NE-10 neuroendocrine cancer promotes the LNCaP xenograft growth in castrated mice.
Increases in neuroendocrine (NE) cells and their secretory products are closely correlated with tumor progression and androgen-independent prostate cancer. However, the mechanisms by which NE cells influence prostate cancer growth and progression, especially after androgen ablation therapy, are poorly understood. To investigate the role of NE cells on prostate cancer growth, LNCaP xenograft tumors were implanted into nude mice. After the LNCaP tumors were established, the NE mouse prostate allograft (NE-10) was implanted on the opposite flank of these nude mice to test whether NE tumor-derived systemic factors can influence LNCaP growth. Mice bearing LNCaP tumors with or without NE allografts were castrated 2 weeks after NE tumor inoculation, and changes in LNCaP tumor growth rate and gene expression were investigated. After castration, LNCaP tumor growth decreased in mice bearing LNCaP tumors alone, and this was accompanied by a loss of nuclear androgen receptor (AR) localization. In contrast, in castrated mice bearing both LNCaP and NE-10 tumors, LNCaP tumors continued to grow, had increased levels of nuclear AR, and secreted prostate-specific antigen. Therefore, in the absence of testicular androgens, NE secretions were sufficient to maintain LNCaP cell growth and androgen-regulated gene expression in vivo. Furthermore, in vitro experiments showed that NE secretions combined with low levels of androgens activated the AR, an effect that was blocked by the antiandrogen bicalutamide. Because an increase in AR level has been reported to be sufficient to account for hormone refractory prostate cancers, the NE cell population ability to increase AR level/activity can be another mechanism that allows prostate cancer to escape androgen ablation therapy.
Department of Urologic Surgery, Vanderbilt University Medical Center, A-1302 Medical Center North, Nashville, TN 37232-2765, USA.
Ren Jie
RJ
Jin
Yongqing
Y
Wang
Naoya
N
Masumori
Kenichiro
K
Ishii
Taiji
T
Tsukamoto
Scott B
SB
Shappell
Simon W
SW
Hayward
Susan
S
Kasper
Robert J
RJ
Matusik
D000728:Androgens / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002454:Cell Differentiation; D002455:Cell Division; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism / Q000473:pathology; D018358:Neuroendocrine Tumors / Q000473:pathology*; D009919:Orchiectomy; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000728:Androgens; D011944:Receptors, Androgen; D017430:Prostate-Specific Antigen