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In Vivo Expression of Insulin-Like Growth Factor-Binding Protein-2 in Human Gliomas Increases with the Tumor Grade¹

Pediatric Endocrinology, Children’s Hospital (M.W.E., M.B.R., B.S.S.), Institute of Brain Research (M.H.D., R.M.), and Department of Neurosurgery (F.D., E.H.G.), University of Tuebingen, D-72076 Tuebingen, Germany

Address all correspondence and requests for reprints to: Dr. Martin W. Elmlinger, Section of Pediatric Endocrinology, Children’s Hospital, University of Tuebingen, Hoppe-Seyler Strasse 1, D-72076 Tuebingen, Germany. E-mail: martin.elmlinger{at}med.uni-tuebingen.de

Human central nervous system tumors and glioma cell lines highly express the insulin-like growth factor-binding protein (IGFBP)-2. As IGFBP-2 can affect tumor growth, we studied the relationship between IGFBP-2 expression and the malignancy of brain tumors in vivo. To do so, we investigated by immunohistochemistry the accumulation of IGFBP-1, -2, and -3 in 50 human gliomas classified by the WHO Malignancy Scale. Double labeling using anti-CD68 (monocytes/macrophages), antiglial fibrillary acidic protein, and anti-CD3 (T cells) antibodies was performed to further characterize the IGFBP-1, -2, and -3⁺ cells. The expression of IGFBP messenger RNAs (mRNAs) was tested by RT-PCR in tumor samples from nine gliomas of different grades and in eight cell lines representing the cellular composition of human glioma. As controls, the accumulation of IGFBP-2 was investigated in normal brain and in the rat C6 glioblastoma model. IGFBP-1 and -3 accumulated in endothelial and macrophage/microglial cells. IGFBP-2⁺ macrophage/microglial and glioma cells clustered in the immediate vicinity of focal necrosis of the human gliomas as well as of the rat C6 glioblastoma. The labeling score of IGFBP-1 accumulation in endothelial cells correlated negatively (P = 0.0229), and that of IGFBP-2 accumulation in glioma cells correlated positively (P < 0.0006) with the tumor grade of the gliomas. In addition, RT-PCR analysis confirmed mRNA expression of IGFBP-1, -2, and -3 by the gliomas and glial cells. Small amounts of IGFBP-1 and -3 mRNA, but high amounts of IGFBP-2 mRNA, were detectable in macrophage-like and glioma cell lines.

The results suggest cell type-specific accumulation of IGFBP-1, -2, and -3 in human glial tumors of the brain. The increase in IGFBP-2 expression with this malignancy suggests a role of IGFBP-2 in the biology of human gliomas.