Insulin-like growth factor binding protein 2 (IGFBP2) has recently been shown to be overexpressed in 80% of the most advanced type of diffuse glioma, glioblastoma multiforme (GBM), by combined cDNA microarray and tissue microarray approaches. Furthermore, overexpressed IGFBP2 correlates with poor survival in diffuse gliomas. In vitro functional studies have provided evidence that IGFBP2 increases glioma cell migration and invasion. We therefore hypothesize that IGFBP2 is a key regulator of glioma progression. We tested our hypothesis using the somatic gene transfer RCAS-tva mouse model system, which permits the introduction of specific genes into specific cell lineages. In this system, avian virus receptor is expressed exclusively in glial cells via linkage to the neuroglial-specific nestin promoter. Genes of interest are cloned into an avian RCAS vector and viral particles are expanded in DF1 avian fibroblasts. When injected into the neonatal mouse brain, the virions infect only glial cells and the genes of interest borne by the virions are thus only expressed in glial cells. For these experiments, the study genes were IGFBP2, platelet-derived growth factor (PDGF), K-Ras, and Akt, which were delivered separately and in combination. Our results show that PDGF signaling leads exclusively to the formation of low-grade (WHO grade II) oligodendrogliomas. PDGF delivered in combination with IGFBP2 results in the formation of anaplastic oligodendrogliomas (WHO grade III). These higher-grade tumors are characterized by increased cellular density, vascular proliferation, and poor survival. Combined K-Ras and Akt leads to the formation of astrocytomas; K-Ras alone or Akt alone do not result in tumor formation. IGFBP2 in combination with K-Ras produces astrocytomas, which are histologically similar to the gliomas resulting from K-Ras/Akt stimulation. No tumor formation resulted from the simultaneous delivery of Akt and IGFBP2, suggesting that IGFBP2 and Akt likely lie in the same pathway or in converging pathways. The present studies show that: 1) IGFBP2 is associated with progression from low-grade O to high-grade AO in gliomas initiated by PDGFb overexpression in vivo, and 2) IGFBP2 can synergize with the Ras pathway to produce diffuse gliomas in vivo. Collectively, the data demonstrate that IGFBP2 actively contributes to diffuse glioma initiation and progression. Studies are ongoing to further elucidate the signaling pathways of IGFBP2-induced gliomagenesis.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]