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  • Though studied less extensively than in cholangiopathies and

    2021-11-30

    Though studied less extensively than in cholangiopathies and fatty liver diseases, the Hh pathway is active in other forms of human liver disease, such as Schistosomiasis[58], [101] and chronic viral hepatitis,[100], [125] as well as in several animal models of liver disease, including drug-induced liver injury,[62], [126] radiotherapy-induced liver injury[127], [128] and liver injury caused by ischaemia-reperfusion. The aggregate data identify the Hh signalling pathway as a promising therapeutic target to prevent various types of fibrogenic liver disease. However, much more must be learned before the available information can be applied in a clinical setting. For example, it will be important to clarify if Hh pathway inhibition is safe in patients with ongoing liver injury, since Hh signalling is crucial for liver regeneration. An improved understanding of the relative contributions of canonical vs. non-canonical activation of the Hh pathway in liver disease pathogenesis may also help to guide strategies to modulate Hh pathway activity during chronic liver disease. This is particularly important because the Hh pathway is highly regulated and involves both self-inhibitory and self-enhancing loops. Hence non-canonical signalling might not be blocked if the pathway is inhibited too far upstream. Conversely, blocking terminal activation of pathway targets is likely to have multiple off-target consequences because this approach would entirely abrogate much of the regulation that controls signalling initiated via either pathway.
    Hedgehog in liver cancer The Hh pathway has been implicated in the pathogenesis of different liver cancers, namely hepatocellular carcinoma, cholangiocarcinoma,[34], [130], [131], [132], [133], [134] infantile hepatoblastoma[135], [136] and gallbladder cancer.[137], [138], [139], [140], [141] The most extensively studied primary liver cancer is hepatocellular carcinoma. Different hepatoma cell lines demonstrate constitutive activation of the Hh pathway, with upregulation of the expression of several ligands and crm1 proteins and downregulation of the Hh inhibitor Hhip.[142], [143], [144] A frequent mechanism of Hhip downregulation in hepatoma cell lines is the hypermethylation of its promoter. Hepatoma cell lines with higher upregulation of the Hh pathway tend to be more undifferentiated, with a more mesenchymal and invasive phenotype, and resistant to chemo and radiotherapy.[146], [147] Furthermore, manipulation of the Hh pathway in hepatoma cell lines confirms that Hh inhibits apoptosis, promoting viability, proliferation, migration and invasiveness.[142], [143], [144], [148], [149], [150] Hh signalling activation has been consistently described in different animal models of hepatocellular carcinoma, such as chronic alcohol feeding, MDR2 deficient mice with spontaneous fibrotic cholangiopathy and hepatocellular carcinoma, and xenograft models of primary liver cancer.[151], [152], [153], [154] Genetically inducing activation of Hh in only 2–5% of hepatocytes was able to enhance oncogene-induced hepatocarcinogenesis in mice. Importantly, pharmacological treatment with Smo inhibitors was able to decrease tumour size, angiogenesis and metastasis, as well as increase radiosensitivity, in those models.[152], [153], [154], [156], [157] Studies in patients with hepatocellular carcinoma showed Hh activation in more than half the cases. Higher levels of pathway activity tend to associate with higher tumour burden, invasion, metastatic disease, chemoresistance and worse prognosis with decreased overall survival and increased recurrence after liver transplant.[142], [143], [147], [158], [159], [160], [161] Phase I studies on Smo inhibitors are currently ongoing (NCT0215864). Smo inhibitors have been successfully used to treat other solid cancers such as basal cell carcinoma. However, the acquired resistance caused by de novo mutations and non-canonical Smo-independent Hh activation has generally challenged the treatment of malignancies with Smo inhibitors. Further, it is possible that Hh targets might be activated downstream of Smo in at least some hepatocellular carcinomas, given the recent discovery of a chromosomal translocation that constitutively activates Gli-1 in a subset of hepatic adenomas.