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. ( J. Clin. Invest. 1997. 99:1028-1036.)

E-cadherin involved in inactivation of WNT/β-catenin signalling in urothelial carcinoma and normal urothelial cells

“…Nevertheless, the activation of typical WNT/b-catenin target genes such as CCND1 and MYC is required for the proliferation of uroepithelial cells, too. Proliferation of NUEC is stimulated by growth factors such as EGF and, in an autocrine fashion, HB-EGF (Freeman et al, 1997). Since these factors act via MAPK signalling (Swiatkowski et al, 2002), they seem quite sufficient to stimulate the necessary transcription of CCND1 and MYC in an alternative fashion to WNT/b-catenin signalling.…”

Composite scaffolds for the engineering of hollow organs and tissues

“…We used primary cells harvested from canine bladders using established protocols (10,(37)(38)(39). Bladder tissue was microdissected, and the mucosal and muscular layers were scalpel under sterile conditions.…”

Sensitivity of Normal, Paramalignant, and Malignant Human Urothelial Cells to Inhibitors of the Epidermal Growth Factor Receptor Signaling Pathway

“…In normal urothelium, the regenerative response is considered a crucial feature that contributes to the maintenance and repair of urinary barrier integrity and is driven, at least in part, through the autocrine production of epidermal growth factor (EGF) family ligands acting on the EGF receptor (EGFR; ErbB1 or Her1; refs. [4][5][6][7][8].…”