681 REDUCED ANDROGEN DEPENDENT AND INDEPENDENT GROWTH OF HUMAN PROSTATE CANCER XENOGRAFTS IN GROWTH HORMONE RELEASING HORMONE RECEPTOR MUTANT HOSTS

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research V1 Apr 2010681 REDUCED ANDROGEN DEPENDENT AND INDEPENDENT GROWTH OF HUMAN PROSTATE CANCER XENOGRAFTS IN GROWTH HORMONE RELEASING HORMONE RECEPTOR MUTANT HOSTS Kiyoshi Takahara, Howard Tearle, Tabitha Tombe, Martin E. Gleave, and Michael E. Cox Kiyoshi TakaharaKiyoshi Takahara More articles by this author , Howard TearleHoward Tearle More articles by this author , Tabitha TombeTabitha Tombe More articles by this author , Martin E. GleaveMartin E. Gleave More articles by this author , and Michael E. CoxMichael E. Cox More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.1080AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Signaling through the growth hormone/insulin-like growth factor (GH/IGF) axis has been linked to prostate cancer (PCa) risk. Previous studies have indicated that human breast cancer xenografts and murine PCa models develop more slowly in little murine hosts. The little (lit/lit) phenotype is due to a D60G missense mutation in the GH-releasing hormone receptor (GHRHR) resulting in loss of pituitary GHRHR function and suppression of GH and IGF-1 expression. We hypothesized that the GH/IGF axis influences PCa growth and castration-resistant (CR) progression of human PCa xenografts. METHODS To determine whether PCa growth in vivo models is influenced by the host GH/IGF axis, we performed in vivo growth studies using the androgen-responsive human PCa cell line, LNCaP, and CR human PCa cell line, PC3, in Nod/SCID lit/lit mice and compared them to growth and CR progression in mice heterozygous for the lit allele (lit/+). To assess whether suppressed GH/IGF levels affected androgen-responsive growth of PCa xenografts, we monitored tumor size and serum PSA levels before and after castration of LNCaP tumor-bearing lit/lit and lit/+ mice. We also monitored growth rate of PC3 xenografts in intact mice to assess the impact of GH/IGF axis deficiencies on CR PCa. Growth of LNCaP and PC3 cells in vitro using serum from lit/lit mice or lit/+ mice serum was examined to complement the in vivo experiments. RESULTS In intact mice, androgen-responsive growth rate of LNCaP xenografts was significantly reduced in lit/lit mice as compared to lit/+ mice [mm3/day (mean±SD) 56.0±8.5 vs 93.2±16.3, p < 0.05]. CR progression of LNCaP xenografts was also significantly delayed in lit/lit mice as compared to lit/+ mice [mm3/day (mean±SD) 65.2±12.8 vs 147.2±47.3, p < 0.1]. After castration, serum PSA levels in lit/lit mice was significantly lower than in lit/+ mice [ng/ml/day (mean±SD) 18.0±6.5 vs 60.0±33.0, p < 0.1]. Growth of CR PC3 xenografts was significantly delayed in lit/lit mice (n=19) as compared to lit/+ mice (n=17) [mm3/day (mean±SD) 234.5±24.1 vs 441.6±42.4, p < 0.001]. LNCaP and PC3 cells grown in vitro with serum from lit/lit mice showed decreased proliferation as compared with serum from lit/+ mice. CONCLUSIONS The GH/IGF axis appears to be an important stimulator of both androgen-responsive growth and CR progression of these PCa xenograft models. The results motivate clinical trials of novel hormonal treatment strategies that target the GH/IGF axis for PCa patients. Vancouver, Canada© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e266 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kiyoshi Takahara More articles by this author Howard Tearle More articles by this author Tabitha Tombe More articles by this author Martin E. Gleave More articles by this author Michael E. Cox More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...