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Published on: January 7, 2014
Characterization of an imatinib-sensitive subset of high-grade human glioma cultures
D Hägerstrand1, G Hesselager, S Achterberg
1Department of Oncology/Pathology, Karolinska Institutet, Cancer Center Karolinska, Stockholm, Sweden.
Abstract:
High-grade gliomas, including glioblastomas, are malignant brain tumors for which improved treatment is urgently needed. Genetic studies have demonstrated the existence of biologically distinct subsets. Preliminary studies have indicated that platelet-derived growth factor (PDGF) receptor signaling contributes to the growth of some of these tumors. In this study, human high-grade glioma primary cultures were analysed for sensitivity to treatment with the PDGF receptor inhibitor imatinib/Glivec/Gleevec/STI571. Six out of 15 cultures displayed more than 40% growth inhibition after imatinib treatment, whereas seven cultures showed less than 20% growth inhibition. In the sensitive cultures, apoptosis contributed to growth inhibition. Platelet-derived growth factor receptor status correlated with imatinib sensitivity. Supervised analyses of gene expression profiles and real-time PCR analyses identified expression of the chemokine CXCL12/SDF-1 (stromal cell-derived factor 1) as a predictor of imatinib sensitivity. Exogenous addition of CXCL12 to imatinib-insensitive cultures conferred some imatinib sensitivity. Finally, coregulation of CXCL12 and PDGF alpha-receptor was observed in glioblastoma biopsies. We have thus defined the characteristics of a novel imatinib-sensitive subset of glioma cultures, and provided evidence for a functional relationship between imatinib sensitivity and chemokine signaling. These findings will assist in the design and evaluation of clinical trials exploring therapeutic effects of imatinib on malignant brain tumors.
Insights
This study identifies a subset of high-grade glioma brain tumors sensitive to imatinib, a platelet-derived growth factor receptor inhibitor. Chemokine signaling, specifically CXCL12, predicts and influences this imatinib sensitivity in gliomas.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- High-grade gliomas, including glioblastomas, are aggressive brain tumors with limited treatment options.
- Platelet-derived growth factor (PDGF) receptor signaling is implicated in the growth of certain glioma subsets.
- There is an urgent need for targeted therapies for malignant brain tumors.
Purpose of the Study:
- To investigate the sensitivity of human high-grade glioma primary cultures to imatinib, a PDGF receptor inhibitor.
- To identify biomarkers predicting imatinib sensitivity in glioma.
- To explore the role of chemokine signaling in mediating imatinib response.
Main Methods:
- Analysis of human high-grade glioma primary cultures treated with imatinib.
- Assessment of growth inhibition and apoptosis induction.
- Gene expression profiling and real-time PCR to identify predictive markers.
- Functional studies involving exogenous CXCL12 addition.
Main Results:
- Six out of 15 glioma cultures showed >40% growth inhibition with imatinib; seven showed <20% inhibition.
- Apoptosis contributed to growth inhibition in sensitive cultures.
- PDGF receptor status correlated with imatinib sensitivity.
- CXCL12 expression predicted imatinib sensitivity and exogenous CXCL12 enhanced sensitivity in resistant cultures.
- Coregulation of CXCL12 and PDGF alpha-receptor was observed in glioblastoma biopsies.
Conclusions:
- A novel subset of imatinib-sensitive glioma cultures was defined.
- CXCL12 (stromal cell-derived factor 1) and PDGF receptor signaling are key determinants of imatinib sensitivity in gliomas.
- These findings support the development of clinical trials for imatinib in specific glioma patient populations.
