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Synergy between truncated c-Met (cyto-Met) and c-Myc in liver oncogenesis: importance of TGF-β signalling in the control of liver homeostasis and transformation

Oncogene volume 21, pages 1335–1345 (2002)Cite this article

Abstract

The c-Met tyrosine kinase receptor and its ligand, Hepatocyte Growth Factor/ Scatter Factor, have been implicated in human cancer. We have previously described that the transgenic expression of a truncated form of human c-Met (cyto-Met) in the liver confers resistance to several apoptotic stimuli. Here we show the impact of cyto-Met expression on liver proliferation and transformation. Despite a sixfold increase of hepatocyte proliferation, adult transgenic livers displayed normal size and architecture. We present evidence showing that activation of TGF-β1 signalling controls the liver mass in cyto-Met mice. The oncogenic potential of cyto-Met was further assessed in the context of c-Myc-induced hepatocarcinogenesis, using WHV/c-Myc transgenic mice. Co-expression of cyto-Met and c-Myc further enhanced hepatocyte proliferation and caused a dramatic acceleration of the Myc-induced tumorigenesis, leading to the emergence of hepatocarcinomas in 3–4-month-old animals. Importantly, the TGF-β receptor type II expression was strongly downregulated in most tumours, indicating that impairment of TGF-β1-mediated growth inhibition plays a major role in accelerated neoplastic development. The strong potential of cyto-Met for oncogenic cooperation without direct transforming activity designates cyto-Met mice as an ideal tool for studying the early steps of multistage hepatocarcinogenesis and for identification of prognostic markers of transformation.

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Acknowledgements

We thank Claudio Cavallari and Claire Angélique Renard for expert technical assistance. This work was supported by the Associazione Italiana Ricerca sul Cancro (AIRC), by the Ministero dell'Università e Ricerca Scientifica (MURST), by a CNR target project on Biotechnology and by Ricerca Finalizzata Ministero della Sanità.

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Authors and Affiliations

  1. Dipartimento di Biotecnologie Cellulari ed Ematologia, Fondazione Istituto Pasteur-Cenci Bolognetti, Sezione di Genetica Molecolare, Università La Sapienza, Rome, 00161, Italy

    Laura Amicone, Barbara Costabile, Carla Cicchini, Francesco Lozupone & Marco Tripodi

  2. Département des Rétrovirus, Unité de Recombinaison et Expression Génétique, Institut Pasteur, Paris, Cedex 15, 75724, France

    Olivier Terradillos & Marie Annick Buendia

  3. Dipartimento di Medicina Sperimentale e Patologia, Sezione di Anatomia Patologica, Università ‘La Sapienza’, Rome, 00161, Italy

    Carlo Della Rocca

  4. Istituto Nazionale Malattie Infettive IRCCS ‘L Spallanzani’, Rome, Italy

    Ludovica Calvo, Mauro Piacentini & Marco Tripodi

  5. Dipartimento di Biologia, Università ‘Tor Vergata’, 00133 Rome, Italy

    Mauro Piacentini

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  1. Laura Amicone
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  2. Olivier Terradillos
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  3. Ludovica Calvo
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Correspondence to Marco Tripodi.

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This work is dedicated to the late Franco Tato, dear friend, colleague and mentor of our research

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Amicone, L., Terradillos, O., Calvo, L. et al. Synergy between truncated c-Met (cyto-Met) and c-Myc in liver oncogenesis: importance of TGF-β signalling in the control of liver homeostasis and transformation. Oncogene 21, 1335–1345 (2002). https://doi.org/10.1038/sj.onc.1205199

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