"Paradoxical" findings of tumor vascularity and oxygenation in recurrent glioblastomas refractory to bevacizumab.

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

doi:10.18632/oncotarget.21978

Abstract

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.

Highlights

Glioblastoma (GBM) is a highly vascularized malignant tumor, and inhibiting angiogenesis is an attractive treatment strategy
We previously demonstrated that Bev induces the apparent normalization of vascular structure, decreases microvessel density (MVD), and improves tumor oxygenation in human GBMs resected under Bev treatment [9]
As previously reported [9], improvement of tumor oxygenation was noted in eight of the nine tumors, and the MVD and nestin-positive cell ratio were significantly decreased compared with the preBev initial tumors

Summary

Introduction

Glioblastoma (GBM) is a highly vascularized malignant tumor, and inhibiting angiogenesis is an attractive treatment strategy. The response of GBM to Bev is invariably transient, and recurrent tumors after Bev treatment are associated with a more aggressive and invasive phenotype [5,6,7]. Because the targets of Bev are not tumor cells but are vascular endothelial cells, the mechanism of resistance to Bev is likely different from those of other chemotherapeutic agents that target tumor cells. We previously demonstrated that Bev induces the apparent normalization of vascular structure, decreases microvessel density (MVD), and improves tumor oxygenation in human GBMs resected under Bev treatment [9]

Methods

Results

Conclusion