4.6 Article

Impact of Regorafenib on Endothelial Transdifferentiation of Glioblastoma Stem-like Cells

Journal

CANCERS
Volume 14, Issue 6, Pages -

Publisher

MDPI
DOI: 10.3390/cancers14061551

Keywords

regorafenib; glioblastoma; glioblastoma stem-like cells; transdifferentiation; tumour-derived endothelial cells; ionising radiation

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Funding

  1. Bayer Pharma
  2. Institut National de la Sante et de la Recherche Medicale (INSERM-The French National Institute for Health and Medical Research)

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Glioblastomas (GBM) are aggressive brain tumors with limited treatment options. This study investigates the impact of regorafenib on GBM stem cells (GSC) and tumor-derived endothelial cells (TDEC) and suggests that regorafenib may be a promising therapeutic option for highly aggressive brain tumors.
Simple Summary Glioblastomas (GBM) are the most frequent and aggressive adult brain tumours with a poor prognosis despite heavy therapy that combines surgical resection and radio-chemotherapy. There is a real therapeutic failure concerning these tumours and it highlights the need for new efficient and usable molecules in these particular and not easily reachable cancers. GBM are also characterised by abnormal and abundant vascularisation, of which some vessels originate from transdifferentiation of GBM stem cells (GSC) to tumour-derived endothelial cells (TDEC). As this mechanism was described as essential for tumour growth, we evaluated the impact of regorafenib, a multikinase inhibitor with anti-angiogenic and anti-tumourigenic activity on transdifferentiation but also directly on GSC. Regorafenib significantly decreases GSC proliferation in vitro but also in vivo. Regorafenib also inhibits transdifferentiation by decreasing phenotypic and functional endothelial features of TDEC obtained from non-irradiated GSC but also of TDEC obtained from irradiated GSC. All these results confirm that regorafenib clearly impacts GSC tumour formation and transdifferentiation and may therefore be a promising therapeutic option in combination with chemo/radiotherapy for the treatment of these highly aggressive brain tumours. Glioblastomas (GBM) are aggressive brain tumours with a poor prognosis despite heavy therapy that combines surgical resection and radio-chemotherapy. The presence of a subpopulation of GBM stem cells (GSC) contributes to tumour aggressiveness, resistance and recurrence. Moreover, GBM are characterised by abnormal, abundant vascularisation. Previous studies have shown that GSC are directly involved in new vessel formation via their transdifferentiation into tumour-derived endothelial cells (TDEC) and that irradiation (IR) potentiates the pro-angiogenic capacity of TDEC via the Tie2 signalling pathway. We therefore investigated the impact of regorafenib, a multikinase inhibitor with anti-angiogenic and anti-tumourigenic activity, on GSC and TDEC obtained from irradiated GSC (TDEC IR+) or non-irradiated GSC (TDEC). Regorafenib significantly decreases GSC neurosphere formation in vitro and inhibits tumour formation in the orthotopic xenograft model. Regorafenib also inhibits transdifferentiation by decreasing CD31 expression, CD31+ cell count, pseudotube formation in vitro and the formation of functional blood vessels in vivo of TDEC and TDEC IR+. All of these results confirm that regorafenib clearly impacts GSC tumour formation and transdifferentiation and may therefore be a promising therapeutic option in combination with chemo/radiotherapy for the treatment of highly aggressive brain tumours.

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