Antitumorigenic effect of interferon-β by inhibition of undifferentiated glioblastoma cells

Yamamuro, Shun; Sano, Emiko; Okamoto, Yutaka; Ochiai, Yushi; Ohta, Takashi; Ogino, Akiyoshi; Natsume, Atsushi; Wakabayashi, Toshihiko; Ueda, Takuya; Hara, Hiroyuki; Nakayama, Tomohiro; Yoshino, Atsuo; Katayama, Yoichi

doi:10.3892/ijo.2015.3165

Cited by 8 publications

(10 citation statements)

References 41 publications

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“…3 a). IFN-β might represent an effective agent for controlling cell differentiation in hGSCs (Yamamuro et al 2015 ). S100-β has long been considered a biomarker for astrocytes (Castets et al 1997 ).…”

Section: Resultsmentioning

confidence: 99%

Interferon-beta inhibits human glioma stem cell growth by modulating immune response and cell cycle related signaling pathways

Han

Jin

et al. 2022

Cell Regen

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Malignant Glioma is characterized by strong self-renewal potential and immature differentiation potential. The main reason is that malignant glioma holds key cluster cells, glioma stem cells (GSCs). GSCs contribute to tumorigenesis, tumor progression, recurrence, and treatment resistance. Interferon-beta (IFN-β) is well known for its anti-proliferative efficacy in diverse cancers. IFN-β also displayed potent antitumor effects in malignant glioma. IFN-β affect both GSCs and Neural stem cells (NSCs) in the treatment of gliomas. However, the functional comparison, similar or different effects of IFN-β on GSCs and NSCs are rarely reported. Here, we studied the similarities and differences of the responses to IFN-β between human GSCs and normal NSCs. We found that IFN-β preferentially inhibited GSCs over NSCs. The cell body and nucleus size of GSCs increased after IFN-β treatment, and the genomic analysis revealed the enrichment of the upregulated immune response, cell adhesion genes and down regulated cell cycle, ribosome pathways. Several typical cyclin genes, including cyclin A2 (CCNA2), cyclin B1 (CCNB1), cyclin B2 (CCNB2), and cyclin D1 (CCND1), were significantly downregulated in GSCs after IFN-β stimulation. We also found that continuous IFN-β stimulation after passage further enhanced the inhibitory effect. Our study revealed how genetic diversity resulted in differential effects in response to IFN-β treatment. These results may contribute to improve the applications of IFN-β in anti-cancer immunotherapy. In addition, these results may also help to design more effective pharmacological strategies to target cancer stem cells while protecting normal neural stem cells.

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Section: Resultsmentioning

confidence: 99%

Interferon-beta inhibits human glioma stem cell growth by modulating immune response and cell cycle related signaling pathways

Han

Jin

et al. 2022

Cell Regen

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“…IFN-β is one of the classic tumor suppressors, which has been proven to significantly inhibit tumor cell growth and induce cell apoptosis in vitro [3, 4]. However, daily subcutaneous or intraperitoneal injection of large doses of IFN-β has not exhibited an effective antitumor effect in the animal xenograft models [10, 22].…”

Section: Discussionmentioning

confidence: 99%

“…Interferon-β (IFN-β), a therapeutically attractive member of the IFN family, is one of the classic tumor suppressors, which has been proven to significantly inhibit tumor cell growth and induce apoptosis in vitro [3, 4]. The new mechanisms by which IFN-β exerts its anticancer effect have also been explored [5, 6].…”

Section: Introductionmentioning

confidence: 99%

The growth inhibitory effect of human gingiva-derived mesenchymal stromal cells expressing interferon-β on tongue squamous cell carcinoma cells and xenograft model

Liang

et al. 2019

Stem Cell Res Ther

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Background Interferon-β (IFN-β) is a cytokine with pleiotropic cellular functions, including antiviral, antiproliferative, and immunomodulatory activities. IFN-β inhibits multiple tumor cell growth in vitro. However, the contradiction between the therapeutic dose of IFN-β and its maximally tolerated dose is still inextricable in vivo. Human gingiva-derived mesenchymal stromal cells (GMSCs) represent promising vehicles for cancer gene therapy. This study evaluated the potential of GMSCs genetically engineered to produce IFN-β as a targeted gene delivery system to treat tongue squamous cell carcinoma (TSCC) in vitro and in vivo. Methods A lentiviral vector encoding IFN-β was constructed and transfected into GMSCs to obtain IFN-β gene-modified GMSCs (GMSCs/IFN-β). Enzyme-linked immunosorbent assay (ELISA) was used to measure the IFN-β concentration in conditioned medium (CM) from GMSCs/IFN-β. The Cell Counting Kit-8 (CCK8), colony formation assay, and flow cytometry were used to detect the effects of GMSCs/IFN-β on TSCC cell line CAL27 cell growth and apoptosis in vitro. TSCC xenograft model was developed by subcutaneous injection of CAL27 cells into BALB/c nude mouse, and the role of intravenously injected GMSCs/IFN-β in engrafting in TSCC and controlling tumor progression was measured in vivo. Results GMSCs/IFN-β expressed a high level of IFN-β. Both CCK8 and colony forming assay showed that GMSCs/IFN-β significantly inhibited the proliferation of CAL27 cells compared with the GMSCs, GMSCs/vector, or DMEM group. Flow cytometry analysis demonstrated that the CAL27 cell apoptosis rate was higher in the GMSCs/IFN-β group than in the other three groups. The in vivo experiment revealed that GMSCs/IFN-β engrafted selectively in TSCC xenograft and expressed a high level of IFN-β. There were smaller tumor volume and lower number of Ki67-positive cells in the GMSCs/IFN-β group than in the GMSCs, GMSCs/vector, or phosphate-buffered saline (PBS) group. Interestingly, GMSCs and GMSCs/vector also presented the potential of CAL27 cell growth inhibition in vitro and in vivo, although such an effect was weaker than GMSCs/IFN-β. Conclusions GMSCs/IFN-β inhibits the proliferation of TSCC cells in vitro and in vivo. These results provide evidence that delivery of IFN-β by GMSCs may be a promising approach to develop an effective treatment option for TSCC therapy.

