Glioblastoma cell migration is directed by electrical signals

Significance

Glioblastoma multiforme, also known as grade IV astrocytoma is an aggressive brain tumor which can manifest clinically as personality changes, headaches, seizures, nausea, and other symptoms consistent with stroke. It’s known to invade nearby brain tissues but doesn’t spread to distant organs. Glioblastoma multiforme can occur at all ages, but a majority of patients are diagnosed later in life, at a median age of 64. With no known cure, glioblastoma multiforme patients’ survival rates average 3 months, and between 10-15 months with combined radio- and chemotherapies, and surgical resection interventions.

Bold therapeutic advancements have been made in systemic cancer treatment, but disease recurrence seem to plague glioblastoma multiforme treatment, rendering it incurable. The almost-certain recurrence rate can be traced back to the infiltrative nature of glioblastoma multiforme, where residual cells are inevitably and inadvertently spared in surgical resection.

Glioma stem cells, a subpopulation of glioblastoma multiforme cells, are thought to be responsible for glioblastoma multiforme malignant characteristics. These cells are highly tumorigenic due to their stem-like features of multilineage differentiation, resistance to cell death, self-renewal, and dysregulated proliferation. Glioma stem cells in glioblastoma multiforme have been implicated in the poor survival rates and the invasive behavior of glioblastoma multiforme. In this regard, understanding glioblastoma multiforme migration and its invasion could provide potential avenues for targeted therapeutic approaches.

Glioblastoma multiforme cell migration occurs along the white matter tracts and perivascular regions of the brain. During the process, the cell becomes morphologically polarized as a result of cytoskeletal changes. Research has shown that electrical fields direct neural stem cells migration, where cells tend to migrate towards the cathode. Electrical fields guided cell migration, electrotaxis, has been identified in various cancers at endogenous voltages, including prostate, breast, and recently, brain cancers. Unfortunately, there has been little research done on electrotaxis of glioblastoma multiforme.

In view of this, University of Aberdeen researchers, Hannah Clancy, Michal Pruski, Bing Lang, Dr. Jared Ching, and Professor Colin D. McCaig, sought to investigate the effect of an applied electrical field on the migration of both differentiated and de-differentiated glioblastoma multiforme cell lines. Their study’s objective was to understand the infiltrative behavior of glioblastoma multiforme. The original research article is now published in the journal, Experimental Cell Research.

The research team used the differentiated primary glioblastoma multiforme cell lines HROG02-Diff, HROG05-Diff and HROG24-Diff. Two of these cell lines were de-differentiated into glioma stem cells, HROG02-GSC and HROG05-GSC. They then tracked the cells using time-lapse microscopy, calculating their velocity and directedness with/without an applied electric field. Directedness values of +1 were for perfect anodal migration and -1 for perfect cathodal migration.

The authors observed that a higher proportion of HROG02-Diff, HROG05-Diff and HROG24 cells migrated towards the anode when they applied a higher electrical field. However, with no electrical field, the cells didn’t preferentially migrate to either of the poles. Electrical field application, however, induced a predominant anodal migration with approximately 84% of HROG02-Diff cells, approximately 74% of HROG05-Diff cells, and approximately 90% of HROG24-Diff migrating to the anode at 200 mV/mm potential .The researchers reported a stepwise increase in the directedness of cell migration for both differentiated cell lines. Electrical field application gave an appreciable statistical change in HROG05-Diff and HROG02-Diff. When they increased the electrical field, they observed a statistical increase in cell migration velocity.

To the authors’ surprise, they found that the glioma stem cells migrated in the opposite direction in an applied electric field, with approximately 70% of HROG02-GSC and approximately 68% of HROG05-GSC migrating to the cathode at 200 mV/mm. Again, with no applied electrical field, glioma stem cells had no directed cell migration. Further, a stepwise increase in applied voltage resulted in increased glioma stem cell directedness and migration velocity.

