Development of an androgen receptor-null model for identifying the initiation site for androgen stimulation of proliferation and suppression of programmed (apoptotic) death of PC-82 human prostate cancer cells.
Whether androgen regulates the proliferation and survival of androgen-responsive prostate cancer cells directly or indirectly via a paracrine pathway initiated in androgen receptor (AR)-expressing stromal cells is unknown. To resolve this issue, female mice heterozygous for the testicular feminized male loss of function mutation in their X-linked AR genes were cross-bred to T cell-defective homozygous male nude mice. Using a PCR-based restriction enzyme digestion method, the resulting AR/tfm, Nu/nu F1 hybrid females were identified and back-crossed to homozygous male nude mice to produce AR-null male nude mice lacking both AR and T-cell function. Androgen-responsive PC-82 human prostate cancers were xenografted into these AR-null versus AR-wild-type male nude mice. In both backgrounds, the cancer cells did not grow in nonandrogenized hosts. In contrast, PC-82 prostate cancer cells grew with identical characteristics (i.e., take rate, morphology, PSA expression, growth rate, and percentage of cell proliferating or dying) in androgenized hosts of both backgrounds. Likewise, in both backgrounds, androgen ablation of mice bearing growing PC-82 cancers resulted in the inhibition of proliferation and activation of programmed (apoptotic) cell death of the cancer cells. These results demonstrate that both the androgen-stimulated proliferation and the suppression of programmed cell death of PC-82 human prostate cancer cells are initiated by the AR pathway directly within these cancer cells themselves and do not involve initiation by AR-expressing stromal cells in a paracrine manner.
Gao
J
J
Johns Hopkins Oncology Center, Baltimore, Maryland 21231, USA.
Isaacs
J T
JT
D000728:Androgens / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D003094:Collagen; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007797:Laminin; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000473:pathology* / Q000648:ultrastructure*; D011509:Proteoglycans; D011944:Receptors, Androgen / Q000235:genetics / Q000502:physiology*; D014183:Transplantation, Heterologous
D000728:Androgens; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D011944:Receptors, Androgen; C059485:matrigel; D003094:Collagen