ML, Scheurer ME, Malmer B, Barnholtz-Sloan JS, Davis FG, Il’yasova D, Kruchko C, McCarthy BJ, Rajaraman P, Schwartzbaum JA, Sadetzki S, Schlehofer B, Tihan T, Wiemels JL, Wrensch M, Buffler PA (2008) Brain tumor epidemiology: consensus from the Brain Tumor Epidemiology Consortium. Cancer 113(7 Suppl):1953–1968. doi:10.1002/cncr.23741 PubMedCrossRef

Hess KR, Broglio KR, Bondy ML (2004) Adult glioma incidence trends in the United States, 1977–2000. Cancer 101(10):2293–2299. doi:10.1002/cncr.20621 PubMedCrossRef

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 Engl J Med 352(10):987–996. doi:10.1056/NEJMoa043330 PubMedCrossRef

Park DM, Rich JN (2009) Biology of glioma cancer stem cells. Mol Cells 28(1):7–12. doi:10.1007/s10059-009-0111-2 PubMedCrossRef

Gomez GG, Kruse CA (2006) Mechanisms of malignant glioma immune resistance and sources of immunosuppression. Gene therapy & molecular biology 10 (A):133–146

Li R, Li G, Deng L, Liu Q, Dai J, Shen J, Zhang J (2010) IL-6 augments the invasiveness of U87MG human glioblastoma multiforme cells via up-regulation of MMP-2 and fascin-1. Oncol Rep 23(6):1553–1559. doi:10.3892/or_00000795 PubMed

Liu Q, Li G, Li R, Shen J, He Q, Deng L, Zhang C, Zhang J (2010) IL-6 promotion of glioblastoma cell invasion and angiogenesis in U251 and T98G cell lines. J Neurooncol 100(2):165–176. doi:10.1007/s11060-010-0158-0 PubMedCrossRef

Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB (2004) Identification of human brain tumour initiating cells. Nature 432(7015):396–401. doi:10.1038/nature03128 PubMedCrossRef

Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A, De Vitis S, Fiocco R, Foroni C, Dimeco F, Vescovi A (2004) Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 64(19):7011–7021. doi:10.1158/0008-5472.can-04-1364 PubMedCrossRef

10.

Yuan X, Curtin J, Xiong Y, Liu G, Waschsmann-Hogiu S, Farkas DL, Black KL, Yu JS (2004) Isolation of cancer stem cells from adult glioblastoma multiforme. Oncogene 23(58):9392–9400. doi:10.1038/sj.onc.1208311 PubMedCrossRef

11.

Hide T, Takezaki T, Nakamura H, Kuratsu J, Kondo T (2008) Brain tumor stem cells as research and treatment targets. Brain Tumor Pathol 25(2):67–72. doi:10.1007/s10014-008-0237-5 PubMedCrossRef

12.

Rich JN, Eyler CE (2008) Cancer stem cells in brain tumor biology. Cold Spring Harb Symp Quant Biol 73:411–420. doi:10.1101/sqb.2008.73.060 PubMedCrossRef

13.

Rolhion C, Penault-Llorca F, Kemeny JL, Lemaire JJ, Jullien C, Labit-Bouvier C, Finat-Duclos F, Verrelle P (2001) Interleukin-6 overexpression as a marker of malignancy in human gliomas. J Neurosurg 94(1):97–101. doi:10.3171/jns.2001.94.1.0097 PubMedCrossRef

14.

Loeffler S, Fayard B, Weis J, Weissenberger J (2005) Interleukin-6 induces transcriptional activation of vascular endothelial growth factor (VEGF) in astrocytes in vivo and regulates VEGF promoter activity in glioblastoma cells via direct interaction between STAT3 and Sp1. Int J Cancer 115(2):202–213. doi:10.1002/ijc.20871 PubMedCrossRef

15.

