title: Human prostate cancer xenografts in lit/lit mice exhibit reduced growth and androgen-independent progression.
abstract: BACKGROUND
  The growth hormone/insulin-like growth factor I (GH/IGF-I) axis has been linked to prostate cancer (PCa) risk. Although previous studies indicate that human breast cancers and a murine PCa model develop more slowly in murine hosts homozygous for a missense mutation in the GH-releasing hormone receptor (lit/lit) whose "little" dwarfed phenotype is caused by suppressed GH and IGF-I production, the role of these two hormones remains controversial.
  
  
  METHODS
  To assess how the GH/IGF-I axis influences androgen-responsive, castration-resistant (CR), and androgen-independent (AI) growth of human PCa, we compared xenograft growth of the androgen-responsive human PCa cells, LNCaP, and AI human PCa cells, PC3, in intact and castrate Nod/SCID lit/lit and lit/+ mice, and in vitro growth of these cell lines in lit/lit and lit/+ serum-containing media supplemented with GH or IGF-I.
  
  
  RESULTS
  Tumor growth and PSA accumulation rates were suppressed in LNCaP tumor-bearing lit/lit mice pre- and post-castration. Growth of PC3 xenografts in lit/lit mice was also suppressed. In vitro proliferation of LNCaP and PC3 cells cultured in media containing lit/lit mouse serum was decreased as compared to growth in media containing lit/+ serum. Suppressed growth in lit/lit serum could be restored by the addition of IGF-I, and to a lesser extent, GH. Differences in growth correlated with differences in steady-state AKT and ERK1/2 activation.
  
  
  CONCLUSIONS
  This study demonstrates that circulating GH and IGF-I can promote androgen-responsive growth, CR progression, and AI expansion of PTEN-deficient human PCa cell xenografts and indicates that IGF-I can promote PCa growth in a suppressed GH environment.
authors.affiliation: The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takahara
authors.forename: Howard
authors.initials: H
authors.lastname: Tearle
authors.forename: Mazyar
authors.initials: M
authors.lastname: Ghaffari
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gleave
authors.forename: Michael
authors.initials: M
authors.lastname: Pollak
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cox
mesh_terms: D000728:Androgens / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D001835:Body Weight / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D019382:Human Growth Hormone / Q000097:blood / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000378:metabolism; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009376:Neoplasms, Hormone-Dependent / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000097:blood / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*
chemical_list: D000728:Androgens; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D051058:Oncogene Protein v-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D017430:Prostate-Specific Antigen