Research Papers:

“Paradoxical” findings of tumor vascularity and oxygenation in recurrent glioblastomas refractory to bevacizumab

Yohei Yamamoto, Ryota Tamura, Toshihide Tanaka _, Kentaro Ohara, Yukina Tokuda, Keisuke Miyake, Jun Takei, Yasuharu Akasaki, Kazunari Yoshida, Yuichi Murayama and Hikaru Sasaki

PDF  |  HTML  |  How to cite

Oncotarget. 2017; 8:103890-103899. https://doi.org/10.18632/oncotarget.21978

Metrics: PDF 1413 views  |   HTML 2537 views  |   ?  


Yohei Yamamoto1, Ryota Tamura2, Toshihide Tanaka1, Kentaro Ohara3, Yukina Tokuda2, Keisuke Miyake4, Jun Takei1, Yasuharu Akasaki5, Kazunari Yoshida2, Yuichi Murayama5 and Hikaru Sasaki2

1Department of Neurosurgery, Jikei University School of Medicine Kashiwa Hospital, Kashiwa-shi, Chiba 277-8567, Japan

2Department of Neurosurgery, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan

3Division of Diagnostic Pathology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan

4Department of Neurosurgery, Kagawa University Hospital, Kita-gun, Kagawa 761-0793, Japan

5Department of Neurosurgery, Jikei University School of Medicine, Minato-ku, Tokyo 105-8461, Japan

Correspondence to:

Toshihide Tanaka, email: [email protected]

Keywords: bevacizumab, glioblastoma, vascular endothelial growth factor, hypoxia, neoadjuvant therapy

Received: February 08, 2017     Accepted: October 17, 2017     Published: October 24, 2017


Anti-angiogenic therapy induces the apparent normalization of vascular structure, decreases microvessel density (MVD), and improves tumor oxygenation in glioblastomas (GBMs). Six initial and recurrent tumor pairs after bevacizumab (Bev) treatment were compared with GBMs from nine patients resected under neoadjuvant Bev treatment with regard to histological characteristics; MVD; MIB-1 index; and expression of vascular endothelial growth factor (VEGF) and its receptors, hypoxia markers (hypoxia-inducible factor 1 alpha, carbonic anhydrase 9), and nestin as a marker of glioma stem-like cells. In recurrent tumors post-Bev treatment, while the MVD remained low compared with the paired initial tumors (pre-Bev tumors), the expression of hypoxic markers were increased and were even higher in expression compared with the paired pre-Bev tumors in three of the six cases. MIB-1 indices were similar among the initial GBMs, neoadjuvant group, and recurrent tumors post-Bev treatment. The nestin-positive cell ratio of the post-Bev recurrent tumors was as high as that of the pre-Bev tumors. The expression of VEGF and VEGFR1 was increased in the post-Bev recurrent tumors in three and four cases, respectively, compared with the paired pre-Bev tumors. In the majority of Bev-refractory GBMs, tumor hypoxia was present with a paradoxical decrease in MVD. These findings suggest that re-activation of tumor angiogenesis is not initially involved in the acquisition of resistance to Bev.

Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 21978