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Senescence surveillance of pre-malignant hepatocytes limits liver cancer development

Nature volume 479, pages 547–551 (2011)Cite this article

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Abstract

Upon the aberrant activation of oncogenes, normal cells can enter the cellular senescence program, a state of stable cell-cycle arrest, which represents an important barrier against tumour development in vivo1. Senescent cells communicate with their environment by secreting various cytokines and growth factors, and it was reported that this ‘secretory phenotype’ can have pro- as well as anti-tumorigenic effects2,3,4,5. Here we show that oncogene-induced senescence occurs in otherwise normal murine hepatocytes in vivo. Pre-malignant senescent hepatocytes secrete chemo- and cytokines and are subject to immune-mediated clearance (designated as ‘senescence surveillance’), which depends on an intact CD4+ T-cell-mediated adaptive immune response. Impaired immune surveillance of pre-malignant senescent hepatocytes results in the development of murine hepatocellular carcinomas (HCCs), thus showing that senescence surveillance is important for tumour suppression in vivo. In accordance with these observations, ras-specific Th1 lymphocytes could be detected in mice, in which oncogene-induced senescence had been triggered by hepatic expression of NrasG12V . We also found that CD4+ T cells require monocytes/macrophages to execute the clearance of senescent hepatocytes. Our study indicates that senescence surveillance represents an important extrinsic component of the senescence anti-tumour barrier, and illustrates how the cellular senescence program is involved in tumour immune surveillance by mounting specific immune responses against antigens expressed in pre-malignant senescent cells.

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Figure 1: Intrahepatic expression of oncogenic Nras G12V induces cellular senescence.
Figure 2: Pre-malignant senescent hepatocytes are cleared by liver-infiltrating immune cells.
Figure 3: Impaired senescence surveillance results in liver cancer development.
Figure 4: Immune surveillance of pre-malignant senescent hepatocytes is orchestrated by antigen-specific CD4 + T cells.

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Acknowledgements

We thank D. Largaespada and M. Kay for providing transposon vectors and transposase encoding vectors. We thank L. Gröbe, A. Rinkel, N. Struever, H. Riedesel, the team of the Helmholtz Centre for Infection Research (HZI) animal facility, M. Rothe, K. Schulze, A. Kobold, F. Heinzmann, N. Jedicke, C. Schneider, M. Pesic, H. Klimek and A. Samuels for technical assistance and assistance with animal work, and F. Alves, S. Kimmina, C. Dullin and S. Greco for assistance with flat panel-volumetric computer tomography. We thank the tissue bank of the National Center for Tumor Diseases Heidelberg for providing liver explant tissues. We thank S. Lowe, H. Tillmann, F. Greten and members of the Lowe and Zender laboratory for advice and discussions. This work was supported by the Helmholtz Association of German Research Centres (VH-NG-424 to L.Z.), the German Research Foundation, DFG (Emmy Noether Programme ZE 545/2-1 to L.Z., SFB/TRR77 and the ‘Rebirth’ Cluster of Excellence), the Wilhelm Sander Stiftung, the Bear Necessities Pediatric Cancer Foundation, the Federal German Ministry for Education and Research (BMBF) (ARCHES AWARD to L.Z.) and the European Commission (project ‘Heptromic’). L.Z. holds an adjunct assistant Professorship with the Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA. This work is dedicated to J. Wehland.

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Author notes

  1. Tae-Won Kang and Tetyana Yevsa: These authors contributed equally to this work.

Authors and Affiliations

  1. Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany

    Tae-Won Kang, Tetyana Yevsa, Lisa Hoenicke, Torsten Wuestefeld, Daniel Dauch, Anja Hohmeyer, Marcus Gereke, Ramona Rudalska, Anna Potapova, Siegfried Weiss, Dunja Bruder & Lars Zender

  2. Hannover Medical School, Dept. of Gastroenterology, Hepatology and Endocrinology, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany

    Tetyana Yevsa, Norman Woller, Torsten Wuestefeld, Anja Hohmeyer, Michael Manns & Lars Zender

  3. Twincore Centre for Experimental and Clinical Infection Research, Feodor-Lynen Strasse 7, 30625 Hannover, Germany

    Marcus Iken & Michael Ott

  4. Department of Internal Medicine III, University Hospital Aachen, 52074 Aachen, Germany

    Mihael Vucur, Frank Tacke & Tom Luedde

  5. Department of Pathology, University Hospital Zurich, CH 8091 Zurich, Switzerland

    Mathias Heikenwalder

  6. Institute of Virology, Helmholtz Centre Munich, Technical University Munich, 81675 Munich, Germany

    Mathias Heikenwalder

  7. MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, Hammersmith Campus, London W12 0NN, UK

    Sadaf Khan & Jesus Gil

  8. University of Heidelberg, Institute of Pathology, Im Neuenheimer Feld 220/21, 69120 Heidelberg, Germany

    Peter Schirmacher & Thomas Longerich

  9. Clinic for Internal Medicine, District Hospital Reutlingen, Steinenbergstrasse 31, 72764 Reutlingen, Germany

    Stefan Kubicka

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Contributions

L.Z. designed and guided the research and wrote the manuscript. T.-W.K., T.Y. and N.W. conducted experiments and contributed to research design and manuscript preparation. L.H., T.W., D.D., A.H., M.G., R.R., A.P., M.I., M.V., S.W., M.H., S.K., J.G., F.T., To.L., D.B. M.M., M.O. and S.K. contributed to research design and/or conducted experiments. P.S. and Th.L. performed histopathological analyses.

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Correspondence to Lars Zender.

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The authors declare no competing financial interests.

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Kang, TW., Yevsa, T., Woller, N. et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547–551 (2011). https://doi.org/10.1038/nature10599

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