CD44 expression in the tumor periphery predicts the responsiveness to bevacizumab in the treatment of recurrent glioblastoma
Abstract Antiangiogenic therapy with bevacizumab (Bev), a monoclonal antibody targeting vascular endothelial growth factor (VEGF), is a common treatment for recurrent glioblastoma (GBM), but its survival benefit is limited. Resistance to Bev is thought to be a major cause of ineffectiveness on Bev t...
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Online Access: | https://doi.org/10.1002/cam4.3767 |
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doaj-c9c9b0ba3246479ab1c5326b3e7cd5052021-03-15T05:30:25ZengWileyCancer Medicine2045-76342021-03-011062013202510.1002/cam4.3767CD44 expression in the tumor periphery predicts the responsiveness to bevacizumab in the treatment of recurrent glioblastomaMasahiro Nishikawa0Akihiro Inoue1Takanori Ohnishi2Hajime Yano3Yonehiro Kanemura4Shohei Kohno5Shiro Ohue6Saya Ozaki7Shirabe Matsumoto8Satoshi Suehiro9Yawara Nakamura10Seiji Shigekawa11Hideaki Watanabe12Riko Kitazawa13Junya Tanaka14Takeharu Kunieda15Department of Neurosurgery Ehime University School of Medicine Toon JapanDepartment of Neurosurgery Ehime University School of Medicine Toon JapanDepartment of Neurosurgery Washoukai Sadamoto Hospital Matsuyama JapanDepartment of Molecular and Cellular Physiology Ehime University School of Medicine Toon JapanDepartment of Biomedical Research and Innovation Institute for Clinical Research National Hospital Organization Osaka National Hospital Osaka JapanDepartment of Neurosurgery Ehime University School of Medicine Toon JapanDepartment of Neurosurgery Ehime Prefectural Central Hospital Matsuyama JapanDepartment of Neurosurgery Ehime University School of Medicine Toon JapanDepartment of Neurosurgery Ehime University School of Medicine Toon JapanDepartment of Neurosurgery Ehime University School of Medicine Toon JapanDepartment of Neurosurgery Ehime University School of Medicine Toon JapanDepartment of Neurosurgery Ehime University School of Medicine Toon JapanDepartment of Neurosurgery Ehime University School of Medicine Toon JapanDivision of Diagnostic Pathology Ehime University Hospital Toon JapanDepartment of Molecular and Cellular Physiology Ehime University School of Medicine Toon JapanDepartment of Neurosurgery Ehime University School of Medicine Toon JapanAbstract Antiangiogenic therapy with bevacizumab (Bev), a monoclonal antibody targeting vascular endothelial growth factor (VEGF), is a common treatment for recurrent glioblastoma (GBM), but its survival benefit is limited. Resistance to Bev is thought to be a major cause of ineffectiveness on Bev therapy. To optimize Bev therapy, identification of a predictive biomarker for responsiveness to Bev is required. Based on our previous study, we focused on the expression and functions of CD44 and VEGF in the Bev therapy. Here, we analyze a relationship between CD44 expression and responsiveness to Bev and elucidate the role of CD44 in anti‐VEGF therapy. CD44 and VEGF expression in the tumor core and periphery of 22 GBMs was examined, and the relationship between expression of these molecules and progression‐free time on Bev therapy was analyzed. The degree of CD44 expression in the tumor periphery was evaluated by the ratio of the mRNA expression in the tumor periphery to that in the tumor core (P/C ratio). VEGF expression was evaluated by the amount of the mRNA expression in the tumor periphery. To elucidate the roles of CD44 in the Bev therapy, in vitro and in vivo studies were performed using glioma stem‐like cells (GSCs) and a GSC‐transplanted mouse xenograft model, respectively. GBMs expressing high P/C ratio of CD44 were much more refractory to Bev than those expressing low P/C ratio of CD44, and the survival time of the former was much shorter than that of the latter. In vitro inhibition of VEGF with siRNA or Bev‐activated CD44 expression and increased invasion of GSCs. Bev showed no antitumor effects in mice transplanted with CD44‐overexpressing GSCs. The P/C ratio of CD44 expression may become a useful biomarker predicting responsiveness to Bev in GBM. CD44 reduces the antitumor effect of Bev, resulting in much more highly invasive tumors.https://doi.org/10.1002/cam4.3767bevacizumabCD44glioblastomaglioma stem cellinvasionvascular endothelial growth factor |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Masahiro Nishikawa Akihiro Inoue Takanori Ohnishi Hajime Yano Yonehiro Kanemura Shohei Kohno Shiro Ohue Saya Ozaki Shirabe Matsumoto Satoshi Suehiro Yawara Nakamura Seiji Shigekawa Hideaki Watanabe Riko Kitazawa Junya Tanaka Takeharu Kunieda |
