Interleukin-1 beta and transforming growth factor-beta cooperate to induce neurosphere formation and increase tumorigenicity of adherent LN-229 glioma cells

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dc.contributor.author Wang, Lei
dc.contributor.author Liu, Ziyan
dc.contributor.author Balivada, Sivasai
dc.contributor.author Shrestha, Tej Bahadur
dc.contributor.author Bossmann, Stefan H.
dc.contributor.author Pyle, Marla
dc.contributor.author Pappan, Loretta
dc.contributor.author Shi, Jishu N.
dc.contributor.author Troyer, Deryl L.
dc.date.accessioned 2012-05-31T15:53:18Z
dc.date.available 2012-05-31T15:53:18Z
dc.date.issued 2012-02-10
dc.identifier.uri http://hdl.handle.net/2097/13883
dc.description.abstract Introduction: Glioma stem cells (GSCs) have the property of self-renewal and appear to be a driving force for the initiation and recurrence of gliomas. We recently found that the human tumorigenic LN-229 glioma cell line failed to form neurospheres in serum-free conditions and generated mostly small tumors in vivo, suggesting that either LN-229 GSCs are not active in these conditions or GSCs are absent in the LN-229 cell line. Methods: Using self-renewal assay, soft-agar colony assay, cell proliferation assay, invasion assay, real time PCR analysis, ELISA and in vivo tumorigenic assay, we investigated the effects of interleukin (IL)-1beta and transforming growth factor (TGF)-beta on the development of GSCs from LN-229 cells. Results: Here, we demonstrate that the combination of IL-1beta and TGF-beta can induce LN-229 cells to form neurospheres in serum-free medium. IL-1beta/TGF-beta-induced neurospheres display up-regulated expression of stemness factor genes (nestin, Bmi-1, Notch-2 and LIF), and increased invasiveness, drug resistance and tumor growth in vivo: hallmarks of GSCs. These results indicate that IL-1beta and TGF-beta cooperate to induce a GSC phenotype in the LN-229 cell line. Induction of nestin, LIF and Notch-2 by IL-1beta/TGF-beta can be reverted after cytokine withdrawal. Remarkably, however, up-regulated Bmi-1 levels remained unchanged after cytokine withdrawal; and the cytokine-withdrawn cells maintained strong clonogenicity, suggesting that Bmi-1 may play a crucial role in tumorigenesis. Conclusions: Our finding indicates that glioma cells without self-renewal capability in standard conditions could also contribute to glioma malignancy when cytokines, such as IL-1beta and TGF-beta, are present in the tumor environment. Targeting GSC-promoting cytokines that are highly expressed in glioblastomas may contribute to the development of more effective glioma therapies. en_US
dc.relation.uri http://doi.org/10.1186/scrt96 en_US
dc.subject Glioma stem cells en_US
dc.subject Interleukin-1 beta en_US
dc.subject Transforming growth factor-beta en_US
dc.subject Neurosphere formation en_US
dc.subject Tumorigenicity en_US
dc.title Interleukin-1 beta and transforming growth factor-beta cooperate to induce neurosphere formation and increase tumorigenicity of adherent LN-229 glioma cells en_US
dc.type Article (publisher version) en_US
dc.date.published 2012 en_US
dc.citation.doi 10.1186/scrt96 en_US
dc.citation.issue 1 en_US
dc.citation.jtitle Stem Cell Research & Therapy en_US
dc.citation.spage 5 en_US
dc.citation.volume 3 en_US
dc.contributor.authoreid jshi en_US
dc.contributor.authoreid leiwang en_US
dc.contributor.authoreid liuziyan en_US
dc.contributor.authoreid sivasai en_US
dc.contributor.authoreid tbs3 en_US
dc.contributor.authoreid sbossman en_US
dc.contributor.authoreid mpyle en_US
dc.contributor.authoreid troyer en_US


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