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The role of signaling pathways in the development and treatment of hepatocellular carcinoma

Oncogene volume 29, pages 4989–5005 (2010)Cite this article

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Abstract

Hepatocellular carcinoma (HCC) is a highly prevalent, treatment-resistant malignancy with a multifaceted molecular pathogenesis. Current evidence indicates that during hepatocarcinogenesis, two main pathogenic mechanisms prevail: (1) cirrhosis associated with hepatic regeneration after tissue damage caused by hepatitis infection, toxins (for example, alcohol or aflatoxin) or metabolic influences, and (2) mutations occurring in single or multiple oncogenes or tumor suppressor genes. Both mechanisms have been linked with alterations in several important cellular signaling pathways. These pathways are of interest from a therapeutic perspective, because targeting them may help to reverse, delay or prevent tumorigenesis. In this review, we explore some of the major pathways implicated in HCC. These include the RAF/MEK/ERK pathway, phosphatidylinositol-3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, WNT/β-catenin pathway, insulin-like growth factor pathway, hepatocyte growth factor/c-MET pathway and growth factor-regulated angiogenic signaling. We focus on the role of these pathways in hepatocarcinogenesis, how they are altered, and the consequences of these abnormalities. In addition, we also review the latest preclinical and clinical data on the rationally designed targeted agents that are now being directed against these pathways, with early evidence of success.

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Acknowledgements

We would like to thank John D Zoidis, MD (Bayer HealthCare Pharmaceuticals, Montville, NJ, USA), and Anna Hunt and Catherine Crookes (GeoMed, Macclesfield, Cheshire, UK) for writing and editorial support, with funding from Bayer HealthCare Pharmaceuticals.

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  1. Dana-Farber Cancer Institute, Boston, MA, USA

    S Whittaker

  2. The Broad Institute, Cambridge, MA, USA

    S Whittaker

  3. Institute of Cancer Research, London, UK

    R Marais

  4. Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA

    A X Zhu

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Steven Whittaker and Richard Marais have no competing financial interests in relation to this work. Richard Marais is on the editorial board of Oncogene. Andrew X Zhu has participated in advisory activities and has received research support from Bayer HealthCare Pharmaceuticals and Genentech, Inc.

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Whittaker, S., Marais, R. & Zhu, A. The role of signaling pathways in the development and treatment of hepatocellular carcinoma. Oncogene 29, 4989–5005 (2010). https://doi.org/10.1038/onc.2010.236

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