nach oben

Digestive Diseases and Sciences

Erschienen in:

01.06.2013 | Original Article

TGF-β1 Secreted by Hepatocellular Carcinoma Induces the Expression of the Foxp3 Gene and Suppresses Antitumor Immunity in the Tumor Microenvironment

verfasst von: Yi Wang, Bin Deng, Wenqing Tang, Taotao Liu, Xizhong Shen

Erschienen in: Digestive Diseases and Sciences | Ausgabe 6/2013

Einloggen, um Zugang zu erhalten

Abstract

Aim

The purpose of this study was to explore the mechanisms of TGF-β1 mediated immunosuppression in tumor stroma.

Methods

The expression of TGF-β1 was investigated in Huh7, Hep 3B, SGC-7901, Eca-109 and Hepa1-6 cell lines using immunofluorescence. Knocked-down TGF-β1 of the Hepa1-6 cell line was established through lentivirus-based RNA interference. The interference efficiency of the TGF-β1 gene was tested by real-time PCR and ELISA; the expression of Foxp3, IFN-γ and CD83 in CD4⁺, CD8⁺ or dendritic cells was examined via flow cytometry; and the tumorigenic ability of the cancer cells was investigated in the animal experiments.

Results

The diverse digestive cancer cells were found to secrete TGF-β1, mRNA of which was knocked down by 78 % thanks to lentivirus-based interference in Hepa1-6 cells. Flow cytometry showed that CD4⁺CD25⁺Foxp3⁺ regulatory T cells significantly increased in hepatocellular carcinoma patients when compared with those in the healthy controls. The supernatant from Hepa1-6 cells and recombinant TGF-β1 significantly induced the expression of Foxp3 gene in vitro, while that from sh TGF-β1 Hepa1-6 cells restored it. Hepa1-6 cells inhibited IFN-γ and CD83 expression in CD8⁺ or dendritic cells by secreting TGF-β1. The animal experiments indicated that the knockdown TGF-β1 gene impaired the tumorigenic ability of Hepa1-6 cells.

Conclusion

TGF-β1, expressed in cancer cells, might be a potential therapeutic target for cancer treatment.

Newfeld SJ, Wisotzkey RG, Kumar S. Molecular evolution of a developmental pathway: phylogenetic analyses of transforming growth factor-beta family ligands, receptors and Smad signal transducers. Genetics. 1999;152:783–795.PubMed

Govinden R, Bhoola KD. Genealogy, expression, and cellular function of transforming growth factor-beta. Pharmacol Ther. 2003;98:257–265.PubMedCrossRef

Chang H, Brown CW, Matzuk MM. Genetic analysis of the mammalian transforming growth factor-beta superfamily. Endocr Rev. 2002;23:787–823.PubMedCrossRef

Li MO, Wan YY, Sanjabi S, Robertson AKL, Flavell RA. Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol. 2006;24:99–146.PubMedCrossRef

Moustakas A, Pardali K, Gaal A, Heldin CH. Mechanisms of TGF-beta signaling in regulation of cell growth and differentiation. Immunol Lett. 2002;82:85–91.PubMedCrossRef

Shull MM, Ormsby I, Kier AB, et al. Targeted disruption of the mouse TGF-β1 gene results in multifocal inflammatory diseases. Nature. 1992;359:693–699.PubMedCrossRef

Kulkarni AB, Huh CG, Becker D, et al. TGF-β1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci USA. 1993;90:770–774.PubMedCrossRef

Xu J, Lamouille S, Derynck R. TGF-beta-induced epithelial to mesenchymal transition. Cell Res. 2009;19:156–172.PubMedCrossRef

Akhurst RJ, Derynck R. TGF-beta signaling in cancer—a double-edged sword. Trends Cell Biol. 2001;11:S44–S51.PubMed

10.

Gravdal K, Halvorsen OJ, Haukaas SA, Akslen LA. A switch from E-cadherin to N-cadherin expression indicates epithelial to mesenchymal transition and is of strong and independent importance for the progress of prostate cancer. Clin Cancer Res. 2007;13:7003–7011.PubMedCrossRef

11.

Portella G, Cumming SA, Liddell J, et al. Transforming growth factor beta is essential for spindle cell conversion of mouse skin carcinoma in vivo: implications for tumor invasion. Cell Growth Differ. 1998;9:393–404.PubMed

12.

Xu Z, Shen MX, Ma DZ, Wang LY, Zha XL. TGF-beta 1-promoted epithelial-to-mesenchymal transformation and cell adhesion contribute to TGF-beta 1-enhanced cell migration in SMMC-7721 cells. Cell Res. 2003;13:343–350.PubMedCrossRef

13.

