Additive effect on survival of Raf kinase inhibitor protein and signal transducer and activator of transcription 3 in high-grade glioma

Authors

  • Judith Maresch MD,

    1. Clinical Institute of Pathology, Medical University of Vienna, Währinger Gürtel 18-20, Vienna A-1097, Austria
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  • Peter Birner MD,

    1. Clinical Institute of Pathology, Medical University of Vienna, Währinger Gürtel 18-20, Vienna A-1097, Austria
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  • Mikhail Zakharinov MD,

    1. Department of Neurosurgery, Pirogov Emergency Hospital, 21 General Eduard Totleben Boulevard, BG-1606, Sofia, Bulgaria
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  • Kalina Toumangelova-Uzeir MS,

    1. Laboratory of Neuropathology, St. Ivan Rilsky Hospital, 15 Akad. I. Geschov Boulevard, Sofia BG-1431, Bulgaria
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  • Sevdalin Natchev MD, PhD,

    1. Laboratory of Neuropathology, St. Ivan Rilsky Hospital, 15 Akad. I. Geschov Boulevard, Sofia BG-1431, Bulgaria
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  • Marin Guentchev MD, PhD

    Corresponding author
    1. Department of Neurosurgery, Pirogov Emergency Hospital, 21 General Eduard Totleben Boulevard, BG-1606, Sofia, Bulgaria
    • Department of Neurosurgery, Emergency Hospital Pirogov, 21 General Eduard Totleben Boulevard, BG-1606, Sofia, Bulgaria
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    • Fax: (011) (359)-2-9201144


Abstract

BACKGROUND:

Animal studies have shown cooperative contribution of the Ras/Raf/MAPK and PI3K/Akt/mTOR signaling pathways in glioblastoma formation. However, this joint action has not yet been confirmed in human studies.

METHODS:

The expression of Raf kinase inhibitory protein (RKIP) was examined in 159 patients with high-grade and low-grade gliomas and correlated with previously obtained data on the activation of signal transducer and activator of transcription 3 (STAT3), a downstream effector of the PI3K/Akt/mTOR signaling pathway.

RESULTS:

RKIP expression was associated with a longer overall survival in high-grade glioma cases without showing a direct or inverse correlation with tyrosine-705 phosphorylation of STAT3 (pSTAT3). Notably, RKIP-positive and pSTAT3 negative cases demarcate a patients group with exceptionally long survival, exceeding the prognostic impact of each single marker.

CONCLUSIONS:

The results of this study indicated that 1) RKIP expression correlates with tumor grade and is a marker for good prognosis in high-grade gliomas; 2) RKIP expression and lack of pSTAT3 have a cumulative prognostic impact; and 3) RKIP and pSTAT3 are likely to operate independently to influence survival. These findings represented the first human evidence of an additive effect of 2 distinct signaling pathways in high-grade glioma, suggesting that simultaneous inhibition of multiple pathways should be considered as a treatment strategy for these patients. Cancer 2011. © 2010 American Cancer Society.

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