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“…3a). IFN-β might represent an effective agent for controlling cell differentiation in hGSCs [34]. S100-β has long been considered a biomarker for astrocytes [35].…”

Section: The Nuclear Sizes Of Hgscs Was Decreased By Ifn-βmentioning

confidence: 99%

Interferon-Beta Inhibits Human Glioma Stem Cells Rather Than Neural Stem Cells via Cell Cycle and Immune Signaling

Han

Jin

et al. 2021

Preprint

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BackgroundMalignant Glioma is considered to be a highly heterogeneous brain tumor, which may have originated from mutated neural stem cells (NSCs) many years before it was diagnosed. Malignant Glioma is characterized by strong self-renewal potential and immature differentiation potential. The main reason is that malignant glioma holds a key cluster cells, glioma stem cells (GSCs). GSCs contribute to tumorigenesis, tumor progression, recurrence, and treatment resistance. Interferon-beta (IFN-β) is well known for its anti-proliferative efficacy in diversity cancers. IFN-β also displayed potent antitumor results in malignant glioma. IFN-β treatments administered in response to gliomas affect both GSCs and NSCs. However, the function comparison, similarities and differences of IFN-β on GSCs and NSCs are rarely reported. MethodsWe used human GSCs and NSCs to detect the response difference between two cells by IFN-β. Human GSCs were constructed by ourselves and human normal NSCs line were differentiated from human embryonic stem cells. Various concentrations of IFN-β were separately used to treat human GSCs (hGSCs) and human NSCs (hNSCs). Cell morphology, growth, expression of special stemness genes, neural-related makers or proliferation related genes were staining and observed, such as SRY-box transcription factor 2 (Sox2), S100 calcium binding protein B (S100-beta) and marker of proliferation Ki-67 (Ki67). Genetic alterations were carefully analyzed by RNA-seq. We used repetitive stimulation treatment and compared the different response between hGSCs and hNSCs with IFN-β. Genomic analysis was also performed to identify genes with changes in expression levels in hGSCs but stable expression levels in hNSCs. ResultsWe found that IFN-β preferentially inhibited GSCs rather than NSCs. The cell body and nucleus size of GSCs increased after IFN-β treatment. The expression of special stemness gene Sox2 and marker of proliferation Ki67 significantly decreased. S100-beta, which was a central nervous system enrichment, cycle progression and differentiation related gene, also reduced after IFN-β treatment. Significant differences were observed between hGSCs and human NSCs after continuous IFN-β treatment. Genomic analysis revealed the enrichment of the immune response, cell adhesion, cell cycle, and ribosome pathways such as proto-oncogene NF-kB subunit ( RELB ), TRAF interacting protein with forkhead associated domain ( TIFA ), nuclear factor kappa B subunit 1 ( NFKB )and signal transducer and activator of transcription 6 ( STAT6 ). Several typical cyclin genes, including cyclin A2 ( CCNA2) , cyclin B1 ( CCNB1) , cyclin B2 ( CCNB2) , and cyclin D1 ( CCND1) , were significantly downregulated in GSCs after IFN-β stimulation. ConclusionsOur study revealed how genetic diversity resulted in differential effects in response to IFN-β treatment. These results may contribute to improve the applications of IFN-β anti-cancer immunotherapy. In addition, these results may also help to design more effective pharmacological strategies to target killing cancer stem cells while protecting normal neural stem cells.

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Antitumorigenic effect of interferon-β by inhibition of undifferentiated glioblastoma cells

Cited by 8 publications

References 41 publications

Interferon-beta inhibits human glioma stem cell growth by modulating immune response and cell cycle related signaling pathways

Interferon-beta inhibits human glioma stem cell growth by modulating immune response and cell cycle related signaling pathways

The growth inhibitory effect of human gingiva-derived mesenchymal stromal cells expressing interferon-β on tongue squamous cell carcinoma cells and xenograft model

Interferon-Beta Inhibits Human Glioma Stem Cells Rather Than Neural Stem Cells via Cell Cycle and Immune Signaling

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