Hao C, Parney IF, Roa WH, Turner J, Petruk KC, Ramsay DA (2002) Cytokine and cytokine receptor mRNA expression in human glioblastomas: evidence of Th1, Th2 and Th3 cytokine dysregulation. Acta Neuropathol 103(2):171–178. doi:10.1007/s004010100448 PubMedCrossRef

16.

Parney IF, Farr-Jones MA, Chang LJ, Petruk KC (2000) Human glioma immunobiology in vitro: implications for immunogene therapy. Neurosurgery 46 (5):1169-1177; discussion 1177-1168. doi:10.1097/00006123-200005000-00030

17.

Qiu B, Zhang D, Wang C, Tao J, Tie X, Qiao Y, Xu K, Wang Y, Wu A (2011) IL-10 and TGF-beta2 are overexpressed in tumor spheres cultured from human gliomas. Mol Biol Rep 38(5):3585–3591. doi:10.1007/s11033-010-0469-4 PubMedCrossRef

18.

Qiu B, Zhang D, Tao J, Tie X, Wu A, Wang Y (2012) Human brain glioma stem cells are more invasive than their differentiated progeny cells in vitro. J Clin Neurosci 19(1):130–134. doi:10.1016/j.jocn.2011.06.014 PubMedCrossRef

19.

Kleihues P, Louis DN, Scheithauer BW, Rorke LB, Reifenberger G, Burger PC, Cavenee WK (2002) The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol 61 (3):215–225; discussion 226–219

20.

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):5821–5828PubMed

21.

Vik-Mo EO, Sandberg C, Olstorn H, Varghese M, Brandal P, Ramm-Pettersen J, Murrell W, Langmoen IA (2010) Brain tumor stem cells maintain overall phenotype and tumorigenicity after in vitro culturing in serum-free conditions. Neuro Oncol 12(12):1220–1230. doi:10.1093/neuonc/noq102 PubMed

22.

Saidi A, Hagedorn M, Allain N, Verpelli C, Sala C, Bello L, Bikfalvi A, Javerzat S (2009) Combined targeting of interleukin-6 and vascular endothelial growth factor potently inhibits glioma growth and invasiveness. Int J Cancer 125(5):1054–1064. doi:10.1002/ijc.24380 PubMedCrossRef

23.

Hong DS, Angelo LS, Kurzrock R (2007) Interleukin-6 and its receptor in cancer: implications for translational therapeutics. Cancer 110(9):1911–1928. doi:10.1002/cncr.22999 PubMedCrossRef

24.

Van Meir E, Sawamura Y, Diserens AC, Hamou MF, de Tribolet N (1990) Human glioblastoma cells release interleukin six in vivo and in vitro. Cancer Res 50(20):6683–6688PubMed

25.

Weissenberger J, Loeffler S, Kappeler A, Kopf M, Lukes A, Afanasieva TA, Aguzzi A, Weis J (2004) IL-6 is required for glioma development in a mouse model. Oncogene 23(19):3308–3316. doi:10.1038/sj.onc.1207455 PubMedCrossRef

26.

Tchirkov A, Khalil T, Chautard E, Mokhtari K, Veronese L, Irthum B, Vago P, Kemeny JL, Verrelle P (2007) Interleukin-6 gene amplification and shortened survival in glioblastoma patients. Br J Cancer 96(3):474–476. doi:10.1038/sj.bjc.6603586 PubMedCrossRef

27.

Tchirkov A, Rolhion C, Bertrand S, Dore JF, Dubost JJ, Verrelle P (2001) IL-6 gene amplification and expression in human glioblastomas. Br J Cancer 85(4):518–522. doi:10.1054/bjoc.2001.1942 PubMedCrossRef

28.

Miyamoto Y, Hosotani R, Doi R, Wada M, Ida J, Tsuji S, Kawaguchi M, Nakajima S, Kobayashi H, Masui T, Imamura M (2001) Interleukin-6 inhibits radiation induced apoptosis in pancreatic cancer cells. Anticancer Res 21(4A):2449–2456PubMed

29.

