Journal Article

Involvement of epidermal growth factor receptor in chemically induced mouse bladder tumour progression

Ahmed El Marjou, Annie Delouvée, Jean Paul Thiery and Francıois Radvanyi

in Carcinogenesis

Volume 21, issue 12, pages 2211-2218
Published in print December 2000 | ISSN: 0143-3334
Published online December 2000 | e-ISSN: 1460-2180 | DOI: https://dx.doi.org/10.1093/carcin/21.12.2211
Involvement of epidermal growth factor receptor in chemically induced mouse bladder tumour progression

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This study was designed to investigate the role of the epidermal growth factor receptor (EGFR) and its ligands in chemically induced mouse bladder cancer. Bladder tumours were induced in C57Bl/6 and B6D2F1 mice by treatment with the carcinogen, N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). The levels of mRNA for EGFR and its ligands were analysed by reverse transcription–polymerase chain reaction (RT–PCR) in bladder tumours and in normal bladder urothelia. EGFR mRNA was detected in all tumours, transforming growth factor α (TGFα) mRNA levels were similar to those in normal bladder urothelia or were decreased and mRNA levels for amphiregulin, heparin-binding epidermal growth factor-like factor (HB-EGF) and betacellulin were significantly higher than those in normal urothelia. Seven cell lines were derived from chemically induced tumours. These cell lines were able to grow in serum-free conditions. All the cell lines tested expressed the genes encoding EGFR and at least one of its ligands. Proliferation of these cell lines was inhibited by AG1478, a specific EGFR tyrosine kinase inhibitor, strongly suggesting that EGFR was involved in cell growth. As expected, EGFR was found to be phosphorylated in serum-free medium, this phosphorylation being inhibited by AG1478. Conditioned medium of a bladder cancer cell line had EGFR-stimulating activity and an antibody directed against EGFR inhibited proliferation by 45%. This suggests that tumour cell growth is stimulated by an autocrine loop involving EGFR and secreted growth factors. AG1478 decreased the expression of genes for amphiregulin, HB-EGF and betacellulin, showing that EGFR activation induces up-regulation of the EGFR ligands. These results suggest that EGFR plays a critical role in bladder tumour progression.

Keywords: BBN, N-butyl-N-(4-hydroxybutyl)nitrosamine; BTC, betacellulin; DMEM, Dulbecco's modified Eagle's medium; EGFR, epidermal growth factor receptor; FCS, fetal calf serum; HB-EGF, heparin-binding epidermal growth factor-like factor; RT–PCR, reverse transcription–polymerase chain reaction; TBP, TATA-binding protein; TGFα, transforming growth factor α.

Journal Article.  6232 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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