Notch signaling inhibits hepatocellular carcinoma following inactivation of the RB pathway

Patrick Viatour, Ursula Ehmer, Louis A. Saddic, Craig Dorrell, Jesper B. Andersen, Chenwei Lin, Anne Flore Zmoos, Pawel K. Mazur, Bethany E. Schaffer, Austin Ostermeier, Hannes Vogel, Karl G. Sylvester, Snorri S. Thorgeirsson, Markus Grompe, Julien Sage

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118 Scopus citations

Abstract

Hepatocellular carcinoma (HCC) is the third cancer killer worldwide with >600,000 deaths every year. Although the major risk factors are known, therapeutic options in patients remain limited in part because of our incomplete understanding of the cellular and molecular mechanisms influencing HCC development. Evidence indicates that the retinoblastoma (RB) pathway is functionally inactivated in most cases of HCC by genetic, epigenetic, and/or viral mechanisms. To investigate the functional relevance of this observation, we inactivated the RB pathway in the liver of adult mice by deleting the three members of the Rb (Rb1) gene family: Rb, p107, and p130. Rb family triple knockout mice develop liver tumors with histopathological features and gene expression profiles similar to human HCC. In this mouse model, cancer initiation is associated with the specific expansion of populations of liver stem/ progenitor cells, indicating that the RB pathway may prevent HCC development by maintaining the quiescence of adult liver progenitor cells. In addition, we show that during tumor progression, activation of the Notch pathway via E2F transcription factors serves as a negative feedback mechanism to slow HCC growth. The level of Notch activity is also able to predict survival of HCC patients, suggesting novel means to diagnose and treat HCC.

Original languageEnglish (US)
Pages (from-to)1963-1976
Number of pages14
JournalJournal of Experimental Medicine
Volume208
Issue number10
DOIs
StatePublished - Sep 26 2011

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Viatour, P., Ehmer, U., Saddic, L. A., Dorrell, C., Andersen, J. B., Lin, C., Zmoos, A. F., Mazur, P. K., Schaffer, B. E., Ostermeier, A., Vogel, H., Sylvester, K. G., Thorgeirsson, S. S., Grompe, M., & Sage, J. (2011). Notch signaling inhibits hepatocellular carcinoma following inactivation of the RB pathway. Journal of Experimental Medicine, 208(10), 1963-1976. https://doi.org/10.1084/jem.20110198