Insulin-like growth factor-binding protein 2 (IGFBP2) is increasingly recognized as a glioma oncogene, emerging as a target for therapeutic intervention. In this study, we used an integrative approach to characterizing the IGFBP2 network, combining transcriptional profiling of human glioma with validation in glial cells and the replicationcompetent ASLV long terminal repeat with a splice acceptor/tv-a glioma mouse system. We demonstrated that IGFBP2 expression is closely linked to genes in the integrin and integrin-linked kinase (ILK) pathways and that these genes are associated with prognosis. We further showed that IGFBP2 activates integrin β1 and downstream invasion pathways, requires ILK to induce cell motility, and activates NF-κB. Most significantly, the IGFBP2/integrin/ILK/NF-κB network functions as a physiologically active signaling pathway in vivo by driving glioma progression; interfering with any point in the pathway markedly inhibits progression. The results of this study reveal a signaling pathway that is both targetable and highly relevant to improving the survival of glioma patients. E levated insulin-like growth factor-binding protein 2 (IGFBP2) expression is found in many malignancies and can often serve as a prognostic factor (1). It is one of the most consistently elevated proteins in high-grade glioma, and high IGFBP2 expression is directly correlated with poor survival (2, 3). The finding that IGFBP2 is a driver of glioma development and progression in a spontaneous mouse model has provided the most convincing evidence of the significance of IGFBP2 in glioma (4). Given the clinical challenge of treating glioma and the lack of effective therapies, the elucidation of key protein-signaling networks that are essential to tumor growth and maintenance, such as IGFBP2, could provide new approaches to therapeutic intervention and significantly affect clinical outcome.IGFBP2 is a member of the IGF system in which it binds and modulates IGF1 and IGF2 activity (5); however, IGFBP2 is better known for its IGF-independent roles in cancer, such as integrin binding through an arginine-glycine-aspartic acid (RGD) motif in the C terminus (6, 7). The interaction of IGFBP2 with integrin α5 has been reported to promote cellular de-adhesion and migration in Ewing's sarcoma (8), and we previously found that integrin α5 binding to IGFBP2 is responsible for the promigratory characteristics of glioma cells (7). Integrins transduce signaling through proteins such as integrin-linked kinase (ILK), which binds to the cytoplasmic domains of β1 and β3 integrins (9). ILK contributes to the oncogenic phenotype by stimulating invasion and migration, encouraging anchorage-independent growth, and inducing tumor angiogenesis (10). Although the function of ILK has been intimately associated with integrin function, no association with IGFBP2 has been reported.IGFBP2 has been reported to influence multiple transcriptional factors, including the up-regulation of NF-κB (6), which activates the transcription of an array of cancer-pro...

The levels of insulin-like growth factor-binding protein 2 (IGFBP2) are elevated during progression of many human cancers. By using a glial-specific transgenic mouse system (RCAS/Ntv-a), we reported previously that IGFBP2 is an oncogenic factor for glioma progression in combination with platelet-derived growth factor-␤ (PDGFB). Because the INK4a-ARF locus is often deleted in highgrade gliomas (anaplastic oligodendroglioma and glioblastoma), we investigated the effect of the Ink4a-Arf-null background on IGFBP2-mediated progression of PDGFB-initiated oligodendroglioma. We demonstrate here that homozygous deletion of Ink4a-Arf bypasses the requirement of exogenously introduced IGFBP2 for glioma progression. Instead, absence of Ink4a-Arf resulted in elevated endogenous tumor cell IGFBP2. An inverse relationship between p16 INK4a and IGFBP2 expression was also observed in human glioma tissue samples and in 90 different cancer cell lines by using Western blotting and reverse-phase protein lysate arrays. When endogenous IGFBP2 expression was attenuated by an RCAS vector expressing antisense IGFBP2 in our mouse model, a decreased incidence of anaplastic oligodendroglioma as well as prolonged survival was observed. Thus, p16 INK4a is a negative regulator of the IGFBP2 oncogene. Loss of Ink4a-Arf results in increased IGFBP2, which contributes to glioma progression, thereby implicating IGFBP2 as a marker and potential therapeutic target for Ink4a-Arf-deleted gliomas.

h The genetic consequences resulting from environmental exposure to ionizing radiation have a significant impact on both radiation regulatory policies and the comprehension of the human health risks associated with radiation exposure. The primary objectives of the study were to assess 1) genotoxicity of exposure to radiation as a function of absorbed dose and dose rate, and 2) induction of a radio-adaptive response following a priming dose at varying dose rates. Results demonstrated that sub-acute environmental exposures of 10cGy gamma radiation resulted in indistinguishable levels of chromosomal damage as compared to controls. A radio-adaptive response was observed in all experimental groups, exposed to a subsequent acute challenge dose of 1.5 Gy, demonstrating that low dose rates of low energy transfer (LET) radiation are effective in reducing genetic damage from a subsequent acute low-LET radiation exposure. Furthermore, the data presented herein demonstrate a potential beneficial effect of sub-chronic exposure to low levels of low-LET radiation in an environmental setting and do not support the Linear No Threshold (LNT) hypothesis.

The aggressive and invasive nature of brain tumors has hampered progress in the design and implementation of efficacious therapies. The recent success of targeted therapies in other tumor types makes this an attractive area for research yet complicating matters is the ability of brain tumors to circumvent the targeted pathways to develop drug resistance. Effective therapies will likely need to target more than one signaling pathway or target multiple nodes within a given pathway. Key to identifying these targets is the elucidation of the driver and passenger molecules within these pathways. Animal models provide a useful tool with many advantages in the study of these pathways. These models provide a means to dissect the critical components of tumorigenesis, as well as serve as agents for preclinical testing. This review focuses on the use of the RCAS/tv-a mouse model of brain tumors and describes their unique ability to provide insight into the role of Oncogene cooperation in tumor development and progression.

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