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

Abstract

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.

Characterization of Glioblastoma Cells Response to Regorafenib

“…Finally, we addressed the impact of regorafenib on the ability of GSCs to form spheres. It has been previously reported that regorafenib impairs this ability [ 31 ], which is an indicator of the cells self-renewal capability, a major stem-cell feature. To address this specific issue in our experimental model, we performed a clonogenic assay.…”

Regorafenib and glioblastoma: a literature review of preclinical studies, molecular mechanisms and clinical effectiveness

“…A significant impact of regorafenib on the glioma stem cell (GSC) sub-population was also reported (Ref. 39). GSCs represent the cellular fraction responsible for GBM recurrence, and are the cellular subpopulation which is most resistant to anticancer drugs (Ref.…”

“…A recent paper specifically addressed the issue of regorafenib impact on GSCs differentiation towards the endothelial phenotype (Ref. 39 ). Authors treated two GSC cell lines (derived from a classical and from a proneural GBM, respectively) with regorafenib, either in vitro or in mouse xenografts, and obtained a consistent reduction of CD31-expressing cells, as well as a general, dose-dependent reduction of GSCs pro-angiogenic ability.…”

Glioblastoma-Specific Strategies of Vascularization: Implications in Anti-Angiogenic Therapy Resistance

“…Recently, it has been demonstrated that regorafenib, a multikinase inhibitor that targets angiogenic kinases (VEGFR 1–3 and PDGFR-b), as well as, oncogenic kinases (c-KIT, RET, FGFR, and Raf), has an impact on the endothelial transdifferentiation of GSCs [ 137 , 138 ]. Deshors et al demonstrated that this drug significantly reduces tumor-derived ECs as well as their proangiogenic abilities, both in vitro and in vivo.…”

“…Intriguingly, the authors also demonstrated that regorafenib can inhibit the irradiation-induced transdifferentiation of GSCs in vivo. Indeed, the mice irradiated and treated with regorafenib had significantly fewer functional blood vessels than the irradiated mice [ 138 ]. Regorafenib has recently been approved for second-line treatment of recurrent GBM.…”