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Glioma Stem-like Cell Survival is Affected by their Macropinocytic Uptake and Targeted Trafficking of Bevacizumab

Müller-Greven, Gaëlle Melanie
http://orcid.org/0000-0002-6777-1841
http://rave.ohiolink.edu/etdc/view?acc_num=kent1520520113612687

Abstract Details

2018, PHD, Kent State University, College of Arts and Sciences / School of Biomedical Sciences.
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.
Candece Gladson (Advisor)
Gail Fraizer (Committee Member)
Edgar Kooijman (Committee Member)
Robert Silverman (Committee Member)
Douglas Kline (Committee Member)
143 p.
Biomedical Research; Cellular Biology; Molecular Biology; Oncology
glioblastoma, cancer stem cells, perivascular niche, therapeutic antibodies, trafficking

Recommended Citations

Citations

  • Müller-Greven, G. M. (2018). Glioma Stem-like Cell Survival is Affected by their Macropinocytic Uptake and Targeted Trafficking of Bevacizumab [Doctoral dissertation, Kent State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=kent1520520113612687

    APA Style (7th edition)

  • Müller-Greven, Gaëlle. Glioma Stem-like Cell Survival is Affected by their Macropinocytic Uptake and Targeted Trafficking of Bevacizumab. 2018. Kent State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=kent1520520113612687.

    MLA Style (8th edition)

  • Müller-Greven, Gaëlle. "Glioma Stem-like Cell Survival is Affected by their Macropinocytic Uptake and Targeted Trafficking of Bevacizumab." Doctoral dissertation, Kent State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=kent1520520113612687

    Chicago Manual of Style (17th edition)

kent1520520113612687
464
© 2018, all rights reserved.
This open access ETD is published by Kent State University and OhioLINK.