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Glucocorticoids induce G1 cell cycle arrest in human neoplastic thymic epithelial cells

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Abstract

Purpose

Glucocorticoids exert anti-proliferative effects in various cell types and have long been known to induce apoptosis in thymocytes. Although a few reports have described the regression of human thymoma with glucocorticoid therapy, its effects on neoplastic thymic epithelial cells (TECs) have not been reported. In the present study, we investigated glucocorticoid receptor (GR) expression on neoplastic TECs and the effects of glucocorticoids in vitro on the cell cycle progression of tumor cells.

Patients and methods

Thymoma specimens were obtained during surgery from 21 patients. Three of the specimens with glucocorticoid therapy were examined using the TdT-mediated dUTP-biotin nick-end labeling method. Primary tumor specimens from ten untreated thymomas were examined for GR expression by immunohistochemistry. Isolated neoplastic TECs from the remaining eight untreated thymomas were examined using immunohistochemistry, flow cytometric and cell cycle analysis.

Results

GR are expressed on neoplastic TECs as well as on non-neoplastic thymocytes in thymomas, regardless of WHO histological classification. Glucocorticoids caused an accumulation of TEC in G0/G1 phase in all cases examined (n=6), and also induced apoptosis in the three with the lowest levels of Bcl-2 expression.

Conclusions

Our results indicate that neoplastic TECs express GR and that glucocorticoids directly suppress their in vitro proliferation.

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Abbreviations

GR:

Glucocorticoid receptor

TEC:

Thymic epithelial cell

References

  1. Auphan N, DiDonato JA, Rosette C, Helmberg A, Karin M (1995) Immunosupression by glucocorticoids: inhibition of NF-κB activity through induction of IκB synthesis. Science 270:286–290

  2. Beato M, Herrlich P, Schutz G (1995) Steroid hormone receptors: many actors in search of a plot. Cell 83:851–857

  3. Berki T, Kumanovics G, Kumanovics A, Falus A, Ujhelyi E, Nemeth P (1998) Production and flow cytometric application of a monoclonal anti-glucocorticoid receptor antibody. J Immunol Methods 214:19–27

  4. Berki T, Palinkas L, Boldizsar F, Nemeth P (2002) Glucocorticoid (GC) sensitivity and GC receptor expression differ in thymocyte subpopulations. Int Immunol 14:463–469

  5. Cohen JJ, Duke RC (1984) Glucocorticoid activation of a calcium-dependent endonuclease in thymocyte nuclei leads to cell death. J Immunol 132:38–42

  6. Cole TJ, Blendy JA, Monaghan AP, Krieglstein K, Schmid W, Aguzzi A, Fantuzzi G, Hummler E, Unsicker K, Schutz G (1995) Targeted disruption of the glucocorticoid receptor gene blocks adrenergic chromaffin cell development and severely retards lung maturation. Genes Dev 9:1608–1621

  7. Corroyer S, Nabeyrat E, Clement A (1997) Involvement of the cell cycle inhibitor CIP1/WAF1 in lung alveolar epithelial cell growth arrest induced by glucocorticoids. Endocrinology 138:3677–3685

  8. Florian RG, Michael K (2004) The IKK/NF-κB activation pathway—a terget for prevention and treatment of cancer. Cancer Lett 206:193–199

  9. Gilhus NE, Jones M, Turley H, Gatter KC, Nagvekar N, Newsom-Davis J, Willcox N (1995) Oncogene proteins and proliferation antigens in thymomas: increased expression of epidermal growth factor and Ki67 antigen. J Clin Pathol 48:447–455

  10. Greenberg AK, Hu J, Basu S, Hay J, Reibman J, Yie TA, Tchou-Wong KM, Rom WN, Lee TC (2002) Glucocorticoide inhibit lung cancer cell growth through both the extracellular signal-related kinase patheway and cell cycle regulators. Am J Respir Cell Mo Biol 27:320–328

  11. Grilli M, Chiu JJ, Lenardo MJ (1993) NF-kappa B and Rel: participants in a multiform transcriptional regulatory system. Int Rev Cytol 143:1–62

  12. Hiroshima K, Iyoda A, Toyozaki T, Supriatna Y, Shibuya K, Shimamura F, Haga Y, Yoshida S, Fujisawa T, Ohwada H (2002) Proliferative activity and apoptosis in thymic epithelial neoplasms. Mod Pathol 15:1326–1332

  13. Hu E, Levine J (1986) Chemotherapy of malignant thymoma. Case report and review of the literature. Cancer 57:1101–1104

  14. Inoue M, Fujii Y, Okumura M, Takeuchi Y, Shiono H, Miyoshi S, Matsuda H, Shirakura R (1998) Neoplastic thymic epithelial cells of human thymoma support T cell development from CD4-CD8- cells to CD4+CD8+ cells in vitro. Clin Exp Immunol 112:419–426

  15. Inoue M, Okumura M, Miyoshi S, Shiono H, Fukuhara K, Kadota Y, Shirakura R, Matsuda H (1999) Impaired expression of MHC class II molecules in response to interferon-gammna (INF-γ) on human thymoma neoplastic epithalial cells. Clin Exp Immunol 117:1–7

  16. Kadota Y, Okumura M, Miyoshi S, Kitagawa-Sakakida S, Inoue M, Shiono H, Maeda Y, Kinoshita T, Shirakura R, Matsuda H (2000) Altered T cell development in human thymoma is related to impairment of MHC class II transactivator expression induced by interferon-gamma (IFN-γ). Clin Exp Immunol 121:59–68

