Abnormal cdc2 activity is more prevalent in high grade versus low grade glial neoplasms

Dissecting the distinct molecular pathways in astrocytomas and oligodendrogliomas will lead to better understanding of the genesis of these tumors and, hopefully, to the generation of specific molecular targets. Poisoning of the G2→M phase transition is a prevalent strategy used in cancer therapy that has been met with limited success in glioblastoma (GBM). In order to study aberrancies of this pathway in gliomas we assayed the activity of cdc2, a cyclin dependent kinase whose activity is required for the G2→M phase transition, by immunohistochemical staining for the activated and inhibited forms of cdc2 in glial tumor arrays. Tissue arrays composed of 46 newly diagnosed GBM cases, 15 GBMs treated with chemoradiation, 38 oligodendroglioma cases, and 26 ependymoma cases were examined. Most GBMs and three anaplastic oligodendrogliomas paradoxically showed elevated staining of both inhibited and activated cdc2 relative to Grade II oligodenrogliomas and ependymomas. Mitotic cells positive for inhibited cdc2 were detected in GBM and anaplastic oligodendroglioma, suggesting that these tumors transitioned from G2→M phase despite “inhibited” cdc2. Elevated staining for inhibited phospho‐cdc2 was correlated with elevated levels of phosphorylated glycogen synthase kinase 3beta, a direct phosphorylation target of the EGF receptor. The increased prevalence of aberrancies in the cdc2 pathway in GBM and anaplastic oligodendrogliomas suggests a mechanism by which these tumors show resistance to drugs targeting G2→M phase transition.