spellingShingle |
Masahiro Nishikawa Akihiro Inoue Takanori Ohnishi Hajime Yano Yonehiro Kanemura Shohei Kohno Shiro Ohue Saya Ozaki Shirabe Matsumoto Satoshi Suehiro Yawara Nakamura Seiji Shigekawa Hideaki Watanabe Riko Kitazawa Junya Tanaka Takeharu Kunieda CD44 expression in the tumor periphery predicts the responsiveness to bevacizumab in the treatment of recurrent glioblastoma Cancer Medicine bevacizumab CD44 glioblastoma glioma stem cell invasion vascular endothelial growth factor |
author_facet |
Masahiro Nishikawa Akihiro Inoue Takanori Ohnishi Hajime Yano Yonehiro Kanemura Shohei Kohno Shiro Ohue Saya Ozaki Shirabe Matsumoto Satoshi Suehiro Yawara Nakamura Seiji Shigekawa Hideaki Watanabe Riko Kitazawa Junya Tanaka Takeharu Kunieda |
author_sort |
Masahiro Nishikawa |
title |
CD44 expression in the tumor periphery predicts the responsiveness to bevacizumab in the treatment of recurrent glioblastoma |
title_short |
CD44 expression in the tumor periphery predicts the responsiveness to bevacizumab in the treatment of recurrent glioblastoma |
title_full |
CD44 expression in the tumor periphery predicts the responsiveness to bevacizumab in the treatment of recurrent glioblastoma |
title_fullStr |
CD44 expression in the tumor periphery predicts the responsiveness to bevacizumab in the treatment of recurrent glioblastoma |
title_full_unstemmed |
CD44 expression in the tumor periphery predicts the responsiveness to bevacizumab in the treatment of recurrent glioblastoma |
title_sort |
cd44 expression in the tumor periphery predicts the responsiveness to bevacizumab in the treatment of recurrent glioblastoma |
publisher |
Wiley |
series |
Cancer Medicine |
issn |
2045-7634 |
publishDate |
2021-03-01 |
description |
Abstract Antiangiogenic therapy with bevacizumab (Bev), a monoclonal antibody targeting vascular endothelial growth factor (VEGF), is a common treatment for recurrent glioblastoma (GBM), but its survival benefit is limited. Resistance to Bev is thought to be a major cause of ineffectiveness on Bev therapy. To optimize Bev therapy, identification of a predictive biomarker for responsiveness to Bev is required. Based on our previous study, we focused on the expression and functions of CD44 and VEGF in the Bev therapy. Here, we analyze a relationship between CD44 expression and responsiveness to Bev and elucidate the role of CD44 in anti‐VEGF therapy. CD44 and VEGF expression in the tumor core and periphery of 22 GBMs was examined, and the relationship between expression of these molecules and progression‐free time on Bev therapy was analyzed. The degree of CD44 expression in the tumor periphery was evaluated by the ratio of the mRNA expression in the tumor periphery to that in the tumor core (P/C ratio). VEGF expression was evaluated by the amount of the mRNA expression in the tumor periphery. To elucidate the roles of CD44 in the Bev therapy, in vitro and in vivo studies were performed using glioma stem‐like cells (GSCs) and a GSC‐transplanted mouse xenograft model, respectively. GBMs expressing high P/C ratio of CD44 were much more refractory to Bev than those expressing low P/C ratio of CD44, and the survival time of the former was much shorter than that of the latter. In vitro inhibition of VEGF with siRNA or Bev‐activated CD44 expression and increased invasion of GSCs. Bev showed no antitumor effects in mice transplanted with CD44‐overexpressing GSCs. The P/C ratio of CD44 expression may become a useful biomarker predicting responsiveness to Bev in GBM. CD44 reduces the antitumor effect of Bev, resulting in much more highly invasive tumors. |
topic |
bevacizumab CD44 glioblastoma glioma stem cell invasion vascular endothelial growth factor |
url |
https://doi.org/10.1002/cam4.3767 |
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