  17. Karin M (1998) New twists in gene regulation by glucocorticoid receptor: is DNA binding dispensable? Cell 93:487–490

  18. Levine GD, Rosai J (1978) Thymic hyperplasia and neoplasia: a review of current concepts. Hum Pathol 9:495–515

  19. Loehrer PJ Sr, Wang W, Johnson DH, Aisner SC, Ettinger DS (2004) Octreotide alone or with prednisone in patients with advanced thymoma and thymic carcinoma: an Eastern Cooperative Oncology Group Phase II Trial. J Clin Oncol 22:293–299

  20. Masaoka A, Monden Y, Nakahara K, Tanioka T (1981) Follow-up study of thymomas with special reference to their clinical stages. Cancer 48:2485–2492

  21. Masuda A, Ohtsuka K, Matsuyama M (1990) Establishment of functional epithelial cell lines from a rat thymoma and a rat thymus. In Vitro Cell Dev Biol 26:713–721

  22. Müller-Hermelink HK, Marino M, Palestro G, Schumacher U, Kirchner T (1985) Immunohistological evidences of cortical and medullary differentiation in thymoma. Virchows Arch A 408:143–161

  23. Palmieri G, Lastoria S, Colao A, Vergara E, Varrella P, Biondi E, Selleri C, Catalano L, Lombardi G, Bianco AR, Salvatore M (1997) Successful treatment of a patient with a thymoma and pure red-cell aplasia with octreotide and prednisone. N Engl J Med 23:263–265

  24. Pan CC, Chen PC, Wang LS, Lee JY, Chiang H (2003) Expression of apoptosis-related markers and HER-2/neu in thymic epithelial tumours. Histopathology 43:165–172

  25. Ramdas J, Liu W, Harmon JM (1999) Glucocorticoid-induced cell death requires autoinduction of glucocorticoid receptor expression in human leukemic T cells. Cancer Res 59:1378–1385

  26. Rogatsky I, Hittelman AB, Pearce D, Garabedian MJ (1999) Distinct glucocorticoid receptor transcriptional regulatory surfaces mediate the cytotoxic and cytostatic effects of glucocorticoids. Mol Cell Biol 19:5036–5049

  27. Rosai J, Sobin LH (1999) Histological typing of tumors of the thymus. International histological classification of tumors, 2nd edn. Springer, Heidelberg Berlin New York

  28. Scheinman RI, Cogswell PC, Lofquist AK, Baldwin AS Jr (1995a) Role of transcriptional activation of IκBα in mediation of immunosupression by glucocorticoids. Science 270:283–286

  29. Scheinman RI, Gualberto A, Jewell CM, Cidlowski JA, Baldwin AS Jr (1995b) Characterization of mechanisms involved in transrepression of NF-κB by activated glucocorticoid receptors. Mol Cell Biol 15:943–953

  30. Soffer LJ, Gabrilove JL, Wolf BS (1952) Effect of ACTH on thymic masses. J Clin Endocrinol Metab 12:690–696

  31. Tateyama H, Takahashi E, Saito Y, Fukai I, Fujii Y, Niwa H, Eimoto T (2001) Histopathologic changes of thymoma preoperatively treated with corticosteroids. Virchows Arch 438:238–247

  32. Termeer A, Visser FJ, Mravunac M (2001) Regression of invasive thymoma following corticosteroid therapy. Neth J Med 58:181–184

  33. Wang CY, Mayo MW, Korneluk RC, Goeddel DV, Baldwin AS Jr (1998) NF-κB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1and c-IAP2 to suppress caspase-8 activation. Science 281:1680–1683

  34. Wang W, Wykrzykowska J, Johnson T, Sen R, Sen J (1999) A NF-κB/c-myc-dependent survival pathway is targeted by corticosteroids in immature thymocytes. J Immunol 162:314–322

  35. Wiegers GJ, Knoflach M, Bock G, Niederegger H, Dietrich H, Falus A, Boyd R, Wick G (2001) CD4+CD8+TCRlow thymocytes express low levels of glucocorticoid receptors while being sensitive to glucocorticoid-induced apoptosis. Eur J Immunol 31:2293–2301

  36. Wyllie AH (1980) Glucocorticoid-induced thymocyte apoptosis is associated with endogenous nuclease activation. Nature 284:555–556

  37. Yamamoto KR (1985) Steroid receptor regulated transcription of specific genes and gene networks. Annu Rev Genet 19:209–252

  38. Young IT (1977) Proof without prejudice: use of the Kolmogorov-Smirnov test for analysis of histograms from flow systems and other sources. J Histochem Cytochem 25:935–941

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Acknowledgements

We are grateful to Nick Willcox for critically reading the manuscript. We wish to thank Keiji Iuchi (National Kinki Central Hospital), Katsuhiro Nakagawa (Osaka Prefectural Habikino Hospital), Hajime Maeda (National Toneyama Hospital), Hirohumi Sueki (Ohtemae Hospital), Hiroto Tada (Osaka City General Hospital), Hyung-Eng Yoon (Rinku Medical Center), Akinori Akashi, Yukiyasu Takeuchi (Takarazuka City Hospital), Tetsuo Kido (Osaka Police Hospital), and Yoshitomo Okumura (Hyogo Medical University) for their submission of the specimens, and also Al Averbach for editing the manuscripts

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Correspondence to Hiroyuki Shiono.

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Funakoshi, Y., Shiono, H., Inoue, M. et al. Glucocorticoids induce G1 cell cycle arrest in human neoplastic thymic epithelial cells. J Cancer Res Clin Oncol 131, 314–322 (2005). https://doi.org/10.1007/s00432-004-0646-8

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Keywords

  • Thymoma
  • Thymic epithelial cell
  • Glucocorticoid
  • Glucocorticoid receptor
  • Apoptosis