Grade-Specific Expression of Insulin-like Growth Factor–Binding Proteins-2, -3, and -5 in Astrocytomas: IGFBP-3 Emerges as a Strong Predictor of Survival in Patients with Newly Diagnosed Glioblastoma

Abstract

Background: Insulin-like growth factor (IGF)-binding protein (IGFBP) isoforms have been implicated in the pathogenesis of human neoplasms including glioma. In view of this, we evaluated the expression of IGFBP isoforms (IGFBP-2, -3, and -5) during malignant progression of astrocytoma and their prognostic significance in glioblastoma.Methods: The expression of IGFBP isoforms was analyzed in diffusely infiltrating astrocytomas by realtime quantitative PCR (n = 203) and immunohistochemistry (n = 256). Statistical methods were used to assess their grade-specific expression pattern and mRNA-protein intercorrelation. Survival analyses were done on a uniformly treated, prospective cohort of adult patients with newly diagnosed glioblastoma (n = 136) by using Cox regression models.Results: The mean transcript levels of IGFBP-2 and -3 were significantly higher in glioblastomas (GBM) relative to anaplastic astrocytoma (AA), diffuse astrocytoma (DA), and controls whereas IGFBP-5 mRNA was higher in GBM relative to AA and controls (P < 0.05). By immunohistochemistry, the mean labeling index of all isoforms was significantly higher in GBM compared with AA, DA, and control (P < 0.05). A strong positive correlation was observed between their respective mRNA and protein expressions (P < 0.01). Multivariate analysis revealed IGFBP-3 expression (hazard ratio, 1.021; P = 0.030) and patient age (hazard ratio, 1.027; P = 0.007) to be associated with shorter survival in glioblastoma.Conclusions: This study shows the associations of IGFBP-2, -3, and -5 expression with increasing grades of malignancy in astrocytomas. IGFBP-3 is identified as a novel prognostic glioblastoma biomarker. The strong correlation between their mRNA and protein expression patterns suggests their role in the pathogenesis of these tumors.Impact: IGFBP isoforms have emerged as biomarkers with diagnostic and prognostic utility in astrocytomas.

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

“…Enhanced activation of NF-κB signaling pathway in glioblastoma cells (Wang et al, 2004) may also be involved in the upregulation of IGFBP-2 transcription (Cazals et al, 1999). The prognostic impact of IGFBPs expression in patients with newly diagnosed glioblastoma was recently reported (Santosh et al, 2010), with protein expression of IGFBP2, IGFBP 3 and IGFBP5 being significantly associated with shorter survival by univariate Cox regression analysis. However, multivariate Cox proportional hazards model showed that only IGFBP3 had independent prognostic impact.…”

Clinicopathological significance and impact on outcomes of the gene expression levels of IGF-1, IGF-2 and IGF-1R, IGFBP-3 in patients with colorectal cancer: Overexpression of the IGFBP-3 gene is an effective predictor of outcomes in patients with colorectal cancer

“…High expression levels of the IGFBP-3 gene were associated with unfavorable prognostic characteristics in breast cancer (32). Santosh et al (33) reported that IGFBP-3 overexpression in tumor tissues was an independent predictor of reduced survival rate in patients with newly diagnosed glioblastoma. By contrast, Aishima et al (34) identified that high expression levels of IGFBP-3 were independently associated with an improved survival rate in patients with hepatocellular carcinoma.…”

A DNA Methylation Prognostic Signature of Glioblastoma: Identification of NPTX2-PTEN-NF-κB Nexus

“…Genetic heterogeneity in GBM has been proposed to explain the limitations in the effectiveness of current therapies, which necessitates the need for prognostic gene signature (2). Many genetic and epigenetic alterations as well as expression of some genes have been correlated with poor or better prognosis (3)(4)(5)(6)(7). In addition, molecular biomarkers like methyl guanine methyl transferase (MGMT) promoter methylation, isocitrate dehydrogenase 1 (IDH1) mutation status, and Glioma-CpG Island Methylator Phenotype (G-CIMP) have been identified as GBM prognostic indicators (1,8,9).…”