American Association for Cancer Research
10780432ccr170249-sup-178154_2_supp_4233244_qv7jj5.pdf (180.97 kB)

SFigure 1 from Macropinocytosis of Bevacizumab by Glioblastoma Cells in the Perivascular Niche Affects their Survival

Download (180.97 kB)
journal contribution
posted on 2023-03-31, 19:26 authored by Gaëlle Müller-Greven, Cathleen R. Carlin, Monica E. Burgett, Manmeet S. Ahluwalia, Adam Lauko, Amy S. Nowacki, Cameron J. Herting, Maha A. Qadan, Markus Bredel, Steven A. Toms, Justin D. Lathia, Dolores Hambardzumyan, Jann N. Sarkaria, Petra Hamerlik, Candece L. Gladson

Figure S1 shows that bevacizumab gains access to the perivascular tumor space and is internalized by tumor cells when administered to an orthotopic xenograft model of GBM and confirmation of cancer stem-like cell markers in vivo.



Mayo Brain Tumor

Velosano Foundation



Purpose: Bevacizumab, a humanized monoclonal antibody to VEGF, is used routinely in the treatment of patients with recurrent glioblastoma (GBM). However, very little is known regarding the effects of bevacizumab on the cells in the perivascular space in tumors.Experimental Design: Established orthotopic xenograft and syngeneic models of GBM were used to determine entry of monoclonal anti-VEGF-A into, and uptake by cells in, the perivascular space. Based on the results, we examined CD133+ cells derived from GBM tumors in vitro. Bevacizumab internalization, trafficking, and effects on cell survival were analyzed using multilabel confocal microscopy, immunoblotting, and cytotoxicity assays in the presence/absence of inhibitors.Results: In the GBM mouse models, administered anti-mouse-VEGF-A entered the perivascular tumor niche and was internalized by Sox2+/CD44+ tumor cells. In the perivascular tumor cells, bevacizumab was detected in the recycling compartment or the lysosomes, and increased autophagy was found. Bevacizumab was internalized rapidly by CD133+/Sox2+-GBM cells in vitro through macropinocytosis with a fraction being trafficked to a recycling compartment, independent of FcRn, and a fraction to lysosomes. Bevacizumab treatment of CD133+ GBM cells depleted VEGF-A and induced autophagy thereby improving cell survival. An inhibitor of lysosomal acidification decreased bevacizumab-induced autophagy and increased cell death. Inhibition of macropinocytosis increased cell death, suggesting macropinocytosis of bevacizumab promotes CD133+ cell survival.Conclusions: We demonstrate that bevacizumab is internalized by Sox2+/CD44+-GBM tumor cells residing in the perivascular tumor niche. Macropinocytosis of bevacizumab and trafficking to the lysosomes promotes CD133+ cell survival, as does the autophagy induced by bevacizumab depletion of VEGF-A. Clin Cancer Res; 23(22); 7059–71. ©2017 AACR.

Usage metrics

    Clinical Cancer Research



    Ref. manager