Figure 1.

Versatile cross-talks of CAF with activated progenitor cells and HCC. Liver progenitor cells (activated cholangiocytes, oval cells) emerge once the liver is exposed to repetitive and multiple damage, including chronic inflammation of a “wound that does not heal.” The progenitor cells are more resistant to chronic stress and can differentiate into healthy hepatocytes, when the injury subsides but also to fibrogenic and even cancerogenic epithelial progenitors. They engage in a bi-directional crosstalk with stromal cells that include inflammatory cells like TAM (M2-type macrophages) but also activated HSC/myofibroblasts that mutually sustain their growth and expansion, resulting in advanced fibrosis/cirrhosis and/or HCC and CCC. Apart from this pathway for fibrosis that is also prevalent in pancreatic ductal adenocarcinoma (PDAC) and other desmoplastic cancers, additional “second hits” like genetic alterations induced by hepatitis virus integration into the hepatocyte genome, other mutations or metabolic promoters, like in non-alcoholic steatohepatitis (NASH), further promote and sustain hepatic cancer (bFGF, basic fibroblast growth factor; CAF, Cancer-associated fibroblasts; CCL2, CC-Chemokin-Ligand-2 (CCL2); CTGF, connective tissue growth factor; ET-1, Endothelin-1; HGF, hepatocyte growth factor; IL-6 Interleukin 6; PDGF-BB/AB, platelet-derived growth factor BB/AB; Shh; hedgehog signaling pathway).