Immunohistochemical studies of transforming growth factor-beta (TGF-beta) and its receptors have been carried out on 16 glioma tissues and compared with 5 cases of gliosis. Significantly higher expressions of TGF-beta I, as well as type-I and type-II TGF-beta receptors (T beta R-I and T beta R-II, respectively), were observed in advanced-malignant-glioma tissues when compared with non-tumorous gliosis. Immunoreactivities of TGF-beta and T beta R-I were localized in the cytoplasm of spindle-shaped tumor cells surrounding proliferating vessels or around areas of necrosis. The advancing edge of the tumor clusters frequently stained positive. Similar expression patterns were found for TGF-beta 2 and TGF-beta 3, whereas only weak or no expression was found for endoglin. In low-grade astrocytomas and in gliosis cases, the expression was moderate for T beta R-I and weak for TGF-beta and T beta R-II. In 3 examined human malignant glioma cell lines, clear immunostainings were detected for TGF-beta and its receptors. Ligand-induced heteromeric complexes of the receptors were formed in these cell lines, but the amount of the receptors was less than that of mink lung epithelial cells, which are sensitive target cells for TGF-beta. TGF-beta I showed no growth-inhibitory activity on any of these glioma cell lines. These results suggest that malignant gliomas produce TGF-beta and receptors, but are refractory to TGF-beta, implying dysregulation in the signalling pathway in the tumor cells. It is possible that the released TGF-beta acts on neighboring cells and affects stromal growth, angiogenesis, metastasis or immune surveillance in human glioma.
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