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Updated: May 23, 2026
Characterization of Functionally Associated miRNAs in Glioblastoma and their Engineering into Artificial Clusters for Gene Therapy
Published on: October 4, 2019
Microarray analysis verifies two distinct phenotypes of glioblastomas resistant to antiangiogenic therapy
Michael DeLay1, Arman Jahangiri, W Shawn Carbonell
1Department of Neurological Surgery, University of California, San Francisco, San Francisco, California 94143, USA.
Purpose:
To identify mechanisms and mediators of resistance to antiangiogenic therapy in human glioblastoma.
Experimental Design:
We carried out microarray gene expression analysis and immunohistochemistry comparing 21 recurrent glioblastomas progressing during antiangiogenic treatment with VEGF neutralizing antibody bevacizumab to paired pretreatment tumors from the same patients.
Results:
Microarray analysis revealed that bevacizumab-resistant glioblastomas (BRG) had two clustering patterns defining subtypes that reflect radiographic growth patterns. Enhancing BRGs (EBRG) exhibited MRI enhancement, a long-established criterion for glioblastoma progression, and expressed mitogen-activated protein kinases, neural cell adhesion molecule-1 (NCAM-1), and aquaporin 4. Compared with their paired pretreatment tumors, EBRGs had unchanged vascularity and hypoxia, with increased proliferation. Nonenhancing BRGs (NBRG) exhibited minimal MRI enhancement but had FLAIR-bright expansion, a newer criterion for glioblastoma recurrence since the advent of antiangiogenic therapy, and expressed integrin α5, laminin, fibronectin1, and PDGFRβ. NBRGs had less vascularity, more hypoxia, and unchanged proliferation than their paired pretreatment tumors. Primary NBRG cells exhibited more stellate morphology with a 3-fold increased shape factor and were nearly 4-fold more invasive in Matrigel chambers than primary cells from EBRGs or bevacizumab-naive glioblastomas (P < 0.05).
Conclusion:
Using microarray analysis, we found two resistance patterns during antiangiogenic therapy with distinct molecular profiles and radiographic growth patterns. These studies provide valuable biologic insight into the resistance that has limited antiangiogenic therapy to date.
Insights
Glioblastoma develops resistance to antiangiogenic therapy through two distinct patterns: enhancing tumors with increased proliferation and non-enhancing tumors with increased invasiveness and hypoxia.
Area of Science:
- Neuro-oncology
- Cancer biology
- Molecular pathology
Background:
- Glioblastoma is an aggressive brain tumor.
- Antiangiogenic therapy, targeting vascular endothelial growth factor (VEGF), is a treatment strategy.
- Resistance to antiangiogenic therapy limits treatment efficacy.
Purpose of the Study:
- To identify mechanisms and mediators of resistance to antiangiogenic therapy in human glioblastoma.
- To characterize molecular and radiographic differences between resistant glioblastoma subtypes.
Main Methods:
- Microarray gene expression analysis and immunohistochemistry were performed.
- Paired tumor samples from 21 patients with recurrent glioblastoma treated with bevacizumab were analyzed.
- Tumors were compared before and after antiangiogenic treatment.
Main Results:
- Two distinct glioblastoma subtypes resistant to bevacizumab were identified: enhancing BRGs (EBRG) and non-enhancing BRGs (NBRG).
- EBRGs showed increased proliferation, expressed mitogen-activated protein kinases, NCAM-1, and aquaporin 4, with unchanged vascularity and hypoxia.
- NBRGs exhibited increased invasiveness, expressed integrin α5, laminin, fibronectin1, and PDGFRβ, with reduced vascularity and increased hypoxia.
Conclusions:
- Two resistance patterns with distinct molecular profiles and radiographic features emerge during antiangiogenic therapy in glioblastoma.
- These findings offer biological insights into resistance mechanisms, potentially guiding future therapeutic strategies.
