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Am J Pathol. 2018 Sep 28. pii: S0002-9440(18)30499-1. doi: 10.1016/j.ajpath.2018.07.029. [Epub ahead of print]

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

Author information

1
Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, and Turku Center for Disease Modeling, University of Turku, Turku, Finland; Orion Corporation, Orion Pharma, Finland.
2
Orion Corporation, Orion Pharma, Finland.
3
Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, and Turku Center for Disease Modeling, University of Turku, Turku, Finland.
4
Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
5
Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, and Turku Center for Disease Modeling, University of Turku, Turku, Finland; Department of Mathematics and Statistics, University of Turku, Turku, Finland; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
6
Department of Mathematics and Statistics, University of Turku, Turku, Finland; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
7
Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
8
Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, and Turku Center for Disease Modeling, University of Turku, Turku, Finland; Functional Foods Forum, University of Turku, Turku, Finland.
9
Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, and Turku Center for Disease Modeling, University of Turku, Turku, Finland; Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. Electronic address: matti.poutanen@utu.fi.

Abstract

The role of adrenal androgens as drivers for castration-resistant prostate cancer (CRPC) growth in man is generally accepted; however, the value of preclinical mouse models of CRPC is debatable, since 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 (P4), 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 P4 concentration, whereas orchectomized and adrenalectomized (ORX+ADX) resulted into a significant decrease in serum P4, and into a further reduction in the low levels of serum androgens (androstenedione, testosterone, and dihydrotestosterone), measured by mass spectrometry. In line with this, the serum PSA and growth of VCaP xenografts in mice after ORX+ADX was markedly reduced compared to 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 that in contrast to the current view, and similar to human, mouse adrenals synthesize significant amounts of steroids that contribute to the androgen receptor-dependent growth of CRPC.

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