Abstract 1959: The hierarchy of Akt isoforms in driving glioma progression in a tissue-specific mouse model
Authors: Kristen M. Holmes, Sarah M. Smith, Gregory N. Fuller, Wei Zhang
Journal: Cancer Research (2010)

Abstract Activation of the PI3K-Akt pathway has been shown to be involved in many cellular cancer related processes such as cell proliferation, apoptosis, invasion, metastasis, and collectively, cancer development and progression. Accumulating research data including knockout mouse studies have gathered evidence that the three members of the Akt gene family, Akt1, Akt2, and Akt3, play non-redundant physiological roles in normal and neoplastic processes. Our previous studies showed that the expression and phosphorylation of total Akt are enhanced in human glioma. Recent studies have shown that deletion of PTEN and activation of insulin-like growth factor binding protein 2 (IGFBP2) lead to activation of Akt in glioma. However, we know very little about the differential roles of the Akt isoforms in glioma. Recent analysis of data from The Cancer Genome Atlas (TCGA) showed that Akt3 gene was amplified in a small subset of glioblastoma multiforme (GBM). Using the RCAS/Ntv-a glial specific transgenic mouse system, we previously found that co-expression of PDGFB and IGFBP2 led to frequent anaplastic oligodendroglioma progression, in which the Akt pathway was activated; however, Akt was not activated in gliomas derived from PDGFB alone. Further, glial progenitor cells infected with RCAS particles carrying PDGFB and IGFBP2 were significantly more sensitive to a pan-Akt inhibitor versus when PDGFB was infected alone, indicating that IGFBP2 expression led to a dependence on Akt for cell survival. To determine whether there is a hierarchy among the different isoforms of Akt in driving glioma progression in our mouse model, we first evaluated RCAS-PDGFB in combination with RCAS-myristoylated (activated) Akt1 or Akt3. Akt1 combined with PDGFB led to a 76% overall glioma incidence (19/26); however, Akt1 did not significantly promote tumor progression because there was a 16% Grade 3 incidence (3/19) versus 11% Grade 3 incidence with PDGFB alone (4/35). The Akt3 combination, however, resulted in 100% glioma incidence (35/35), all of which were Grade 3. Gliomas from the Akt3-PDGFB combination showed severe features of advanced tumors with multiple foci of pseudopalisading necrosis and extensive vascular proliferation. Experiments with Akt2-PDGFB combination are ongoing which will reveal a complete hierarchy among the three Akt isoforms in driving progression of glioma. Data will also be acquired to determine whether dominant negative version of Akt3 in combination with IGFBP2 and PDGFB blocks IGFBP2-induced progression, which will provide further evidence that Akt3 activation is the downstream event in the IGFBP2 oncogene in gliomagenesis. In conclusion, we have shown that Akt isoforms have different roles in glioma progression and Akt3 but not Akt1 is responsible for PDGFB-driven oligodendroglioma progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1959.