Notch2 signaling and undifferentiated liver cancers: Evidence of hepatic stem/progenitor cell origin

Authors

  • Vincenzo Cardinale M.D.,

    1. Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Italy
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  • Guido Carpino M.D., Ph.D.,

    1. Department of Anatomical, Histological, Forensic Medicine, and Orthopedics Sciences Sapienza University of Rome, Rome, Italy
    2. Department of Health Sciences, University of Rome “Foro Italico”, Rome, Italy
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  • Lola M. Reid Ph.D.,

    1. Department of Cell Biology and Physiology, Program in Molecular Biology and Biotechnology, University of North Carolina School of Medicine, Chapel Hill, NC
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  • Eugenio Gaudio M.D.,

    1. Department of Anatomical, Histological, Forensic Medicine, and Orthopedics Sciences Sapienza University of Rome, Rome, Italy
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  • Domenico Alvaro M.D.

    1. Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Italy
    2. Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy
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  • Potential conflict of interest: Nothing to report.

  • E.G. was supported by a research project grant from the University “Sapienza” of Rome (FIRB grant no. RBAP10Z7FS_001 and by PRIN grant no. 2009X84L84_001). D.A. was supported by FIRB grant no. RBAP10Z7FS_004 and by PRIN grant no. 2009X84L84_002. The study was also supported by Consorzio Interuniversitario Trapianti d'Organo (Rome, Italy). University of North Carolina funding was derived from a sponsored research grant from Vesta Therapeutics (Bethesda, MD) and from a National Cancer Institute grant (CA016086).

To the Editor:

Dill et al. demonstrated how aberrant activation of Notch2 signaling in albumin-expressing cells of AlbCre/N2ICD mice resulted in hepatocellular carcinomas (HCCs) associated with proliferation and expansion of immature biliary epithelial cells (BECs).[1] HCC formation was enhanced by treatment with diethylnitrosamine (DEN), which induced the appearance of combined HCC-cholangiocarcinoma (CCC) and of CCC with immature BEC features.[1] Expansion of the BEC compartment in AlbCre/N2ICD mice mimics activation of hepatic stem cells (HpSCs) in human diseases characterized by Notch2 up-regulation.[2] Moreover, aberrant Notch2 signaling induces the formation of human liver cancers with HpSC features.[3] Thus, the HpSC compartment is the most likely candidate for oncogenic events in AlbCre/N2ICD mice, supporting the concept that a spectrum of liver cancers could originate from activation of HpSCs. Alternatively, it was proposed that CCCs might originate from dedifferentiation of hepatocytes.[4, 5] This provocative assumption is based on observations by genetic tracing studies that CCCs arose from albumin- or transthyretin-expressing cells.[4, 5] However, albumin and transthyretin are expressed in cells undergoing liver differentiation from embryoid bodies[6] and in hepatic and biliary tree stem/progenitors in intrahepatic (canals of Hering) and/or extrahepatic (peribiliary glands) niches.[7, 8] In the studies by Dill et al.,[1] biliary hyperplasia and large biliary cyst formation were induced, even though the albumin gene promoter was targeted to induce selective hepatic N2ICD overexpression. Therefore, albumin-expressing cells in different anatomical sites could have been targeted. Although dedifferentiation of hepatocytes in oncogenesis cannot be excluded, neoplastic transformation of a stem/progenitor cell subpopulation more easily explains oncogenesis. Identification of the cell(s) of origin and the signaling pathways involved are challenging issues in liver cancers with pivotal implications in the clinicopathological and therapeutic perspectives.

  • VINCENZO CARDINALE, M.D.1

  • GUIDO CARPINO, M.D., PH.D.2,3

  • LOLA M. REID, PH.D.4

  • EUGENIO GAUDIO, M.D.2

  • DOMENICO ALVARO, M.D.1,5

  • 1Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Italy

  • 2Department of Anatomical, Histological, Forensic Medicine, and Orthopedics Sciences Sapienza University of Rome, Rome, Italy

  • 3Department of Health Sciences University of Rome “Foro Italico”, Rome, Italy

  • 4Department of Cell Biology and Physiology, Program in Molecular Biology and Biotechnology, University of North Carolina School of Medicine, Chapel Hill, NC

  • 5Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy

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