A novel 3D in vitro model of glioblastoma reveals resistance to temozolomide which was potentiated by hypoxia

Musah-Eroje, Ahmed; Watson, Sue

Abstract

Purpose
Glioblastoma (GBM) is the most common invasive malignant brain tumour in adults. It is traditionally investigated in vitro by culturing cells as a monolayer (2D culture) or as neurospheres (clusters enriched in cancer stem cells) but neither system accurately reflects the complexity of the three-dimensional (3D) chemoresistant microenvironment of GBM.
Materials and Methods
Using three GBM cell-lines (U87, U251, and SNB19), the effect of culturing cells in a Cultrex-based basement membrane extract (BME) (3D Tumour Growth Assay (TGA)) on morphology, gene expression, metabolism, and temozolomide chemoresistance was investigated.
Results
Cells were easily harvested from the 3D model and cultured as a monolayer (2D) and neurospheres. Indeed, the SNB19 cells formed neurospheres only after they were first cultured in the 3D model. The expression of CD133 and OCT4 was upregulated in the neurosphere and 3D assays respectively. Compared with cells cultured in the 2D model, cells were more resistant to temozolomide in the 3D model and this resistance was potentiated by hypoxia.
Conclusion
Taken together, these results suggest that micro-environmental factors influence GBM sensitivity to temozolomide. Knowledge of the mechanisms involved in temozolomide resistance in this 3D model might lead to the identification of new strategies that enable the more effective use of the current standard of care agents.

Citation

Musah-Eroje, A., & Watson, S. (2019). A novel 3D in vitro model of glioblastoma reveals resistance to temozolomide which was potentiated by hypoxia. Journal of Neuro-Oncology, 142(2), 231-240. https://doi.org/10.1007/s11060-019-03107-0

• Journal Article Type: Article
• Acceptance Date: Jan 16, 2019
• Online Publication Date: Jan 29, 2019
• Publication Date: Apr 1, 2019
• Deposit Date: Jan 29, 2019
• Publicly Available Date: Jan 29, 2019
• Journal: Journal of Neuro-Oncology
• Print ISSN: 0167-594X
• Electronic ISSN: 1573-7373
• Publisher: Springer Verlag
• Peer Reviewed: Peer Reviewed
• Volume: 142
• Issue: 2
• Pages: 231-240
• DOI: https://doi.org/10.1007/s11060-019-03107-0
• Keywords: Glioblastoma, 3D, chemoresistance, temozolomide, hypoxia, CD133, OCT4
• Public URL: https://nottingham-repository.worktribe.com/output/1504358
• Publisher URL: https://link.springer.com/article/10.1007/s11060-019-03107-0
• Additional Information: Received: 19 October 2018; Accepted: 16 January 2019; First Online: 29 January 2019; : ; : There is no conflict of interest.; : This article does not contain any studies with animal/human participants performed by any of the authors.
• Contract Date: Jan 29, 2019