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Erschienen in: Journal of Cancer Research and Clinical Oncology 5/2005

01.05.2005 | Original Paper

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

verfasst von: Yasunobu Funakoshi, Hiroyuki Shiono, Masayoshi Inoue, Yoshihisa Kadota, Mitsunori Ohta, Hikaru Matsuda, Meinoshin Okumura, Tadaaki Eimoto

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 5/2005

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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.
Literatur
Zurück zum Zitat 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 270:286–290PubMed 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 270:286–290PubMed
Zurück zum Zitat Beato M, Herrlich P, Schutz G (1995) Steroid hormone receptors: many actors in search of a plot. Cell 83:851–857CrossRefPubMed Beato M, Herrlich P, Schutz G (1995) Steroid hormone receptors: many actors in search of a plot. Cell 83:851–857CrossRefPubMed
Zurück zum Zitat 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 214:19–27CrossRef 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 214:19–27CrossRef
Zurück zum Zitat Berki T, Palinkas L, Boldizsar F, Nemeth P (2002) Glucocorticoid (GC) sensitivity and GC receptor expression differ in thymocyte subpopulations. Int Immunol 14:463–469CrossRef Berki T, Palinkas L, Boldizsar F, Nemeth P (2002) Glucocorticoid (GC) sensitivity and GC receptor expression differ in thymocyte subpopulations. Int Immunol 14:463–469CrossRef
Zurück zum Zitat Cohen JJ, Duke RC (1984) Glucocorticoid activation of a calcium-dependent endonuclease in thymocyte nuclei leads to cell death. J Immunol 132:38–42 Cohen JJ, Duke RC (1984) Glucocorticoid activation of a calcium-dependent endonuclease in thymocyte nuclei leads to cell death. J Immunol 132:38–42
Zurück zum Zitat 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 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
Zurück zum Zitat 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 138:3677–3685CrossRef 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 138:3677–3685CrossRef
Zurück zum Zitat Florian RG, Michael K (2004) The IKK/NF-κB activation pathway—a terget for prevention and treatment of cancer. Cancer Lett 206:193–199CrossRef Florian RG, Michael K (2004) The IKK/NF-κB activation pathway—a terget for prevention and treatment of cancer. Cancer Lett 206:193–199CrossRef
Zurück zum Zitat 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 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
Zurück zum Zitat 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 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
Zurück zum Zitat 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 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
Zurück zum Zitat 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 15:1326–1332CrossRef 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 15:1326–1332CrossRef
Zurück zum Zitat Hu E, Levine J (1986) Chemotherapy of malignant thymoma. Case report and review of the literature. Cancer 57:1101–1104 Hu E, Levine J (1986) Chemotherapy of malignant thymoma. Case report and review of the literature. Cancer 57:1101–1104
Zurück zum Zitat 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 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
Zurück zum Zitat 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 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
Zurück zum Zitat 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 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
Zurück zum Zitat Karin M (1998) New twists in gene regulation by glucocorticoid receptor: is DNA binding dispensable? Cell 93:487–490CrossRef Karin M (1998) New twists in gene regulation by glucocorticoid receptor: is DNA binding dispensable? Cell 93:487–490CrossRef
Zurück zum Zitat Levine GD, Rosai J (1978) Thymic hyperplasia and neoplasia: a review of current concepts. Hum Pathol 9:495–515PubMed Levine GD, Rosai J (1978) Thymic hyperplasia and neoplasia: a review of current concepts. Hum Pathol 9:495–515PubMed
Zurück zum Zitat 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 22:293–299CrossRef 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 22:293–299CrossRef
Zurück zum Zitat 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 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
Zurück zum Zitat 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 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
Zurück zum Zitat Müller-Hermelink HK, Marino M, Palestro G, Schumacher U, Kirchner T (1985) Immunohistological evidences of cortical and medullary differentiation in thymoma. Virchows Arch A 408:143–161CrossRef Müller-Hermelink HK, Marino M, Palestro G, Schumacher U, Kirchner T (1985) Immunohistological evidences of cortical and medullary differentiation in thymoma. Virchows Arch A 408:143–161CrossRef
Zurück zum Zitat 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 23:263–265CrossRef 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 23:263–265CrossRef
Zurück zum Zitat 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 43:165–172CrossRef 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 43:165–172CrossRef
Zurück zum Zitat 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 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
Zurück zum Zitat 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 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
Zurück zum Zitat Rosai J, Sobin LH (1999) Histological typing of tumors of the thymus. International histological classification of tumors, 2nd edn. Springer, Heidelberg Berlin New York Rosai J, Sobin LH (1999) Histological typing of tumors of the thymus. International histological classification of tumors, 2nd edn. Springer, Heidelberg Berlin New York
Zurück zum Zitat Scheinman RI, Cogswell PC, Lofquist AK, Baldwin AS Jr (1995a) Role of transcriptional activation of IκBα in mediation of immunosupression by glucocorticoids. Science 270:283–286PubMed Scheinman RI, Cogswell PC, Lofquist AK, Baldwin AS Jr (1995a) Role of transcriptional activation of IκBα in mediation of immunosupression by glucocorticoids. Science 270:283–286PubMed
Zurück zum Zitat 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 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
Zurück zum Zitat Soffer LJ, Gabrilove JL, Wolf BS (1952) Effect of ACTH on thymic masses. J Clin Endocrinol Metab 12:690–696 Soffer LJ, Gabrilove JL, Wolf BS (1952) Effect of ACTH on thymic masses. J Clin Endocrinol Metab 12:690–696
Zurück zum Zitat 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 438:238–247CrossRef 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 438:238–247CrossRef
Zurück zum Zitat Termeer A, Visser FJ, Mravunac M (2001) Regression of invasive thymoma following corticosteroid therapy. Neth J Med 58:181–184CrossRef Termeer A, Visser FJ, Mravunac M (2001) Regression of invasive thymoma following corticosteroid therapy. Neth J Med 58:181–184CrossRef
Zurück zum Zitat 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 281:1680–1683CrossRef 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 281:1680–1683CrossRef
Zurück zum Zitat 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 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
Zurück zum Zitat 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 31:2293–2301CrossRef 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 31:2293–2301CrossRef
Zurück zum Zitat Wyllie AH (1980) Glucocorticoid-induced thymocyte apoptosis is associated with endogenous nuclease activation. Nature 284:555–556PubMed Wyllie AH (1980) Glucocorticoid-induced thymocyte apoptosis is associated with endogenous nuclease activation. Nature 284:555–556PubMed
Zurück zum Zitat Yamamoto KR (1985) Steroid receptor regulated transcription of specific genes and gene networks. Annu Rev Genet 19:209–252CrossRef Yamamoto KR (1985) Steroid receptor regulated transcription of specific genes and gene networks. Annu Rev Genet 19:209–252CrossRef
Zurück zum Zitat 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 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
Metadaten
Titel
Glucocorticoids induce G1 cell cycle arrest in human neoplastic thymic epithelial cells
verfasst von
Yasunobu Funakoshi
Hiroyuki Shiono
Masayoshi Inoue
Yoshihisa Kadota
Mitsunori Ohta
Hikaru Matsuda
Meinoshin Okumura
Tadaaki Eimoto
Publikationsdatum
01.05.2005
Verlag
Springer-Verlag
Erschienen in
Journal of Cancer Research and Clinical Oncology / Ausgabe 5/2005
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI
https://doi.org/10.1007/s00432-004-0646-8

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