Format

Send to

Choose Destination
Am J Pathol. 2018 Dec;188(12):2890-2901. doi: 10.1016/j.ajpath.2018.07.029. Epub 2018 Sep 28.

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

Author information

1
Research Centre for Integrative Physiology and Pharmacology, University of Turku, Turku, Finland; Turku Center for Disease Modeling, University of Turku, Turku, Finland; Orion Pharma, the Orion Corporation, Espoo, Finland.
2
Orion Pharma, the Orion Corporation, Espoo, Finland.
3
Research Centre for Integrative Physiology and Pharmacology, University of Turku, Turku, Finland; 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
Research Centre for Integrative Physiology and Pharmacology, University of Turku, Turku, Finland; Turku Center for Disease Modeling, University of Turku, Turku, Finland; Institute of Biomedicine, the Department of Mathematics and Statistics, University of Turku, Turku, Finland; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
6
Institute of Biomedicine, the Department of Mathematics and Statistics, University of Turku, Turku, Finland; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
7
Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
8
Research Centre for Integrative Physiology and Pharmacology, University of Turku, Turku, Finland; Turku Center for Disease Modeling, University of Turku, Turku, Finland; Functional Foods Forum, University of Turku, Turku, Finland.
9
Research Centre for Integrative Physiology and Pharmacology, University of Turku, Turku, Finland; 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 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 (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 in a significant decrease in serum P4 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.

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center