Trikha M, Corringham R, Klein B, Rossi JF (2003) Targeted anti-interleukin-6 monoclonal antibody therapy for cancer: a review of the rationale and clinical evidence. Clin Cancer Res 9(13):4653–4665PubMed

30.

Dubost JJ, Rolhion C, Tchirkov A, Bertrand S, Chassagne J, Dosgilbert A, Verrelle P (2002) Interleukin-6-producing cells in a human glioblastoma cell line are not affected by ionizing radiation. J Neurooncol 56(1):29–34. doi:10.1023/A:1014467804488 PubMedCrossRef

31.

Claes A, Idema AJ, Wesseling P (2007) Diffuse glioma growth: a guerilla war. Acta Neuropathol 114(5):443–458. doi:10.1007/s00401-007-0293-7 PubMedCrossRef

32.

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. doi:10.1093/jnci/djm187 PubMedCrossRef

33.

Wicha MS (2006) Cancer stem cells and metastasis: lethal seeds. Clin Cancer Res 12(19):5606–5607. doi:10.1158/1078-0432.CCR-06-1537 PubMedCrossRef

34.

Oliver TG, Wechsler-Reya RJ (2004) Getting at the root and stem of brain tumors. Neuron 42(6):885–888. doi:10.1016/j.neuron.2004.06.011 PubMedCrossRef

35.

Molina JR, Hayashi Y, Stephens C, Georgescu MM (2010) Invasive glioblastoma cells acquire stemness and increased Akt activation. Neoplasia 12(6):453–463. doi:10.1593/Neo.10126 PubMed

36.

Wang H, Lathia JD, Wu Q, Wang J, Li Z, Heddleston JM, Eyler CE, Elderbroom J, Gallagher J, Schuschu J, MacSwords J, Cao Y, McLendon RE, Wang XF, Hjelmeland AB, Rich JN (2009) Targeting interleukin 6 signaling suppresses glioma stem cell survival and tumor growth. Stem Cells 27(10):2393–2404. doi:10.1002/stem.188 PubMedCrossRef

Titel: Interleukin-6 is overexpressed and augments invasiveness of human glioma stem cells in vitro
verfasst von: Bo Qiu
Dongyong Zhang
Yong Wang
Shaowu Ou
Jun Wang
Jun Tao
Yunjie Wang
Publikationsdatum: 01.12.2013
Verlag: Springer Netherlands
Erschienen in: Clinical & Experimental Metastasis / Ausgabe 8/2013
Print ISSN: 0262-0898
Elektronische ISSN: 1573-7276
DOI: https://doi.org/10.1007/s10585-013-9599-0

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Interleukin-6 is overexpressed and augments invasiveness of human glioma stem cells in vitro

Abstract

Neu im Fachgebiet Onkologie

Erhebliches Risiko für Kehlkopfkrebs bei mäßiger Dysplasie

15% bedauern gewählte Blasenkrebs-Therapie

Erhöhtes Risiko fürs Herz unter Checkpointhemmer-Therapie

Costims – das nächste heiße Ding in der Krebstherapie?

Update Onkologie

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 8/2013

Risk factors and survival outcomes in patients with brain metastases from breast cancer

Acidic pH via NF-κB favours VEGF-C expression in human melanoma cells

Host pigment epithelium-derived factor (PEDF) prevents progression of liver metastasis in a mouse model of uveal melanoma

EGFR activating mutations detected by different PCR techniques in Caucasian NSCLC patients with CNS metastases: short report

Predictive and prognostic factors in locally advanced breast cancer: effect of intratumoral FOXP3+ Tregs

Electrochemotherapy is effective in the treatment of rat bone metastases

Neu im Fachgebiet Onkologie

Erhebliches Risiko für Kehlkopfkrebs bei mäßiger Dysplasie

15% bedauern gewählte Blasenkrebs-Therapie

Erhöhtes Risiko fürs Herz unter Checkpointhemmer-Therapie

Costims – das nächste heiße Ding in der Krebstherapie?

Update Onkologie