Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
, 19 (12)

Fibroinflammatory Liver Injuries as Preneoplastic Condition in Cholangiopathies

Affiliations
Review

Fibroinflammatory Liver Injuries as Preneoplastic Condition in Cholangiopathies

Stefania Cannito et al. Int J Mol Sci.

Abstract

The cholangipathies are a class of liver diseases that specifically affects the biliary tree. These pathologies may have different etiologies (genetic, autoimmune, viral, or toxic) but all of them are characterized by a stark inflammatory infiltrate, increasing overtime, accompanied by an excess of periportal fibrosis. The cellular types that mount the regenerative/reparative hepatic response to the damage belong to different lineages, including cholagiocytes, mesenchymal and inflammatory cells, which dynamically interact with each other, exchanging different signals acting in autocrine and paracrine fashion. Those messengers may be proinflammatory cytokines and profibrotic chemokines (IL-1, and 6; CXCL1, 10 and 12, or MCP-1), morphogens (Notch, Hedgehog, and WNT/β-catenin signal pathways) and finally growth factors (VEGF, PDGF, and TGFβ, among others). In this review we will focus on the main molecular mechanisms mediating the establishment of a fibroinflammatory liver response that, if perpetuated, can lead not only to organ dysfunction but also to neoplastic transformation. Primary Sclerosing Cholangitis and Congenital Hepatic Fibrosis/Caroli's disease, two chronic cholangiopathies, known to be prodrome of cholangiocarcinoma, for which several murine models are also available, were also used to further dissect the mechanisms of fibroinflammation leading to tumor development.

Keywords: Caroli’s disease; cholangiocarcinoma; cholangiocytes; neoplastic transformation; primary sclerosing cholangitis.

Conflict of interest statement

The authors declare no conflicts of interest

Figures

Figure 1
Figure 1
Autocrine and paracrine signaling characterizing the cross-talk among the different cell types involved in the development of cholangiopathies. Following a bile duct insult, cholangiocytes start to secrete several mediators involved in the recruitment and activation of mesenchymal, as well as inflammatory cells. Under the continuous stimulus induced by the chronic damage, fibroblasts could accumulate in the portal tract and, together with hepatic stellate cells, could transdifferentiate to myofibroblasts, directly responsible for the accumulation of periportal fibrosis. Similarly, damaged bile ducts could recruit different types of inflammatory cells, among which T lymphocytes, neutrophils, and macrophages (both M1 and M2), that further sustain the development of the disease.
Figure 2
Figure 2
Chronic inflammation is responsible for the neoplastic transformation of the biliary epithelial cells. Alterations are due to the presence in the hepatic microenvironment of several molecules, such as peroxinitrites and oxygen free radicals that could induce the accumulation of DNA damage. Nitric oxide (NO) is able to stimulate cell proliferation and escape from apoptosis through the activation of COX2 that stimulates the p38 MAPK/JNK axis to secrete PGE2, that further transactivates the epidermal growth factor receptor (EGFR); this latter receptor also activates the PI3K/AKT pathway responsible for the proliferation and resistance to apoptosis in cholangiocarcinoma (CCA).

Similar articles

See all similar articles

Cited by 1 PubMed Central articles

References

    1. Lazaridis K.N., LaRusso N.F. The cholangiopathies. Mayo Clin. Proc. 2015;90:791–800. doi: 10.1016/j.mayocp.2015.03.017. - DOI - PMC - PubMed
    1. Peery A.F., Crockett S.D., Barritt A.S., Dellon E.S., Eluri S., Gangarosa L.M., Jensen E.T., Lund J.L., Pasricha S., Runge T., et al. Burden of gastrointestinal, liver, and pancreatic diseases in the united states. Gastroenterology. 2015;149:1731–1741. doi: 10.1053/j.gastro.2015.08.045. - DOI - PMC - PubMed
    1. Lazaridis K.N., Strazzabosco M., Larusso N.F. The cholangiopathies: Disorders of biliary epithelia. Gastroenterology. 2004;127:1565–1577. doi: 10.1053/j.gastro.2004.08.006. - DOI - PubMed
    1. Fabris L., Spirli C., Cadamuro M., Fiorotto R., Strazzabosco M. Emerging concepts in biliary repair and fibrosis. Am. J. Physiol. Gastrointest. Liver Physiol. 2017;313:G102–G116. doi: 10.1152/ajpgi.00452.2016. - DOI - PMC - PubMed
    1. Banales J.M., Cardinale V., Carpino G., Marzioni M., Andersen J.B., Invernizzi P., Lind G.E., Folseraas T., Forbes S.J., Fouassier L., et al. Expert consensus document: Cholangiocarcinoma: Current knowledge and future perspectives consensus statement from the european network for the study of cholangiocarcinoma (ENS-CCA) Nat. Rev. Gastroenterol. Hepatol. 2016;13:261–280. doi: 10.1038/nrgastro.2016.51. - DOI - PubMed
Feedback