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Intrahepatic Cholangiocarcinoma pp 167–182Cite as

Molecular Pathogenesis: From Inflammation and Cholestasis to a Microenvironment-Driven Tumor

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Abstract

Intrahepatic cholangiocarcinoma is a primary liver cancer originating from the malignant transformation of different epithelial cell sources, not only the cholangiocyte but also the progenitor stem cell or the hepatocyte. Chronic inflammation, also extending outside the portal tract, and cholestasis are the main mechanisms promoting the pathogenetic sequence ultimately leading to the appearance of the neoplastic biliary lesion. Following tumor formation, a dense fibro-inflammatory stroma, termed “tumor reactive stroma,” progressively accumulate nearby the malignant bile ducts, further boosting tumor overgrowth and invasion. A crowd of cells composes the tumor reactive stroma among cancer-associated fibroblasts, tumor-associated macrophages, tumor-infiltrating lymphocytes, and lymphatic vessels, which lay embedded in an abnormally remodeled and stiff extracellular matrix. Herein, we will outline the molecular underpinnings responsible for the oncogenic effects of inflammation and cholestasis, underlining the different pathways and genetic perturbations. The multifaceted role played by the tumor microenvironment in driving invasiveness of intrahepatic cholangiocarcinoma is discussed, focusing on the main stromal cell types and the paracrine factors molding the pro-invasive functions of the tumoral cholangiocyte.

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Acknowledgments

M.C. was supported by Fondazione Cariplo, Grant No. 2014-1099; L.F. was supported by the University of Padua, Progetti di Ricerca di Dipartimento (PRID) 2017.

Conflict of Interest Statement

Authors have nothing to disclose.

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Authors and Affiliations

  1. Department of Molecular Medicine, University of Padua, Padua, Italy

    Eleonora Milani, Luca Fabris & Massimiliano Cadamuro

  2. International Center for Digestive Health (ICDH), University of Milano-Bicocca, Milano, Italy

    Mario Strazzabosco, Luca Fabris & Massimiliano Cadamuro

  3. Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, CT, USA

    Mario Strazzabosco & Luca Fabris

Authors
  1. Eleonora Milani
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  2. Mario Strazzabosco
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  3. Luca Fabris
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  4. Massimiliano Cadamuro
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Corresponding author

Correspondence to Luca Fabris .

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Editors and Affiliations

  1. Wexner Medical Center, The Ohio State University, Columbus, OH, USA

    Timothy M. Pawlik

  2. Wexner Medical Center, The Ohio State University, Columbus, OH, USA

    Jordan M. Cloyd

  3. Wexner Medical Center, The Ohio State University, Columbus, OH, USA

    Mary Dillhoff

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Milani, E., Strazzabosco, M., Fabris, L., Cadamuro, M. (2019). Molecular Pathogenesis: From Inflammation and Cholestasis to a Microenvironment-Driven Tumor. In: Pawlik, T., Cloyd, J., Dillhoff, M. (eds) Intrahepatic Cholangiocarcinoma. Springer, Cham. https://doi.org/10.1007/978-3-030-22258-1_12

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  • DOI: https://doi.org/10.1007/978-3-030-22258-1_12

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  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-22257-4

  • Online ISBN: 978-3-030-22258-1

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