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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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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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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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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DOI: https://doi.org/10.1038/nature10599
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