Adrenals Contribute to Growth of Castration-Resistant VCaP Prostate Cancer Xenografts

被引:19
作者
Huhtaniemi, Riikka [1 ,2 ,5 ]
Oksala, Riikka [5 ]
Knuuttila, Matias [1 ,2 ]
Mehmood, Arfa [6 ]
Aho, Eija [5 ]
Laajala, Teemu D. [1 ,2 ,3 ,7 ]
Nicorici, Daniel [5 ]
Aittokallio, Tero [3 ,7 ]
Laiho, Asta [6 ]
Elo, Laura [6 ]
Ohlsson, Claes [8 ]
Kallio, Pekka [5 ]
Makela, Sari [1 ,2 ,4 ]
Mustonen, Mika V. J. [5 ]
Sipila, Petra [1 ,2 ]
Poutanen, Matti [1 ,2 ,8 ]
机构
[1] Univ Turku, Res Ctr Integrat Physiol & Pharmacol, Turku, Finland
[2] Univ Turku, Turku Ctr Dis Modeling, Turku, Finland
[3] Univ Turku, Inst Biomed, Dept Math & Stat, Turku, Finland
[4] Univ Turku, Funct Foods Forum, Turku, Finland
[5] Orion Corp, Orion Pharma, Espoo, Finland
[6] Univ Turku, Turku Ctr Biotechnol, Turku, Finland
[7] Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland
[8] Univ Gothenburg, Sahlgrenska Acad, Inst Med, Gothenburg, Sweden
基金
瑞典研究理事会; 芬兰科学院;
关键词
ANDROGEN RECEPTOR EXPRESSION; ABIRATERONE ACETATE; HORMONE AGONISTS; MECHANISMS; STEROIDOGENESIS; ENZALUTAMIDE; GENE; ANTIANDROGENS; BIOCONDUCTOR; TESTOSTERONE;
D O I
10.1016/j.ajpath.2018.07.029
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
The role of adrenal androgens as drivers for castration-resistant prostate cancer (CRPC) growth in humans is generally accepted; however, the value of preclinical mouse models of CRPC is debatable, because mouse adrenals do not produce steroids activating the androgen receptor. In this study, we confirmed the expression of enzymes essential for de novo synthesis of androgens in mouse adrenals, with high intratissue concentration of progesterone (P-4) and moderate levels of androgens, such as androstenedione, testosterone, and dihydrotestosterone, in the adrenal glands of both intact and orchectomized (ORX) mice. ORX alone had no effect on serum P-4 concentration, whereas orchectomized and adrenalectomized (ORX + ADX) resulted in a significant decrease in serum P-4 and in a further reduction in the Low levels of serum androgens (androstenedione, testosterone, and dihydrotestosterone), measured by mass spectrometry. In line with this, the serum prostate-specific antigen and growth of VCaP xenografts in mice after ORX + ADX were markedly reduced compared with ORX alone, and the growth difference was not abolished by a glucocorticoid treatment. Moreover, ORX + ADX altered the androgen-dependent gene expression in the tumors, similar to that recently shown for the enzalutamide treatment. These data indicate that in contrast to the current view, and similar to humans, mouse adrenals synthesize significant amounts of steroids that contribute to the androgen receptor dependent growth of CRPC.
引用
收藏
页码:2890 / 2901
页数:12
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