Antiangiogenic therapy reduces tumor vascular permeability and delays tumor progression but may ultimately promote an aggressive treatment-resistant phenotype. In a study reported in Clinical Cancer Research, Piao and colleagues attempted to identify factors responsible for glioblastoma resistance to antiangiogenic therapy.
Glioma stem cell NSC11 and U87 cell lines with acquired resistance to bevacizumab (Avastin) were developed from orthotopic xenografts in nude mice treated with bevacizumab. Genome-wide analyses were used to identify changes in tumor subtype and specific factors associated with resistance.
Mice with established parental NSC11 and U87 cells responded to bevacizumab, whereas glioma cell lines derived at the time of acquired resistance to anti-VEGF therapy were resistant to bevacizumab and did not have prolonged survival compared with untreated controls. Gene-expression profiling showed an increase in genes associated with a mesenchymal origin, cellular migration/invasion, and inflammation in anti-VEGF therapy–resistant cell lines compared with untreated controls.
Bevacizumab-treated tumors showed a highly significant correlation with published mesenchymal gene signatures on gene-set enrichment analysis. Mice with resistant tumors showed significantly greater infiltration of myeloid cells in NSC11 and U87 resistant tumors.
The investigators concluded, “Our studies identify multiple proinflammatory factors associated with resistance and identify a proneural to mesenchymal transition in tumors resistant to antiangiogenic therapy.” ■