Colon cancer cells produce immunoregulatory glucocorticoids

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Sidler_Colon-cancer.pdf
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2011
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Sidler, Daniel
Renzulli, Pietro
Schnoz, C.
Berger, Barbara
Schneider-Jakob, Sabine
Flück, Christa E.
Inderbitzin, Daniel
Corazza, Nadia
Candinas, Daniel
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Zusammenfassung

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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570 Biowissenschaften, Biologie
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Extra-adrenal steroidogenesis, Colon cancer, Immune escape, Nuclear receptors
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ISO 690SIDLER, Daniel, Pietro RENZULLI, C. SCHNOZ, Barbara BERGER, Sabine SCHNEIDER-JAKOB, Christa E. FLÜCK, Daniel INDERBITZIN, Nadia CORAZZA, Daniel CANDINAS, Thomas BRUNNER, 2011. Colon cancer cells produce immunoregulatory glucocorticoids. In: Oncogene. 2011, 30(21), pp. 2411-2419. ISSN 0950-9232. eISSN 1476-5594. Available under: doi: 10.1038/onc.2010.629
BibTex
@article{Sidler2011-05-26Colon-14236,
  year={2011},
  doi={10.1038/onc.2010.629},
  title={Colon cancer cells produce immunoregulatory glucocorticoids},
  number={21},
  volume={30},
  issn={0950-9232},
  journal={Oncogene},
  pages={2411--2419},
  author={Sidler, Daniel and Renzulli, Pietro and Schnoz, C. and Berger, Barbara and Schneider-Jakob, Sabine and Flück, Christa E. and Inderbitzin, Daniel and Corazza, Nadia and Candinas, Daniel and Brunner, Thomas}
}
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