Evidence that androgen-independent stromal growth factor signals promote androgen-insensitive prostate cancer cell growth in vivo.
Activation of tumor-stromal interactions is considered to play a critical role in the promotion of tumorigenesis. To discover new therapeutic targets for hormone-refractory prostate tumor growth under androgen ablation therapy, androgen-sensitive LNCaP cells and the derived sublines, E9 (androgen-low-sensitive), and AIDL (androgen-insensitive), were recombined with androgen-dependent embryonic rat urogenital sinus mesenchyme (UGM). Tumors of E9 + UGM and AIDL + UGM were approximately three times as large as those of LNCaP + UGM. Tumors grown in castrated hosts exhibited reduced growth as compared with those in intact hosts. However, in castrated hosts, E9 + UGM and AIDL + UGM tumors were still approximately twice as large as those of LNCaP + UGM. Cell proliferation in tumors of E9 + UGM and AIDL + UGM grown in castrated host, was significantly higher than that in tumors of LNCaP + UGM. In vitro, expression of fibroblast growth factor (FGF)-2 and IGF-I, but not FGF-7 mRNA, was significantly reduced in UGM under androgen starvation. In cell culture, E9 cells were responsive to FGF-2 and FGF-7 stimulation, while AIDL responded to FGF-7 and IGF-1. Expression of FGFR1 and FGFR2 was considerably higher in E9 than those in LNCaP, similarly expression of FGFR2 and IGF-IR were elevated in AIDL. These data suggest that activation of prostate cancer cell growth through growth factor receptor expression may result in the activity of otherwise androgen-independent stromal growth factor signals such as FGF-7 under conditions of androgen ablation.
Ishii
Kenichiro
K
Department of Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan. kenishii@clin.medic.mie-u.ac.jp
Imamura
Tetsuya
T
Iguchi
Kazuhiro
K
Arase
Shigeki
S
Yoshio
Yuko
Y
Arima
Kiminobu
K
Hirano
Kazuyuki
K
Sugimura
Yoshiki
Y
D000728:Androgens / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D007124:Immunoenzyme Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000187:drug effects* / Q000378:metabolism
D000728:Androgens; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; C496348:FGFR1 protein, human; C496353:FGFR2 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2