HEPARIN-BINDING EPIDERMAL GROWTH FACTOR-LIKE GROWTH-FACTOR STIMULATESMITOGENIC SIGNALING AND IS HIGHLY EXPRESSED IN HUMAN-MALIGNANT GLIOMAS

We previously reported that schwannoma-derived growth factor (SDGF), a member of heparin-binding epidermal growth factor (EGF) family, parti cipates in autocrine pathways and promotes rat glioma cell growth. To investigate the potential role of similar molecules in human gliomas: we examined 7 human glioma cell lines and 11 glioblastoma specimens fo r expression of the human homologue of SDGF, amphiregulin (AR), as wel l as heparin-binding EGF-like growth factor (HB-EGF). Northern blot an alysis revealed that only one cell line and no tumor specimens express ed AR mRNA. In contrast, KB-EGF mRNA was expressed in all human glioma cell lines and its lever of expression was two- to five-fold higher t han that of control brain tissues in 8 of 11 glioblastoma cases. Immun ohistochemistry demonstrated that membrane-anchored HB-EGF (proHB-EGF) and EGFR were co-expressed in 44% of 34 human malignant gliomas. Intr oduction of exogenous HB-EGF (10 ng/ml) increased human glioma cell pr oliferation, and ant-HB-EGF blocking antibodies reduced the growth of glioma cells by 30-40%, confirming the presence of an autocrine loop. When added to the medium, transforming growth factor-alpha, basic fibr oblast growth factor, or HB-EGF rapidly induced HB-EGF mRNA expression . These results indicate that HB-EGF and proHB-EGF contribute to the g rowth of human malignant glioma cells, most likely through autocrine a nd juxtacrine mechanisms.