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Characterisation of the cancer-associated glucocorticoid system: key role of 11β-hydroxysteroid dehydrogenase type 2

Research output: Contribution to journalArticle

  • Nicola Cirillo
  • David J Morgan
  • Maria Carmela Pedicillo
  • Antonio Celentano
  • Lorenzo Lo Muzio
  • Michael J McCullough
  • Stephen S Prime
Original languageEnglish
Pages (from-to)984-993
Number of pages10
JournalBritish Journal of Cancer
Volume117
Issue number7
Early online date10 Aug 2017
DOIs
DateAccepted/In press - 3 Jul 2017
DateE-pub ahead of print - 10 Aug 2017
DatePublished (current) - 26 Sep 2017

Abstract

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.

    Research areas

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1, 11-beta-Hydroxysteroid Dehydrogenase Type 2, Adrenocorticotropic Hormone, CD8-Positive T-Lymphocytes, Carcinoma, Squamous Cell, Cell Adhesion, Cell Proliferation, Cortisone, Culture Media, Conditioned, Down-Regulation, Epithelial Cells, Gene Silencing, Glycyrrhetinic Acid, HT29 Cells, Humans, Hydrocortisone, Keratinocytes, MCF-7 Cells, Melanoma, Paracrine Communication, Receptors, Glucocorticoid, Skin Neoplasms, Journal Article

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  • Full-text PDF (accepted author manuscript)

    Rights statement: This is the author accepted manuscript (AAM). The final published version (version of record) is available online via Springer Nature at https://www.nature.com/articles/bjc2017243#abstract. Please refer to any applicable terms of use of the publisher.

    Accepted author manuscript, 433 KB, PDF document

  • Full-text PDF (final published version)

    Final published version, 1 MB, PDF document

    Licence: CC BY-NC-SA

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