Δ-Catenin promotes bevacizumab-induced glioma invasion

Toshihiko Shimizu, Joji Ishida, Kazuhiko Kurozumi, Tomotsugu Ichikawa, Yoshihiro Otani, Tetsuo Oka, Yusuke Tomita, Yasuhiko Hattori, Atsuhito Uneda, Yuji Matsumoto, Isao Date

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5 Citations (Scopus)

Abstract

The combination of bevacizumab with temozolomide and radiotherapy was shown to prolong progression-free survival in newly diagnosed patients with glioblastoma, and this emphasizes the potential of bevacizumab as a glioma treatment. However, although bevacizumab effectively inhibits angiogenesis, it has also been reported to induce invasive proliferation. This study examined gene expression in glioma cells to investigate the mechanisms of bevacizumab-induced invasion. We made a human glioma U87DEGFR cell xenograft model by stereo-tactically injecting these cells into the brain of animals. We administered bevacizumab intraperitoneally three times per week. At 18 days after tumor implantation, the brains were removed for histopathology and mRNA was extracted. In vivo, bevacizumab treatment increased glioma cell invasion. qRT-PCR array analysis revealed upregulation of d-catenin (CTNND2) and several other factors. In vitro, bevacizumab treatment upregulated d-catenin expression. A low concentration of bevacizumab was not cytotoxic, but tumor cell motility was increased in scratch wound assays and two-chamber assays. Overexpression of d-catenin increased the tumor invasion in vitro and in vivo. However, d-catenin knockdown decreased glioma cell invasiveness. The depth of tumor invasion in the U87DEGFR cells expressing d-catenin was significantly increased compared with empty vector-transfected cells. The increase in invasive capacity induced by bevacizumab therapy was associated with upregulation of d-catenin expression in invasive tumor cells. This finding suggests that d-catenin is related to tumor invasion and migration.

Original languageEnglish
Pages (from-to)812-822
Number of pages11
JournalMolecular cancer therapeutics
Volume18
Issue number4
DOIs
Publication statusPublished - Apr 2019
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Shimizu, T., Ishida, J., Kurozumi, K., Ichikawa, T., Otani, Y., Oka, T., Tomita, Y., Hattori, Y., Uneda, A., Matsumoto, Y., & Date, I. (2019). Δ-Catenin promotes bevacizumab-induced glioma invasion. Molecular cancer therapeutics, 18(4), 812-822. https://doi.org/10.1158/1535-7163.MCT-18-0138