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Pre-Clinical Drug Testing in 2D and 3D Human In Vitro Models of Glioblastoma Incorporating Non-Neoplastic Astrocytes: Tunneling Nano Tubules and Mitochondrial Transfer Modulates Cell Behavior and Therapeutic Respons

1
Brain Tumour Research Centre, Institute of Biological and Biomedical Sciences (IBBS), School of Pharmacy and Biomedical Sciences, University of Portsmouth, White Swan Road, Portsmouth PO1 2DT, UK
2
Department of Chemistry, University College London, 20 Gordon Street, Christopher Ingold Building, London WC1H 0AJ, UK
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(23), 6017; https://doi.org/10.3390/ijms20236017
Received: 30 October 2019 / Revised: 19 November 2019 / Accepted: 23 November 2019 / Published: 29 November 2019
(This article belongs to the Special Issue Advances of Molecular Biology and Translational Aspects in CNS Tumors)
The role of astrocytes in the glioblastoma (GBM) microenvironment is poorly understood; particularly with regard to cell invasion and drug resistance. To assess this role of astrocytes in GBMs we established an all human 2D co-culture model and a 3D hyaluronic acid-gelatin based hydrogel model (HyStem™-HP) with different ratios of GBM cells to astrocytes. A contact co-culture of fluorescently labelled GBM cells and astrocytes showed that the latter promotes tumour growth and migration of GBM cells. Notably, the presence of non-neoplastic astrocytes in direct contact, even in low amounts in co-culture, elicited drug resistance in GBM. Recent studies showed that non-neoplastic cells can transfer mitochondria along tunneling nanotubes (TNT) and rescue damaged target cancer cells. In these studies, we explored TNT formation and mitochondrial transfer using 2D and 3D in vitro co-culture models of GBM and astrocytes. TNT formation occurs in glial fibrillary acidic protein (GFAP) positive “reactive” astrocytes after 48 h co-culture and the increase of TNT formations was greater in 3D hyaluronic acid-gelatin based hydrogel models. This study shows that human astrocytes in the tumour microenvironment, both in 2D and 3D in vitro co-culture models, could form TNT connections with GBM cells. We postulate that the association on TNT delivery non-neoplastic mitochondria via a TNT connection may be related to GBM drug response as well as proliferation and migration. View Full-Text
Keywords: glioblastoma; nano tunneling; in vitro 3D model; human serum supplementation; astrocytes; hyaluronic acid; extracellular matrix; tumour microenvironment; drug screening glioblastoma; nano tunneling; in vitro 3D model; human serum supplementation; astrocytes; hyaluronic acid; extracellular matrix; tumour microenvironment; drug screening
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Civita, P.; M. Leite, D.; Pilkington, G.J. Pre-Clinical Drug Testing in 2D and 3D Human In Vitro Models of Glioblastoma Incorporating Non-Neoplastic Astrocytes: Tunneling Nano Tubules and Mitochondrial Transfer Modulates Cell Behavior and Therapeutic Respons. Int. J. Mol. Sci. 2019, 20, 6017.

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