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The Insulin-Like Growth Factor Type I Receptor Stimulates Growth and Suppresses Apoptosis in Prostatic Stromal Cells

University Department of Surgery, University of Edinburgh, Western General Hospital (E.S.G., M.B.R., F.K.H.), Edinburgh, Scotland EH4 2XU; and the Department of Discovery Biology Central Research Division, Pfizer Ltd. (S.B., A.N.), Kent, United Kingdom CT13 9NJ

Address all correspondence and requests for reprints to: Dr. E. S. Grant, University Department of Surgery, Western General Hospital, Crewe Road South, Edinburgh, Scotland EH4 2XU. E-mail: esg{at}srv0.med.ed.ac.uk

Stromal cells derived from benign prostatic hyperplasia synthesize and secrete measurable levels of insulin-like growth factor (IGF). Seventy-two-hour conditioned medium obtained from these cells contains IGF-II at levels ranging from 125–177 ng/mL·10⁶ cells. IGF-I is almost undetectable. RT-PCR analysis has demonstrated that the genes for both the type I IGF receptor (IGF-IR) and the type II IGF receptor (IGF-IIR) are expressed by benign stromal cells in vitro. Competition binding analysis for IGF-I and IGF-II confirmed the existence of binding sites for both ligands with respective K_d and binding capacities of 4.9 x 10^-9 mol/L and 6.6 x 10⁵ sites/cell and 4.7 x 10^-9 mol/L and 3.8 x 10⁶ sites/cell. Under serum-free conditions, IGF-I and IGF-II at 500 ng/mL induce 80% and 113% increases in stromal cell density, respectively, over a 96-h period. Incubation with the IGF-IR-neutralizing antibody IR3 (50 µg/mL) reduces the rate of stromal cell proliferation by approximately 60–80% even in the presence of stimulatory concentrations of IGFs. Camptothecin-induced apoptosis is inhibited by the addition of IGF-I and -II (500 ng/mL). IR3 suppresses these survival signals and itself induces cell death in the prostatic stroma. The data suggest that IGF-IR is a pivotal molecule in prostatic stromal cell maintenance, and that specific antagonism may offer a novel means of controlling the fibromuscular expansion characteristic of benign prostatic hyperplasia.

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