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Characterization of an imatinib-sensitive subset of high-grade human glioma cultures

Oncogene volume 25, pages 4913–4922 (2006)Cite this article

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 α-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.

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Acknowledgements

AÖ and MN were supported by grants from the Swedish Cancer Society, Karolinska Institutet, the Cancer Society in Stockholm and the Swedish Medical Research Council. Members of the laboratory of AÖ are acknowledged for critical discussions throughout the project and Aris Moustakas for sharing his experience in microarray analysis. The Sanger microarray consortium is funded by the Wellcome Trust, Cancer Research UK and the Ludwig Institute for Cancer Research. We thank the staff of the Sanger Institute Microarray Facility (http://www.sanger.ac.uk/Projects/Microarrays) for supplying arrays, lab protocols, and technical advice (David Vetrie, Cordelia Langford, Adam Whittaker, Neil Sutton), Quantarray/GeneSpring data files and databases relating to array elements (Kate Rice, Rob Andrews, Adam Butler, Harish Chudasama). The human IMAGE cDNA clone collection was from the MRC HGMP Resource Centre (Hinxton, UK). cDNA clone resequencing was performed by Team 56 at the Sanger Institute. Imatinib was kindly provided by Novartis.

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Authors and Affiliations

  1. Department of Oncology/Pathology, Karolinska Institutet, Cancer Center Karolinska, Stockholm, Sweden

    D Hägerstrand, M Nistér & A Östman

  2. Department of Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden

    G Hesselager, U Wickenberg Bolin, M Kastemar & A Isaksson

  3. Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden

    S Achterberg, M Kowanetz & C-H Heldin

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  1. D Hägerstrand
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  2. G Hesselager
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  8. A Isaksson
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  9. M Nistér
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  10. A Östman
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Correspondence to A Östman.

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Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc).

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Hägerstrand, D., Hesselager, G., Achterberg, S. et al. Characterization of an imatinib-sensitive subset of high-grade human glioma cultures. Oncogene 25, 4913–4922 (2006). https://doi.org/10.1038/sj.onc.1209497

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