1432 INSULIN-LIKE GROWTH FACTORS MEDIATE INFLAMMATION-DRIVEN PROLIFERATION OF THE MOUSE PROSTATE

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research VIII1 Apr 20101432 INSULIN-LIKE GROWTH FACTORS MEDIATE INFLAMMATION-DRIVEN PROLIFERATION OF THE MOUSE PROSTATE Travis Jerde, Eliza McFarland, Sanghee Lee, and Wade Bushman Travis JerdeTravis Jerde Madison, WI More articles by this author , Eliza McFarlandEliza McFarland Medford, MA More articles by this author , Sanghee LeeSanghee Lee Madison, WI More articles by this author , and Wade BushmanWade Bushman Madison, WI More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.1125AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Inflammation in the prostate is of considerable importance to urological research because of its association with prostate cancer. Yet, mechanisms by which inflammation promotes cancerous or benign prostatic growth remain obscure. Insulin-like growth factor (IGF) signaling plays a role in prostate development and is postulated to drive prostate tumor and benign prostatic growth in men. Since inflammation is associated with growing prostate cancer, we sought to determine if IGF signaling is involved in inflammation-induced epithelial proliferation. METHODS We initiated inflammatory reactive hyperplasia in mice using our bacterially-induced acute inflammation model. Prostates were harvested 1, 2, 3, 5, 7, and 14 days post-instillation. IGF-1 and IGF-2 expression was determined by RT-PCR, and peptide concentration and release were determined by ELISA. IGF receptor activation was quantified by immunoblotting and spatially detected by immunohistochemistry using phospho-specific antibodies to activated IGF receptor. Normal and cancerous human prostate specimens were also stained for IGF receptor activation. Additional inflamed and control animals were treated with an IGF receptor antagonist (picropodophyllin [PPP]) or vehicle i.p. twice daily for 3 days. Inflammatory index, proliferation, IGF receptor activation, and IGF target pathway activity (phosphorylated Akt) were determined. RESULTS Inflammation caused a significant increase in IGF-1 expression and regulated release within two days of inducing inflammation. This correlated with substantially increased proliferative index and IGF receptor activation. The human prostatic epithelium showed substantial induction of IGF signaling in areas juxtaposed to inflammation. IGF inhibition substantially reduced proliferation rates and hyperplastic response of the mouse prostate. PPP treatment predictably reduced IGF receptor activation and Akt pathway activation, but had minimal effect on inflammation itself indicating that IGF inhibition targets proliferation of the epithelium and stroma but not inflammatory infiltrate. CONCLUSIONS Our data indicate that IGF plays a critical role in the hyperplastic response of the prostate to inflammation. While using IGF inhibition therapeutically has been previously proposed based on an associative increase in gene expression, our work provides clear evidence for a causative role for IGF in inflammation-induced growth and establishes IGF signaling as a logical therapeutic target in reducing epithelial expansion in the prostate. © 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e552 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Travis Jerde Madison, WI More articles by this author Eliza McFarland Medford, MA More articles by this author Sanghee Lee Madison, WI More articles by this author Wade Bushman Madison, WI More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...