Poon RTP, Ng IOL, Lau C, et al. Tumor microvessel density as a predictor of recurrence after resection of hepatocellular carcinoma: a prospective study. J Clin Oncol. 2002;20:1775–1785.PubMedCrossRef

14.

Ananth S, Knebelmann B, Gruning W, et al. Transforming growth factor beta 1 is a target for the von Hippel–Lindau tumor suppressor and a critical growth factor for clear cell renal carcinoma. Cancer Res. 1999;59:2210–2216.PubMed

15.

Tuxhorn JA, McAlhany SJ, Yang F, Dang TD, Rowley DR. Inhibition of transforming growth factor-beta activity decreases angiogenesis in a human prostate cancer-reactive stroma xenograft model. Cancer Res. 2002;62:6021–6025.PubMed

16.

Wang Y, Liu XP, Zhao ZB, Chen JH, Yu CG. Expression of CD4(+) forkhead box P3 (FOXP3)(+) regulatory T cells in inflammatory bowel disease. J Dig Dis. 2011;12:286–294.PubMedCrossRef

17.

Krenger W, Rossi S, Piali L, Hollander GA. Thymic atrophy in murine acute graft-versus-host disease is effected by impaired cell cycle progression of host pro-T and pre-T cells. Blood. 2000;96:347–354.PubMed

18.

Centers for Disease Control and Prevention. Progress in hepatitis B prevention through universal infant vaccination—China, 1997-2006. MMWR Morb Mortal Wkly Rep. 2007;56:441–445.

19.

Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020–1022.PubMedCrossRef

20.

Llovet JM, Bruix J. Novel advancements in the management of hepatocellular carcinoma in 2008. J Hepatol. 2008;48:S20–S37.PubMedCrossRef

21.

Lencioni R, Cioni D, Crocetti L, et al. Early-stage hepatocellular carcinoma in patients with cirrhosis: long-term results of percutaneous image-guided radiofrequency ablation. Radiology. 2005;234:961–967.PubMedCrossRef

22.

Omata M, Tateishi R, Yoshida H, Shiina S. Treatment of hepatocellular carcinoma by percutaneous tumor ablation methods: ethanol injection therapy and radiofrequency ablation. Gastroenterology. 2004;127:S159–S166.PubMedCrossRef

23.

Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology. 2003;37:429–442.PubMedCrossRef

24.

Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–390.PubMedCrossRef

25.

Gold LI. The role for transforming growth factor-beta (TGF-beta) in human cancer. Crit Rev Oncog. 1999;10:303–360.PubMed

26.

Elliott RL, Blobe GC. Role of transforming growth factor beta in human cancer. J Clin Oncol. 2005;23:2078–2093.PubMedCrossRef

27.

Fu J, Xu D, Liu Z, et al. Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology. 2007;132:2328–2339.PubMedCrossRef

28.

Zhou J, Ding T, Pan W, Zhu L-y, Li L, Zheng L. Increased intratumoral regulatory T cells are related to intratumoral macrophages and poor prognosis in hepatocellular carcinoma patients. Int J Cancer. 2009;125:1640–1648.PubMedCrossRef

29.

Gao Q, Qiu S-J, Fan J, et al. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol. 2007;25:2586–2593.PubMedCrossRef

30.

Chen K-J, Lin S-Z, Zhou L, et al. Selective recruitment of regulatory T cell through CCR6-CCL20 in hepatocellular carcinoma fosters tumor progression and predicts poor prognosis. PLoS ONE. 2011;6:e24671.PubMedCrossRef

31.

Riemensberger J, Bohle A, Brandau S. IFN-gamma and IL-12 but not IL-10 are required for local tumour surveillance in a syngeneic model of orthotopic bladder cancer. Clin Exp Immunol. 2002;127:20–26.PubMedCrossRef

32.

Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol. 2004;75:163–189.PubMedCrossRef

33.

Shankaran V, Ikeda H, Bruce AT, et al. IFN gamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature. 2001;410:1107–1111.PubMedCrossRef

Titel: TGF-β1 Secreted by Hepatocellular Carcinoma Induces the Expression of the Foxp3 Gene and Suppresses Antitumor Immunity in the Tumor Microenvironment
verfasst von: Yi Wang
Bin Deng
Wenqing Tang
Taotao Liu
Xizhong Shen
Publikationsdatum: 01.06.2013
Verlag: Springer US
Erschienen in: Digestive Diseases and Sciences / Ausgabe 6/2013
Print ISSN: 0163-2116
Elektronische ISSN: 1573-2568
DOI: https://doi.org/10.1007/s10620-012-2550-4

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Die Highlights vom Kongress des American College of Cardiology 2024

Springer Medizin

TGF-β1 Secreted by Hepatocellular Carcinoma Induces the Expression of the Foxp3 Gene and Suppresses Antitumor Immunity in the Tumor Microenvironment

Abstract