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

Nicola Cirillo, David J Morgan, Maria Carmela Pedicillo, Antonio Celentano, Lorenzo Lo Muzio, Michael J McCullough, Stephen S Prime

Research output: Contribution to journalArticle (Academic Journal)peer-review

9 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)984-993
Number of pages10
JournalBritish Journal of Cancer
Volume117
Issue number7
Early online date10 Aug 2017
DOIs
Publication statusPublished - 26 Sep 2017

Keywords

  • 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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