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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Adrenals Contribute to Growth of Castration-Resistant VCaP Prostate Cancer Xenografts
Riikka Huhtaniemi1, Riikka Oksala2, Matias Knuuttila3
1Research 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.
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.
Insights
Mouse adrenal glands produce steroids that fuel castration-resistant prostate cancer (CRPC) growth, challenging previous assumptions about preclinical models. This finding is crucial for understanding CRPC progression and developing new treatments.
Area of Science:
- Endocrinology
- Oncology
- Cancer Biology
Background:
- Adrenal androgens are recognized drivers of human castration-resistant prostate cancer (CRPC).
- The utility of mouse models for studying CRPC is questioned due to perceived differences in adrenal steroidogenesis.
- Mouse adrenal glands were thought to lack the capacity to produce androgen receptor-activating steroids.
Purpose of the Study:
- To investigate the steroidogenic capacity of mouse adrenal glands in the context of CRPC.
- To determine if mouse adrenals contribute to CRPC growth, similar to human adrenals.
- To re-evaluate the suitability of mouse models for CRPC research.
Main Methods:
- Confirmation of key enzymes for de novo androgen synthesis in mouse adrenal glands.
- Measurement of progesterone and androgen levels in intact and surgically modified mice (orchectomized and adrenalectomized) using mass spectrometry.
- Assessment of VCaP xenograft growth and prostate-specific antigen levels in mice.
- Analysis of androgen-dependent gene expression in tumors.
Main Results:
- Mouse adrenal glands express enzymes for de novo androgen synthesis and contain significant levels of progesterone and moderate androgens.
- Orchectomized and adrenalectomized (ORX + ADX) mice showed significantly reduced serum progesterone and androgens compared to ORX alone.
- VCaP xenograft growth and PSA levels were markedly reduced in ORX + ADX mice, and gene expression patterns shifted, mimicking enzalutamide treatment effects.
- Glucocorticoid treatment did not abolish the growth difference, suggesting adrenal-derived steroids, not just glucocorticoids, impact CRPC.
Conclusions:
- Mouse adrenal glands synthesize significant amounts of steroids that contribute to androgen receptor-dependent CRPC growth.
- Contrary to current views, mouse adrenals play a role in CRPC progression, making them a relevant model for studying the disease.
- These findings necessitate a re-evaluation of preclinical CRPC models and highlight the importance of adrenal-derived steroids in CRPC pathogenesis.
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