Expression of Annexin A1 and Constitutive Activation of the Akt/mTOR Pathway in High-Grade Diffuse Gliomas: A Potential Connection with S Phase Kinase-Associated Protein (Skp2) in Glioma Progression
AE Gullett, X Duan, GN Fuller, R Brown, Y Li, R Luthra, W Wiseman, E Resetkova, H Yao, V Puduvalli, Y Wu, JM Bruner, CT Albarracin. UTHSC, Houston, TX; UT MD Anderson, Houston, TX
Background: Diffuse gliomas constitute the most common type of malignant primary brain tumor. Gliomas of astrocytic lineage have been shown to have a worse prognosis compared to those of oligodendrocytic lineage of similar grade. Annexin A1 (ANXA1) is a calcium binding protein implicated in the EGFR tyrosine kinase pathway. In glioblastomas, amplification of EGFR has been associated with Akt pathway activation. ANXA1 has been shown to be a binding partner of Akt by retrovirus-based protein complementation assay. Similarly, a downstream effector of the Akt/mTOR pathway, Skp2 is overexpressed in a number of malignancies and its downregulation is reported to induce apoptosis in T98G glioma cells. The objective of this study is to evaluate Akt and its downstream effectors, mammalian target of rapamycin (mTOR) and Skp2 in relation with ANXA1 in the different types and grades of diffuse gliomas.
Design: A tissue microarray was assembled from gliomas diagnosed according to the WHO 2007 classification which included: 24 oligodendrogliomas (OL)(Grade II), 10 mixed oligoastrocytomas (MOA)(Grade II), 22 anaplastic oligodendrogliomas (AO)(Grade III), 11 anaplastic mixed oligoastrocytomas (AMOA)(Grade III), 24 anaplastic astrocytomas (AA)(Grade III), 8 gliosarcomas (GS)(Grade IV) and 56 glioblastomas (GBM)(Grade IV). ANXA1, Akt, mTOR and Skp2 expression was determined by immunohistochemistry. Positive results were >30% stained with an intensity of 2 or higher.
Results: ANXA1 was expressed in 51% of GBM, 88% of GS and 27% of AA. In contrast, ANXA1 was expressed in only 9% of AO and none of the low-grade OL. Similarly, Skp2 was expressed in 54% of GBM, 29% of GS, 5% of AA, 6% of AO and none of the OL. ANXA1 and Skp2 expression showed a positive correlation and were present in higher grade gliomas (p<0.0002). Akt and mTOR were expressed in most of the tumor types evaluated and showed no significant correlation to tumor type or grade.
Conclusions: ANXA1 was coexpressed with Skp2 in tumors with an astrocytic component and in higher grade gliomas. Our results confirm the role of the Akt/mTOR pathway in gliomas and support an important role for ANXA1 and Skp2 in the progression to higher grade astrocytic gliomas.
Monday, March 9, 2009 9:30 AM
Poster Session I Stowell-Orbison/Autopsy Award # 220, Monday Morning