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

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 11?-hydroxysteroid dehydrogenases (11?-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. 11?-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 11?-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. 11?-HSDs were detectable in human skin SCCs and melanoma. Analyses of publicly available protein expression data of 11?-HSDs demonstrated that 11?-HSD1 and -HSD2 were dysregulated in the majority (73%) of malignancies. Pharmacological manipulation of 11?-HSD2 activity by 18?-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 11?-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.

SUBMITTER: Cirillo N 

PROVIDER: S-EPMC5625663 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature