Heparin-binding epidermal growth factor-like growth factor is an autocrinemediator of human prostate stromal cell growth in vitro

Purpose: The physiological mechanisms by which soluble mediators of cell pr oliferation and survival alter expansion of the prostatic stroma in benign prostatic hyperplasia are poorly understood. We recently identified heparin -binding epidermal growth factor like growth factor (HB-EGF) as a product p redominantly of the smooth muscle cell compartments of the adult human pros tate. We assess the potential role of this growth factor as a stromal cell regulator. Materials and Methods: Primary cultures of desmin and alpha -actin positive human prostate stromal cells were shown to express several cell associated HB-EGF isoforms as well as the primary cognate HB-EGF receptor, ErbB1/HER1 , suggesting the existence of an autocrine or juxtacrine regulatory loop. T he related receptor tyrosine kinase, ErbB2/HER2, was also expressed as asse ssed by reverse transcriptase (RT) polymerase chain reaction (PCR). HB-EGF messenger RNA levels in human prostate stromal cells increased modestly (70 %) in response to a repetitive mechanical stimulus, a lower response than h as been reported for neonatal rat bladder smooth muscle cells, in which HB- EGF was originally identified as a mechanically responsive gene. Results: HB-EGF, epidermal growth factor and basic fibroblast growth factor stimulated human prostate stromal cell growth, while a specific antagonist of HB-EGF, [Glu(52)]-diphtheria toxin/CRM197, inhibited human prostate str omal growth in serum-free medium by a mechanism that did not involve increa sed apoptosis. A function blocking antibody against CD9/DRAP27/ MRP-1, a ce ll surface binding partner of the membrane form of HB-EGF, also stimulated human prostate stromal cell proliferation. Conclusions: HB-EGF is an endogenously produced human prostate stromal cell growth factor and, thus, may have a role as a physiologically relevant aut ocrine or juxtacrine mediator of stromal expansion in benign prostatic hype rplasia.