Characterisation of the cancer-associated glucocorticoid system: key role of 11 beta-hydroxysteroid dehydrogenase type 2
AuthorCirillo, N; Morgan, DJ; Pedicillo, MC; Celentano, A; Lo Muzio, L; McCullough, MJ; Prime, SS
Source TitleBritish Journal of Cancer
PublisherNATURE PUBLISHING GROUP
AffiliationMelbourne Dental School
Document TypeJournal Article
CitationsCirillo, N., Morgan, D. J., Pedicillo, M. C., Celentano, A., Lo Muzio, L., McCullough, M. J. & Prime, S. S. (2017). Characterisation of the cancer-associated glucocorticoid system: key role of 11 beta-hydroxysteroid dehydrogenase type 2. BRITISH JOURNAL OF CANCER, 117 (7), pp.984-993. https://doi.org/10.1038/bjc.2017.243.
Access StatusOpen Access
BACKGROUND: Recent studies have shown that production of cortisol not only takes place in several non-adrenal peripheral tissues such as epithelial cells but, also, the local inter-conversion between cortisone and cortisol is regulated by the 11β-hydroxysteroid dehydrogenases (11β-HSDs). However, little is known about the activity of this non-adrenal glucocorticoid system in cancers. METHODS: The presence of a functioning glucocorticoid system was assessed in human skin squamous cell carcinoma (SCC) and melanoma and further, in 16 epithelial cell lines from 8 different tissue types using ELISA, western blotting and immunofluorescence. 11β-HSD2 was inhibited both pharmacologically and by siRNA technology. Naïve CD8+ T cells were used to test the paracrine effects of cancer-derived cortisol on the immune system in vitro. Functional assays included cell-cell adhesion and cohesion in two- and three-dimensional models. Immunohistochemical data of 11β-HSD expression were generated using tissue microarrays of 40 cases of human SCCs as well as a database featuring 315 cancer cases from 15 different tissues. RESULTS: We show that cortisol production is a common feature of malignant cells and has paracrine functions. Cortisol production correlated with the magnitude of glucocorticoid receptor (GR)-dependent inhibition of tumour-specific CD8+ T cells in vitro. 11β-HSDs were detectable in human skin SCCs and melanoma. Analyses of publicly available protein expression data of 11β-HSDs demonstrated that 11β-HSD1 and -HSD2 were dysregulated in the majority (73%) of malignancies. Pharmacological manipulation of 11β-HSD2 activity by 18β-glycyrrhetinic acid (GA) and silencing by specific siRNAs modulated the bioavailability of cortisol. Cortisol also acted in an autocrine manner and promoted cell invasion in vitro and cell-cell adhesion and cohesion in two- and three-dimensional models. Immunohistochemical analyses using tissue microarrays showed that expression of 11β-HSD2 was significantly reduced in human SCCs of the skin. CONCLUSIONS: The results demonstrate evidence of a cancer-associated glucocorticoid system and show for the first time, the functional significance of cancer-derived cortisol in tumour progression.
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