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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Show simple item record Wang, Lei Liu, Ziyan Balivada, Sivasai Shrestha, Tej Bahadur Bossmann, Stefan H. Pyle, Marla Pappan, Loretta Shi, Jishu N. Troyer, Deryl L. 2012-05-31T15:53:18Z 2012-05-31T15:53:18Z 2012-02-10
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 Remarkably, however, up-regulated Bmi-1 levels remained unchanged after cytokine withdrawal; and the cytokine-withdrawn cells maintained strong clonogenicity, suggesting that Bmi-1 may play a crucial role in tumorigenesis.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 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 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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