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Smad4-TGF-β Signaling Pathways in Pancreatic Cancer Pathogenesis

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Pancreatic Cancer

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with a 9% 5-year survival rate. For reasons that are not readily evident, KRAS is mutated in 90–95% of PDAC cases, and this truncal alteration is associated with a high frequency of mutations in crucially important tumor suppressor genes, most notably CDKN2A (~90%), a gene that encodes p16, TP53 (~70%), and SMAD4 (~50%). Concomitantly, there is overexpression of transforming growth factor beta (TGF-β) isoforms and of high-affinity tyrosine kinase receptors (TKRs) and their ligands. Enhanced cancer cell proliferation and migration mediated by TKRs, combined with loss of beneficial TGF-β-dependent pathways required to restrain uncontrolled cell proliferation, contributes to PDAC’s biological aggressiveness. This chapter provides an overview of these issues and focuses on the role of alterations in Smad4 expression and function and aberrant TGF-β signaling that combine to promote pancreatic cancer growth through cell autonomous and paracrine actions, thereby contributing in an important manner to PDAC pathobiology.

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Authors and Affiliations

  1. Departments of Medicine, Biochemistry and Molecular Biology, Indiana University School of Medicine, the Melvin and Bren Simon Cancer Center and the Pancreatic Cancer Signature Center, 980 W. Walnut Street, Indianapolis, IN, 46202, USA

    Murray Korc

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  1. Murray Korc
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Correspondence to Murray Korc .

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Editors and Affiliations

  1. DMCCMC, University of Liverpool DMCCMC, Liverpool, United Kingdom

    John P. Neoptolemos

  2. Rochester, Minnesota, USA

    Raul Urrutia

  3. Dept. Gastrointestinal Medical Onco, Duke University Medical Center Dept. Gastrointestinal Medical Onco, Durham, North Carolina, USA

    James Abbruzzese

  4. Heidelberg, Germany

    Markus W. Büchler

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  1. GI Research Unit, Mayo Clinic, 200 First Street SW, 55905, Rochester, MN, USA

    Raul Urrutia

  2. Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany

    M. W. Büchler MD

  3. Department of Surgery, The Royal Liverpool and Broadgreen University Hospitals NHS Trust, Prescot Street, L7 8XP, Liverpool, UK

    John P. Neoptolemos

  4. Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, L69 3GA, Liverpool, UK

    John P. Neoptolemos

  5. NIHR Pancreas Biomedical Research Unit, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK

    John P. Neoptolemos

  6. Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany

    Th. Hackert MD

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Korc, M. (2017). Smad4-TGF-β Signaling Pathways in Pancreatic Cancer Pathogenesis. In: Neoptolemos, J., Urrutia, R., Abbruzzese, J., Büchler, M. (eds) Pancreatic Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-6631-8_17-2

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  • DOI: https://doi.org/10.1007/978-1-4939-6631-8_17-2

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  • Print ISBN: 978-1-4939-6631-8

  • Online ISBN: 978-1-4939-6631-8

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