When the authors added pioglitazone in both differentiated glioblastoma and glioma stem cells subtypes, they recorded a significantly inhibited directed cell migration, where HROG05-GSC demonstrated a reversal in directional preference. Implementing western blot analysis, the researchers couldn’t demonstrate any change in PPARγ expression with or without electrical field application. These findings suggest that the addition of pioglitazone can chemically inhibit electric field directed cell migration in both primary glioblastoma multiforme differentiated cells and glioma stem cells. This further suggests that glioblastoma multiforme electrical field modulation could be a promising target in tumor recurrence prevention. The importance of electric fields and their ability to interfere with the cells’ ability to grow and spread has translated clinically to a wearable device known as Optune, which generates electric fields. Next generation electrical stimulation units using DC stimulation algorithms as in this study may become an option in several countries to help treat some people with glioblastomas.

About the author

Dr Jared Ching initially qualified as a Pharmacist, graduating with first class honours from the University of East Anglia and completing his Master’s Thesis on developing novel anti-tumour agents based on acridine-3-carboximides in Professor Mark Searcey’s Laboratory. He subsequently completed a fast track Medical Degree at the University of Bristol and further developed research interests in cancer therapeutics by proposing a novel treatment strategy for brain tumour epilepsy as a Research Fellow at the Departments of Neurosurgery and Neurology, University of Melbourne Australia, where he discovered that peroxisome proliferator agonists may be a promising adjunctive treatment by increasing expression of excitatory amino acid transporter 2 (EAAT2) and reducing glutamate release in glioblastoma cells. He further developed his interests in cancer cell migration by collaborating with Professor Colin McCaig at the University of Aberdeen as a co-principle investigator examining the role of electric fields on glioblastoma stem cells.

Dr Ching completed his specialist training in Ophthalmology, including an NIHR Academic Clinical Fellowship at the University of Cambridge where he researched gene therapy for neuroprotection and neuro-regeneration at the John Van Geest Centre for Brain repair and MRC Mitochondrial Biology Unit. He is currently finalizing corrections for his Neuroscience PhD thesis on Neuro-Oncology at the University of Plymouth and undertaking an advanced clinical fellowship in Ocular Oncology at Moorfields Eye Hospital.

About the author

Colin McCaig

After gaining a first-class BSc (Hons) in Physiology from the University of Edinburgh, Colin McCaig went on to complete his PhD in Physiology at the University of Glasgow. He then worked as a Postdoctoral fellow in the USA and New Zealand. In 1983 he was awarded a prestigious Beit Memorial Research Fellowship to establish his own laboratory at the University of Edinburgh and moved to Aberdeen in 1986 becoming a Wellcome Trust University Award Lecturer in 1988 and Regius Professor of Physiology in Aberdeen in 2002. He was Head of the Department of Biomedical Sciences for five years and Head of the School of Medical Sciences for 12 years during which time research and teaching regularly were rated as excellent. He was elected a Fellow of the Royal Society of Edinburgh in 2007.

Together with colleagues world-wide his laboratory have been amongst the leaders in uncovering the effects of physiological electrical signals on multiple cell and tissue behaviours. Two seminal papers have been cited over 600 times each:

McCaig, C.D. Rajnicek, A.M., Song, B. Song, B.& Zhao, M. (2005). Controlling cell behaviour electrically: Current views and future potential. Physiological Reviews 85, 943-978.

Zhao, M., Song, B., Pu, J., Wada, T., Reid, B., Tai, G., Wang, F., Guo, A., Walczysko, P., Gu, Y., Sasaki, T., Suzuki, A., Forrester, J.V., Bourne, H., Devreotes, P., McCaig, C.D. & Penninger, J. (2006). Electrical signals control wound healing via phosphatidyl –3 kinase g and PTEN. Nature 442, 457-460.

Reference

Hannah Clancy, Michal Pruski, Bing Lang, Jared Ching, and Colin D. McCaig. Glioblastoma cell migration is directed by electrical signals. Experimental Cell Research, issue 406 (2021) 112736.

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