Glioblastoma resistance to anti-VEGF therapy is associated with myeloid cell infiltration, stem cell accumulation, and a mesenchymal phenotype

Abstract

Vascular endothelial growth factor (VEGF) is a critical regulator of angiogenesis. Inhibiting the VEGF-VEGF receptor (R) signal transduction pathway in glioblastoma has recently been shown to delay progression, but the relative benefit and mechanisms of response and failure of anti-VEGF therapy and VEGFR inhibitors are not well understood. The purpose of our study was to evaluate the relative effectiveness of VEGF sequestration and/or VEGFR inhibition on orthotopic tumor growth and the mechanism(s) of treatment resistance. We evaluated, not only, the effects of anti-VEGF therapy (bevacizumab), anti-VEGFR therapy (sunitinib), and the combination on the survival of mice bearing orthotopic gliomas, but also the differential effects of the treatments on tumor vascularity, cellular proliferation, mesenchymal and stem cell markers, and myeloid cell infiltration using flow cytometry and immunohistochemistry. Bevacizumab significantly prolonged survival compared with the control or sunitinib alone. Both antiangiogenic agents initially reduced infiltration of macrophages and tumor vascularity. However, multitargeted VEGFR inhibition, but not VEGF sequestration, rapidly created a vascular gradient and more rapidly induced tumor hypoxia. Re-infiltration of macrophages was associated with the induction of hypoxia. Combination treatment with bevacizumab and sunitinib improved animal survival compared with bevacizumab therapy alone. However, at the time of tumor progression, a significant increase in CD11b(+)/Gr1(+) granulocyte infiltration was observed, and tumors developed aggressive mesenchymal features and increased stem cell marker expression. Collectively, our results demonstrate a more prolonged decrease in tumor vascularity with bevacizumab than with sunitinib, associated with a delay in the development of hypoxia and sustained reduction of infiltrated myeloid cells.

CNS macrophages and peripheral myeloid cells in brain tumours

“…It is currently a matter of intense investigation if TAM can mediate resistance to Bevacizumab by releasing angiogenic factors alternatively to VEGF-A. Myeloid cells accumulating in GBM can promote the acquisition of a mesenchymal tumour-subtype [84,38,34], which is associated with resistance to Bevacizumab [114,115]. However, as with most pathways controlled by TAM, support of angiogenesis is only one side of the intra-tumoural actions of these immune cells in gliomas.…”

Commentary: Periostin (POSTN) Regulates Tumor Resistance to Antiangiogenic Therapy in Glioma Models

“…A previous study from our group found that anti-VEGF-A therapy increases invasive properties both in a GBM stem cell line (GSC11) and in glioma U87 xenograft tumors 4 . By using microarray analysis we found several genes including POSTN that were upregulated in bevacizumab resistant tumors.…”

“…Recently, we reported that the glioma treated with bevacizumab have higher periostin (POSTN) expression than control tumors in a murine glioma tumor models 3 . In this commentary, we review our recent findings as well as the role of POSTN in antiangiogenic therapy resistance in glioma.A previous study from our group found that anti-VEGF-A therapy increases invasive properties both in a GBM stem cell line (GSC11) and in glioma U87 xenograft tumors 4 . By using microarray analysis we found several genes including POSTN that were upregulated in bevacizumab resistant tumors.…”

How anti-angiogenic drugs are able to induce resistance to their own therapeutic effect in human metastatic renal carcinoma

“…obtained only from pre-clinical models using breast cancer cell lines [12][13] , or glioma cell lines [14] . Thus, using these patient-derived renal cell carcinoma xenografts, we have shown that the number of renal cancer stem cell is directly linked to the percentage of necrosis in the tumor.…”