title: Heparin-binding EGF-like growth factor is an autocrine growth factor for human urothelial cells and is synthesized by epithelial and smooth muscle cells in the human bladder.
abstract: The epidermal growth factor receptor (HER1) has been implicated in regenerative growth and proliferative diseases of the human bladder epithelium (urothelium), however a cognate HER1 ligand that can act as a growth factor for normal human urothelial cells (HUC) has not been identified. Here we show that heparin-binding EGF-like growth factor (HB-EGF), an activating HER1 ligand, is an autocrine regulator of HUC growth. This conclusion is based on demonstration of HB-EGF synthesis and secretion by primary culture HUC, identification of HER1 as an activatable HB-EGF receptor on HUC surfaces, stimulation of HUC clonal growth by HB-EGF, inhibition of HB-EGF-stimulated growth by heparin and of log-phase growth by CRM 197, a specific inhibitor of HB-EGF/HER1 interaction, and identification of human urothelium as a site of HB-EGF precursor (proHB-EGF) synthesis in vivo. ProHB-EGF expression was also detected in the vascular and detrusor smooth muscle of the human bladder. These data suggest a physiologic role for HB-EGF in the regulation of urothelial proliferation and regeneration subsequent to mucosal injury. Expression of proHB-EGF is also a feature of differentiated vascular and detrusor smooth muscle in the bladder. Because proHB-EGF is known to be the high affinity diphtheria toxin (DT) receptor in human cells, synthesis of the HB-EGF precursor by human urothelium also suggests the possibility of using the DT-binding sites of proHB-EGF as an in vivo target for the intraluminal treatment of urothelial diseases.
authors.affiliation: Urology Research, Department of Surgery, Harvard Medical School, Boston, Massachusetts 02115, USA. freeman_m@al.tch.harvard.edu
authors.forename: M R
authors.initials: MR
authors.lastname: Freeman
authors.forename: J J
authors.initials: JJ
authors.lastname: Yoo
authors.forename: G
authors.initials: G
authors.lastname: Raab
authors.forename: S
authors.initials: S
authors.lastname: Soker
authors.forename: R M
authors.initials: RM
authors.lastname: Adam
authors.forename: F X
authors.initials: FX
authors.lastname: Schneck
authors.forename: A A
authors.initials: AA
authors.lastname: Renshaw
authors.forename: M
authors.initials: M
authors.lastname: Klagsbrun
authors.forename: A
authors.initials: A
authors.lastname: Atala
mesh_terms: D001426:Bacterial Proteins / Q000494:pharmacology; D015152:Blotting, Northern; D015153:Blotting, Western; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D002846:Chromatography, Affinity; D002851:Chromatography, High Pressure Liquid; D002999:Clone Cells / Q000378:metabolism; D015342:DNA Probes; D004167:Diphtheria Toxin / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000276:immunology / Q000378:metabolism* / Q000502:physiology* / Q000627:therapeutic use; D066246:ErbB Receptors / Q000378:metabolism / Q000502:physiology; D006493:Heparin / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D009130:Muscle, Smooth / Q000166:cytology / Q000378:metabolism*; D010703:Phorbol Esters / Q000494:pharmacology; D010766:Phosphorylation; D012313:RNA / Q000032:analysis / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D001743:Urinary Bladder / Q000254:growth & development* / Q000378:metabolism*; D001745:Urinary Bladder Diseases / Q000188:drug therapy; D019459:Urothelium / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D015342:DNA Probes; D004167:Diphtheria Toxin; D010703:Phorbol Esters; C028581:CRM197 (non-toxic variant of diphtheria toxin); D014443:Tyrosine; D004815:Epidermal Growth Factor; D012313:RNA; D006493:Heparin; D066246:ErbB Receptors