Differential Expression Of Igfbp Isoforms In Astrocytoma: Prognostic Value Of Igfbp-2,-3, And-5 In Glioblastoma Patients

Insulin-like growth factor binding proteins (IGFBP) are known to modulate the actions of insulin-like growth factors (IGF) mainly by controlling the amount of free IGF that can bind to its receptors. IGFBP are also known to regulate cell survival in an IGF-independent pathway. However, they can have a complex bidirectional effect on tumorigenesis. Among the various IGFBP, the expression and role of IGFBP2 in gliomas has been extensively studied. In an earlier gene-expression profiling study on the various grades of astrocytoma, we identified the upregulation of IGFBP-2, - 5, and -7 in glioblastoma tumors. In order to establish a role for all the IGFBP isoforms in the progression and prognosis of astrocytoma, we analyzed the gene expressions of IGFBP-1 to –5, -7 to -10, and -L1 by real-time quantitative polymerase chain reaction (RT-PCR) and IGFBP-2, -3, -4, -5, and -7 by immunohistochemistry (IHC) in a cohort of 50 diffusely infiltrating astrocytoma tissues. There were greater than two-fold upregulations in the transcript levels of IGFBP-2, -3, and -4 and in the majority of glioblastomas (GBM) relative to anaplastic astrocytomas (AA). On the other hand, IGFBP-5 and -7 were upregulated in the majority of malignant astrocytomas (AA and GBM). In contrast to these observations, IGFBP-9 transcript levels were found to be downregulated in both AA and GBM tumors. Overexpression of IGFBP -2, -3, -4, –5, and -7 was observed by IHC maximally in the tumor cells of GBM. Notably, we found that in an independent set of GBM patients, expression of IGFBP-2 alone and coexpression of IGFBP-2 and -5 in the tumor were indicative of shorter survival. In addition, when IGFBP-3 coexpressed with epidermal growth factor receptor, it indicated shorter patient survival. Our study suggested associations between IGFBP-2, -3, -4, -5, and -7 and malignant transformation in diffusely infiltrating astrocytomas, with maximal expression in GBM. We also showed that overexpression of IGFBP-2, -3, and -5 isoforms portended poor prognosis in GBM patients