In vivo expression of insulin-like growth factor-binding protein-2 in human gliomas increases with the tumor grade

Human central nervous system tumors and glioma cell lines highly express th e insulin-like growth factor-binding protein (IGFBP)-2. As IGFBP-8 can affe ct tumor growth, we studied the relationship between IGFBP-2 expression and the malignancy of brain tumors in vivo. To do so, we investigated by immun ohistochemistry the accumulation of IGFBP-1, -2, and -3 in 50 human gliomas classified by the WHO Malignancy Scale. Double labeling using anti-CD68 (m onocytes/macrophages), antiglial fibrillary acidic protein, and anti-CD3 (T cells) antibodies was performed to further characterize the IGFBP-1, -2, a nd -3(+) cells. The expression of IGFBP messenger RNAs (mRNAs) was tested b y RT-PCR in tumor samples from nine gliomas of different grades and in eigh t cell lines representing the cellular composition of human glioma. As cont rols, the accumulation of IGFBP-8 was investigated in normal brain and in t he rat C6 glioblastoma model. IGFBP-1 and -3 accumulated in endothelial and macrophage/microglial cells. IGFBP-2(+) macrophage/microglial and glioma c ells clustered in the immediate vicinity of focal necrosis of the human gli omas as well as of the rat C6 glioblastoma. The labeling score of IGFBP-1 a ccumulation in endothelial cells correlated negatively(P = 0.0229), and tha t of IGFBP-2 accumulation in glioma cells correlated positively (P < 0.0006 ) with the tumor grade of the gliomas. In addition, RT-PCR analysis confirm ed mRNA expression of IGFBP-1, -2, and -3 by the gliomas and glial cells. S mall 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 c ell 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 sugg ests a role of IGFBP-2 in the biology of human gliomas.