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Colon cancer cells produce immunoregulatory glucocorticoids

Oncogene volume 30, pages 2411–2419 (2011)Cite this article

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Abstract

Glucocorticoids (GC) have important anti-inflammatory and pro-apoptotic activities. Initially thought to be exclusively produced by the adrenal glands, there is now increasing evidence for extra-adrenal sources of GCs. We have previously shown that the intestinal epithelium produces immunoregulatory GCs and that intestinal steroidogenesis is regulated by the nuclear receptor liver receptor homolog-1 (LRH-1). As LRH-1 has been implicated in the development of colon cancer, we here investigated whether LRH-1 regulates GC synthesis in colorectal tumors and whether tumor-produced GCs suppress T-cell activation. Colorectal cancer cell lines and primary tumors were found to express steroidogenic enzymes and regulatory factors required for the de novo synthesis of cortisol. Both cell lines and primary tumors constitutively produced readily detectable levels of cortisol, as measured by radioimmunoassay, thin-layer chromatography and bioassay. Whereas overexpression of LRH-1 significantly increased the expression of steroidogenic enzymes and the synthesis of cortisol, downregulation or inhibition of LRH-1 effectively suppressed these processes, indicating an important role of LRH-1 in colorectal tumor GC synthesis. An immunoregulatory role of tumor-derived GCs could be further confirmed by demonstrating a suppression of T-cell activation. This study describes for the first time cortisol synthesis in a non-endocrine tumor in humans, and suggests that the synthesis of bioactive GCs in colon cancer cells may account as a novel mechanism of tumor immune escape.

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Abbreviations

CRC:

colorectal carcinoma

CYP:

cytochrome P450

GC:

glucocorticoids

LRH-1:

liver receptor homolog-1/NR5A2

SF-1:

steroidogenic factor-1/NR5A1

StAR:

steroid acute regulatory protein

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Acknowledgements

We thank Mario Noti, Pamela Bianchi, Andrea Hirsch, Gabi Hofer and Andreas Kappeler for technical help and advice, the members of the Division of Clinical Histopathology for preparation of tissue sections, and Sam Okret and Kristina Schoonjans for reagents. This work was supported by research grants from Oncosuisse (OCS-02025-02-2007) and the Swiss National Science Foundation (310000-121854) to TB. DS was supported by an MD-PhD fellowship from the Swiss National Science Foundation.

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Author notes

  1. P Renzulli

    Present address: 5Current address: Department of Surgery, Cantonal Hospital, Münsterlingen 8596, Switzerland,

Authors and Affiliations

  1. Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland

    D Sidler, C Schnoz, B Berger, S Schneider-Jakob, N Corazza & T Brunner

  2. Department of Visceral Surgery and Medicine, Insel University Hospital, University of Bern, Bern, Switzerland

    P Renzulli, D Inderbitzin & D Candinas

  3. Division of Pediatric Endocrinology, University Children's Hospital, University of Bern, Bern, Switzerland

    C Flück

  4. Division of Biochemical Pharmacology, Department of Biology, University of Konstanz, Konstanz, Germany

    T Brunner

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  1. D Sidler
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Correspondence to T Brunner.

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Sidler, D., Renzulli, P., Schnoz, C. et al. Colon cancer cells produce immunoregulatory glucocorticoids. Oncogene 30, 2411–2419 (2011). https://doi.org/10.1038/onc.2010.629

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