Abstract
In a subset of gliomas, the platelet-derived growth factor (PDGF) signaling pathway is perturbed. This is usually an early event occurring in low-grade tumors. In high-grade gliomas, the subsequent loss of the INK4a-ARF locus is one of the most common mutations. Here, we dissected the separate roles of Ink4a and Arf in PDGFB-induced oligodendroglioma development in mice. We found that there were differential functions of the two tumor suppressor genes. In tumors induced from astrocytes, both Ink4a-loss and Arf-loss caused a significantly increased incidence compared to wild-type mice. In tumors induced from glial progenitor cells there was a slight increase in tumor incidence in Ink4a−/− mice and Ink4a-Arf−/− mice compared to wild-type mice. In both progenitor cells and astrocytes, Arf-loss caused a pronounced increase in tumor malignancy compared to Ink4a-loss. Hence, Ink4a-loss contributed to tumor initiation from astrocytes and Arf-loss caused tumor progression from both glial progenitor cells and astrocytes. Results from in vitro studies on primary brain cell cultures suggested that the PDGFB-induced activation of the mitogen-activated protein kinase pathway via extracellular signal-regulated kinase was involved in the initiation of low-grade oligodendrogliomas and that the additional loss of Arf may contribute to tumor progression through increased levels of cyclin D1 and a phosphoinositide 3-kinase-dependent activation of p70 ribosomal S6 kinase causing a strong proliferative response of tumor cells.
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Acknowledgements
This work has been supported by grants from the Swedish Cancer Society, The Swedish Research Council, Åke Wiberg's Foundation, Magn. Bergvall's Foundation and Jeansson's Foundation.
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Tchougounova, E., Kastemar, M., Bråsäter, D. et al. Loss of Arf causes tumor progression of PDGFB-induced oligodendroglioma. Oncogene 26, 6289–6296 (2007). https://doi.org/10.1038/sj.onc.1210455
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DOI: https://doi.org/10.1038/sj.onc.1210455
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