Status of alternative angiogenic pathways in glioblastoma resected under and after bevacizumab treatment

Abstract

Abstract Purpose: Glioblastoma acquires resistance to Bevacizumab (Bev) treatment. Bev effects on angiogenic factors other than vascular endothelial growth factor (VEGF), which are poorly understood; therefore, we investigated changes in various angiogenic factors in glioblastoma under and after Bev therapy, including angiopoietin 1, angiopoietin 2 (ANGPT2), placental growth factor (PLGF), fibroblast growth factor 2, and Ephrin A2 (EFNA2). Methods: Fifty-four glioblastoma tissues were analyzed, including 28 specimens from 14 cases as ‘paired specimens from the same patient’ obtained in three settings: initial tumor resection (naïve Bev), tumors resected following Bev therapy (effective Bev), and recurrent tumors after Bev therapy (refractory Bev). Immunohistochemistry was used to investigate angiogenic factor expression in tumor vessels and their association with recurrent MRI patterns. Results: PLGF expression was significantly higher in the effective Bev group than in the naïve Bev group (p = 0.024) and remained high in the refractoryBev group. ANGPT2 and EFNA2 levels were higher in the refractory Bev group than in the naïveBev group (p = 0.047 and 0.028, respectively). Notably, PLGF expression was higher in the refractory Bev group compared with the naïve Bev group for paired specimens (p = 0.036). PLGF was more abundant in T2 diffuse/circumscribe MRI patterns (p = 0.046). Conclusion: This is the first comparative study to evaluate angiogenic factors other than VEGF during effective and refractory Bev therapy in patient-derived glioblastoma specimens. Alternative angiogenesis pathways may be concertedly involved in the resistance, which will inform optimization and development of novel therapeutics for improvedBevtherapy.