Histopathological investigation of glioblastomas resected under bevacizumab treatment

Abstract

To date, no clinical observations have been reported for histopathological changes in human gliomas under antiangiogenic treatment.We collected six glioblastomas resected under bevacizumab treatment. Histopathological investigation was performed by hematoxilyn-eosin staining and immunohistochemistry for CD34, VEGF, VEGFR1/2, HIF-1α, CA9, and nestin as compared to eleven control glioblastomas to assess the differences in histological features, microvessel density, expression of VEGF and its receptors, tumor oxygenation, and status of glioma stem-like cells.In the six tumors resected under bevacizumab, microvascular proliferation was absent, and microvessel density had significantly decreased compared with that of the controls. The expressions of VEGF and its receptors were downregulated in two cases of partial response. HIF-1α or CA9 expression was decreased in five of the six tumors, whereas the decreased expression of these markers was noted in only one of the 11 control glioblastomas. The expression of nestin significantly decreased in the six tumors compared with that of the controls, with the remaining nestin-positive cells being relatively concentrated around vessels.We provide the first clinicopathological evidence that antiangiogenic therapy induces the apparent normalization of vascular structure, decrease of microvessel density, and improvement of tumor oxygenation in glioblastomas. These in situ observations will help to optimize therapy.

Glioma FMISO PET/MR Imaging Concurrent with Antiangiogenic Therapy: Molecular Imaging as a Clinical Tool in the Burgeoning Era of Personalized Medicine

“…Specifically, we hypothesize that bevacizumab induced vascular normalization results in improvement in tissue oxygenation. These findings are supported by histopathological evaluation of the effects of antiangiogenic therapies in patient-derived glioma specimens that demonstrate disappearance of microvascular proliferation, significant reduction of microvessel density, and reduction in endogenous molecular markers for tumor hypoxia suggesting improvement in tissue oxygenation [79]. These histological findings are supported by the observation in our cohort of a correlation between reduction in hypoxic volume and decreased rCBV occurring as a result of bevacizumab therapy.…”

Persistent restoration to the immunosupportive tumor microenvironment in glioblastoma by bevacizumab

“…41 Hypoxiainducible factor-1α was also able to activate the expression of PD-L1 by binding of HIF to a specific hypoxic response element in the promoter of PD-L1 in cancer cells. 42,43 We have previously reported that Bev improves tumor oxygenation in glioblastomas, 4 and that tumor hypoxia is regained in the post-Bev refractory tumors, to a similar or even higher level compared with the paired pre-Bev initial tumors. 5 In the present study, however, immunosuppressive cells and molecules in the tumors of refractory Bev group were still suppressed compared with the naïve Bev group despite recovery of hypoxia.…”

“…The present study used 47 glioblastoma tissues from 31 patients obtained at 3 different settings: 15 tumors resected following Bev therapy (under the Bev efficacy, defined as the "effective Bev group"), 20 tumors of initial glioblastoma (defined as the "naïve Bev group"), and 12 post-Bev recurrent tumors (defined as the "refractory Bev group") ( Table S1). The 15 tumors resected following Bev therapy (cases [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] were the tumors resected after 1-3 times of the preoperative Bev administration at a dose of 10 mg/kg for a safer surgical resection or as a consequence of the clinical course, and included 3 tumors enrolled in the phase II study of neoadjuvant Bev (UMIN000025579). Tumor resection was carried out 21-36 days after the last Bev treatment.…”

“…We have previously reported, using tumor specimens resected following Bev therapy (under the Bev efficacy), that Bev induces the normalization of vascular structure, reduction of microvessel density, and improves tumor oxygenation. 4 In addition, by comparing tumors resected before treatment (initial tumor), following Bev therapy (under the Bev efficacy), and at the time of recurrence, tumor hypoxia was regained while the microvessel density was still paradoxically lowered in recurrent tumors after Bev therapy, suggesting that the re-activation of tumor angiogenesis might not be involved in the first stage of refractoriness to Bev. 5 Bevacizumab is known to enhance the effects of immunotherapy, because VEGF-A suppresses antitumor immunity by inhibiting the maturation of DCs and stimulating the proliferation of Tregs.…”

The role of vascular endothelial growth factor in the hypoxic and immunosuppressive tumor microenvironment: perspectives for therapeutic implications

“…MDSCs are reported to differentiate into TAMs in the hypoxic microenvironment, which is regulated by STAT3 activity [60]. Since these immunosuppressive cells and immune checkpoint molecules show cross talk in the hypoxic TME, anti-VEGF/VEGFR therapy can induce tumor oxygenation [61], resulting in an immune-supportive TME.…”