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

The epidermal growth factor receptor (HER1) has been implicated in reg enerative growth and proliferative diseases of the human bladder epith elium (urothelium), however a cognate HER1 ligand that can act as a gr owth factor for normal human urothelial cells (HUC) has not been ident ified, Here we show that heparin-binding EGF-like growth factor (HB-EG F), an activating HER1 ligand, is an autocrine regulator of HUC growth , This conclusion is based on demonstration of HB-EGF synthesis and se cretion by primary culture HUC, identification of HER1 as an activatab le HB-EGF receptor on HUC surfaces, stimulation of HUC clonal growth b y 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 interact ion, and identification of human urothelium as a site of HB-EGF precur sor (proHB-EGF) synthesis in vivo, ProHB-EGF expression was also detec ted in the vascular and detrusor smooth muscle of the human bladder, T hese data suggest a physiologic role for HB-EGF in the regulation of u rothelial 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 t he possibility of using the DT-binding sites of proHB-EGF as an in viv o target for the intraluminal treatment of urothelial diseases.