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Evidence of Limited Contributions for Intratumoral Steroidogenesis in Prostate Cancer
Open accessPublished version of a preprint
Abstract
Androgen-deprivation therapy for prostate cancer (PC) eventually leads to castration-resistant PC (CRPC). Intratumoral androgen production might contribute to tumor progression despite suppressed serum androgen concentrations. In the present study, we investigated whether PC or CRPC tissue may be capable of intratumoral androgen synthesis. Steroidogenic enzyme mRNAs were quantified in hormonally manipulated human PC cell lines and xenografts as well as in human samples of normal prostate, locally confined and advanced PC, local nonmetastatic CRPC, and lymph node metastases. Overall, the majority of samples showed low or absent mRNA expression of steroidogenic enzymes required for de novo steroid synthesis. Simultaneous but low expression of the enzymes CYP17A1 and HSD3B1, essential for the synthesis of androgens from pregnenolone, could be detected in 19 of 88 patient samples. Of 19 CRPC tissues examined, only 5 samples expressed both enzymes. Enzymes that convert androstenedione to testosterone (AKR1C3) and testosterone to dihydrotestosterone (DHT; SRD5A1) were abundantly expressed. AKR1C3 expression was negatively regulated by androgens in the experimental models and was increased in CRPC samples. Expression of SRD5A1 was upregulated in locally advanced cancer, CRPC, and lymph node metastases. We concluded that intratumoral steroid biosynthesis contributes less than circulating adrenal androgens, implying that blocking androgen production and its intraprostatic conversion into DHT, such as via CYP17A1 inhibition, may represent favorable therapeutic options in patients with CRPC.
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“While the contribution of de-novo intratumoral biosynthesis to local androgens has mostly been excluded (Hofland et al., 2010)”
From Intracrine androgen biosynthesis, metabolism and action revisited (2018) · cites this paper as Hofland et al., 2010
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Metadata
- Authors
- Hofland, J., van Weerden, W. M., Dits, N. F. J., Steenbergen, J., van Leenders, G. J. L. H., Jenster, G., Schröder, F. H., & de Jong, F. H.
- Affiliations
- Erasmus MC (NL)
- Authors' Affiliations: Departments of 1Internal Medicine, 2Urology, and 3Pathology, Erasmus MC, Rotterdam, the Netherlands
- Venue
- Cancer Research
- Published
- 2010-01-31
- Volume
- 70
- Issue
- 3
- Pages
- 1256-1264
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2099477169
- Cited by
- 176
- References
- 40
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 3 · 2023: 6 · 2022: 4 · 2021: 11 · 2020: 6 · 2019: 6 · 2018: 10 · 2017: 10 · 2016: 7 · 2015: 10 · 2014: 25 · 2013: 21 · 2012: 20
- FWCI
- 20.47
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- other-oa
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Keywords
- prostate cancer, castration-resistant prostate cancer, androgen production, CYP17A1, HSD3B1, AKR1C3, SRD5A1, dihydrotestosterone, androgen deprivation therapy, steroidogenic enzyme expression, lymph node metastasis, CYP17 inhibition
- MeSH terms
- Aldo-Keto Reductase Family 1 Member C3, Aged, Aged, 80 and over, Androgens, Androstenedione, Animals, Humans, Hydroxyprostaglandin Dehydrogenases, Male, Middle Aged, Neoplasms, Experimental, Orchiectomy, Pregnenolone, Progesterone Reductase, Prostatic Neoplasms, RNA, Messenger, Dihydrotestosterone, Steroid 17-alpha-Hydroxylase, Testosterone, 3-Oxo-5-alpha-Steroid 4-Dehydrogenase, Transplantation, Heterologous, 3-Hydroxysteroid Dehydrogenases, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Reverse Transcriptase Polymerase Chain Reaction, Cell Line, Tumor, Mice
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