Various components of the insulin‐like growth factor system in tumor tissue, cerebrospinal fluid and peripheral blood of pediatric medulloblastoma and ependymoma patients

Abstract

The insulin-like growth factor (IGF) system plays an important role in neuronal development and may contribute to the development of brain tumors. In this study, we studied mRNA expression levels of IGFs, insulin-like growth factor binding proteins (IGFBPs) and insulin-like growth factor receptors (IGFRs) in 27 pediatric medulloblastomas, 13 pediatric ependymomas and 5 control cerebella. Compared to normal cerebellum, mRNA levels of IGFBP-2 and IGFBP-3 were significantly increased in medulloblastomas and ependymomas. IGFBP-2 expression was indicative of poor prognosis in medulloblastomas, whereas IGFBP-3 mRNA levels were especially high in anaplastic ependymomas. IGFBP-5 and IGF-II mRNA levels were significantly increased in ependymomas compared to control cerebellum. Protein expression levels of IGFs and IGFBPs were analyzed in the cerebrospinal fluid (CSF) of 16 medulloblastoma, 4 ependymoma and 23 control patients by radioimmuno assay to determine whether they could be used as markers for residual disease after surgery. No aberrant CSF protein expression levels were found for ependymoma patients. In medulloblastoma patients, the IGFBP-3 protein levels were significantly higher than in ependymoma patients and controls. Moreover, enhanced levels of proteolytic fragments of IGFBP-3 were found in the CSF of medulloblastoma patients, being in concordance with a significantly increased IGFBP-3 proteolytic activity in the CSF of these patients. In conclusion, our data suggest that the IGF system is of importance in pediatric medulloblastomas and ependymomas. Larger studies should be conducted to validate the predictive values of the levels of intact IGFBP-3 and proteolytic fragments in CSF in the follow-up of medulloblastomas.

Expression Patterns of Insulin-Like Growth Factor Binding Protein Isoforms in Medulloblastoma Subtypes and Clinical Correlation

“…An increased mRNA level of IGFBP-2 has been reported in medulloblastoma [14], but in our study there was no expression of the IGFBP-2 protein in the tumour tissue, suggesting the possibility of a posttranslational modification or proteolysis. Also noteworthy is the absence of IGFBP-2 protein expression in medulloblastoma but a high expression in gliomas which suggests a possibility of IGFBP-2 being a glioma-specific biomarker among primary brain tumours.…”

“…Its mRNA expression levels were reported to be increased in medulloblastoma tissue, especially metastasized medulloblastoma [14]. Also the protein expression level of IGFBP-3 was reported in the CSF of medulloblastoma patients, and interestingly not only the intact IGFBP-3 protein, but also the IGFBP-3 fragments were upregulated in the CSF of patients [14]. We observed a higher labelling index of IGFBP-3 protein in anaplastic and large cell medulloblastoma subtypes as compared to the classical and desmoplastic medulloblastoma (table 1).…”

“…IGF-2 is a downstream target of sonic hedgehog signalling [13], and in concordance, IGF-2 overexpression is predominantly observed in desmoplastic medulloblastomas. There is only one study in which elevated IGFBP-2 and IGFBP-3 mRNA expression levels in medulloblastoma, accompanied by increased IGFBP-3 levels and IGFBP-3 proteolysis in the cerebrospinal fluid (CSF), has been demonstrated [14]. However, the protein expression of these isoforms has not been described earlier.…”

Targeting cerebrospinal fluid for discovery of brain cancer biomarkers

“…[52] A number of other potential CSF protein biomarkers for CNS cancers have been reported in the literature such as Insulinlike growth factor binding protein 2 (IGFBP2), Insulin-like growth factor binding protein 3 (IGFBP3), [66] Polysialicneural cell adhesion molecule (PSANCAM), [63] Total Tau (t-Tau), [67] Tumor necrosis factor (TNF) alpha [68] and CSF , S-100, [69] Neuron-specific (NSE), [70] neuron growth factor, HCG. [71] Apolipoprotein A-II, [72] MIC-1/GDF15, [73] Elevated expression of such markers in the CSF was found to be relatively specific for brain cancer [74,75] however sensitivities and specificities have widely varied.…”

Utilization of Saliva as a Diagnostic Fluid in Determination of Oral Cancer

“…34 Serum derived nucleic acids and proteins in the saliva may be part of the normal salivary secretion (by the acinar cells) 35 or come there either via intracellular routes, such as active transport or passive diffusion 36 from the serum to saliva across cell membranes or extracellular routes, such as ultrafi ltration through tight junctions 37 or as constituents of the outfl owing gingival crevicular fl uid.…”