IGFBP2 is a candidate biomarker for Ink4a-Arf status and a therapeutic target for high-grade gliomas

Abstract

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.

Genomically amplified Akt3 activates DNA repair pathway and promotes glioma progression

“…As previously reported, injection of the RCAS plasmid carrying PDGFB transduces normal, nestin-positive glial cells that are engineered to express the RCAS receptor, tv-a, leading to formation of low-grade glioma (LGG) in more than 80% of mice (24)(25)(26). The introduction of Akt1 in conjunction with PDGFB led to only 16% incidence of high-grade glioma (HGG), which was not statistically significant from PDGFB alone.…”

Global analysis of L1-transcriptomes identified IGFBP-2 as a target of ezrin and NF-κB signaling that promotes colon cancer progression

“…As attempts of targeting cancer development by blocking IGFBP-2 activity [35][36][37] or ezrin phosphorylation 18 are already ongoing, we anticipate that further elucidation of the detailed molecular pathways by which L1 mediates human CRC metastasis will bring us closer to achieving this aim.…”

Insulin-Like Growth Factor Binding Protein-2: A Possible Regulator of Invasive Growth in Glioblastoma

“…Upregulated IGFBP2 expression levels have been reported for various tumor tissues as well, and in many instances, these expression levels correlate with the grade of malignancy (Mishira et al, 1998;Pekonen et al, 1992;Fuller et al, 1999;Rickman et al, 2001;Sallinen et al, 2000). Moreover, an inverse correlation between IGFBP2 and tumor suppressor genes, such as PTEN and p16/INK4, whose loss-of-function is frequently observed in malignant tumors, has also been reported (Perks et al, 2007;Moore et al, 2009). Indeed, induction of PTEN downregulates IGFBP2 expression in glioblastoma and prostate cancer cells (Levitt et al, 2005;Mehrian-Shai et al, 2007).…”

“…Other possibly important promoter regions contain binding sites for AP-4 and nuclear factor κB (NF-κB) (Cazals et al, 1999). The relationship between IGFBP2 expression and loss of tumor suppressor gene function has been recently elucidated (Perks et al, 2007;Moore et al, 2009) and hypoxic microenvironment may also upregulate IGFBP2 gene expression (Feldser et al, 1999). These lines of evidence indicate that upregulated IGFBP2 gene expression should occur in injured tissue and particularly in tumors.…”

“…Furthermore, a recent study using a glial-specific transgenic (RCAS/Ntv-a) mouse system indicated that IGFBP2 in combination with platelet-derived growth factor-(PDGFB) is also an oncogenic factor in glioma development (Dunlap et al, 2007). In this model, the expression of oncogenic IGFBP2 is negatively regulated by Ink4a-Arf, and consequently, loss of Ink4a-Arf results in enhanced IGFBP2 expression (Moore et al, 2009). Indeed, the Ink4a-Arf locus is frequently deleted in human gliomas and IGFBP2 expression is inversely correlated with p16 INK4a status (Moore et al, 2009).…”