Hedgehog pathway activation and epithelial-to-mesenchymal transitions during myofibroblastic transformation of rat hepatic cells in culture and cirrhosis

Abstract

Diehl AM. Hedgehog pathway activation and epithelial-tomesenchymal transitions during myofibroblastic transformation of rat hepatic cells in culture and cirrhosis.

Involvement of cholangiocyte proliferation in biliary fibrosis

“…Evidence suggests that proliferating cholangiocytes have a role in the induction of fibrosis, either directly through epithelial-mesenchymal transition [55] , or indirectly through the activation of hepatic stellate cells [38] . EMT is a complex process that involves cross talk among several signaling pathways that collaborate to affect global, but gradual, changes in cell structure and function [56] . In this dynamic process cells eventually lose their typical epithelial characteristics (proteins that mediate cell-cell, cell-matrix contacts and cytoskeletal organization) [57,58] .…”

“…In this dynamic process cells eventually lose their typical epithelial characteristics (proteins that mediate cell-cell, cell-matrix contacts and cytoskeletal organization) [57,58] . These changes cause epithelial cells to disassociate from their neighbors, gradually acquire a motile phenotype, and eventually migrate out of epithelial sheets and into adjacent mesenchyme [21,56] . There are three biological subtypes of EMT, which have been previously reviewed [57,59] .…”

Keratin 19 Epithelial Patterns in Cirrhotic Stroma Parallel Hepatocarcinogenesis

“…Despite existing controversies in the field of hepatocytic phenotype switch, 30,34 -37 alterations of ductular epithelial phenotype as it relates to progression of adjacent hepatocellular lesions have, to the best of our knowledge, not been reported. Several reports, however, have recently implicated the biliary compartment 4,5,38,39 in addition to the hepatocellular compartment 40,41 as a source of stromal and mesenchymal cells, 36 albeit in the nonneoplastic setting. 42 For example, in EMT, expression of SNAIL leads to repression of ECADH and indirectly triggers expression of FSP-1.…”

“…This hypothesis of paracrine signaling does not exclude additional contributing mechanisms such as non-TGF-␤-mediated triggers (eg, tyrosine-kinase-mediated signaling or hedgehog signaling 39,41,50,56 ); stromal and mesenchymal factors such as immunoregulatory, inflammatory, or stromal cells 4,48,69,70 ; extrahepatic so-called circulating stem cells 71,72 ; autophagy-associated (caspase-independent) cell death 18 ; or changes in anoikis (apoptosis induced by detachment from anchorage). 73 Inasmuch as similar signaling has been demonstrated in the setting of biliary fibrosis, 39 our results implicate the K19 compartment as a morphologically distinct and significant stromal (epithelial) factor in HCC pathogenesis in cirrhosis.…”

Mechanisms of HBx Mediated Liver Cancer: Multiple Pathways and Opportunities

“…More recently, hedgehog signaling and ligand production have been demonstrated to be activated in clinical samples from HBV (and hepatitis C virus) infected patients These ligands promoted the in vitro expansion of liver myofibroblasts, activated endothelial cells, and progenitors expressing markers of tumor stem/initiating cells (Pereira et al, 2010). Independent data has shown that hedgehog signaling is profibrogenic, in that it promotes activation and EMT in quiescent hepatic stellate cells (Choi et al, 2009), and in the context of cholestatic liver injury (Omenetti et al, 2011). Given that hedgehog signaling is www.intechopen.com also known to promote tissue remodeling in the liver (Omenetti & Diehl, 2008), it is possible that this may contribute to the progression and formation of cirrhotic nodules in the liver of chronically infected patients.…”