Title: Hepatic Progenitor Cells: activation, differentiation and their role in cancer.
Other Titles: Hepatische Progenitorcellen: activatie, differentiatie en hun rol in kanker
Authors: Govaere, Olivier
Issue Date: 29-Nov-2012
Abstract: The only present curative option for end-stage liver disease is orthotopic liver transplantation, although there is a great imbalance between the availability of donor organs and the need for them. By understanding what controls the activation and differentiation of hepatic progenitor cells (HPCs), we might be able to promote healthy liver regeneration and reduce the formation of liver cirrhosis in the future. Depending on the cell type that has been damaged the most, HPCs can differentiate either towards cholangiocytes or towards hepatocytes. To study the role of the Notch and Wnt pathway in the differentiation of HPCs, we compared tissue samples obtained from patients with either chronic biliary liver damage or chronic hepatocytic liver damage. We showed in human diseased liver and mouse models of the ductular reaction that Notch and Wnt signaling direct specification of HPCs via their interactions with activated myofibroblasts or macrophages. In particular, we found that during biliary regeneration, expression of Jagged 1 (a Notch ligand) promoted Notch signaling in HPCs and thus their biliary specification to cholangiocytes. Alternatively, during hepatocyte regeneration, macrophage engulfment of hepatocyte debris induced Wnt3a expression, promoting the specification to hepatocytes. It is conceivable that the mechanisms which drive progenitor cell activation, proliferation and differentiation, also play an important role in its neoplastic counterpart. In human, the description of primary hepatic carcinomas with mixed hepatocellular/cholangiocellular features and hepatocellular carcinomas (HCCs) displaying progenitor/stemness features, such as keratin (K) 19 positive HCCs, suggests that at least a part of the primary liver cancers can arise from HPCs. Immunoreactivity for K19 in HCCs, a marker for intrahepatic bile duct cells, HPCs and hepatoblasts, has a significant prognostic value, even in only 5% of the cancer cells, as it has been associated with a worse clinical outcome. Trying to apprehend the behavior of K19 positive HCCs, we might also better understand the role of HPCs in carcinogenesis. We demonstrated that K19 expression in HCCs correlates with microvascular invasion and metastasis. Besides the occurrence of other HPC/biliary markers, K19 positive HCCs expressed a whole range of invasion-/metastasis-related genes, of which some proved to be present in the surrounding non-neoplastic HPCs. In K19 positive HCCs, an aberrant expression of the Notch and Wnt pathway was found, insinuating that HPCs and K19 positive HCC cells share at least some common activated pathways. Epigenetic profiling of K19 positive HCCs and validation in cell lines likewise illustrated the role of microRNAs in maintenance of cancer stemness and microenvironment. Functionally, we showed that K19 expression is related to increased invasive capacity in in vitro models by stimulating invadopodia formation and that K19 positive HCCs have a larger resistant cell fraction. In conclusion, our data not only sheds a light on the mechanisms underlying the K19 HCC phenotype and the differentiation of HPCs, but also demonstrates the similar features between K19 positive HCCs and HPCs.
Publication status: published
KU Leuven publication type: TH
Appears in Collections:Translational Cell & Tissue Research
Embryo and Stemcells (-)
Pharmacology Section (-)

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