Liver regeneration biology: Implications for liver tumour therapies

Figure 1 Cytokine priming of hepatocytes. PH induced increase in portal pressure exerts sheer stress on LSEC inducing IL6 secretion. Gut derived LPS, complement components C3 & C5, ICAM1, and LTXα from T lymphocytes all induce IL6 and TNF expression from Kupffer cells. IL6 & TNFα prime hepatocytes after binding to IL6R and TNFαR. LTXα also acts directly on hepatocytes via the TNFαR. LSEC: Liver sinusoidal endothelial cell; IL6: Interleukin 6; IL6R: Interleukin 6 receptor; LPS: Lipopolysaccharide; TLR: Toll-like receptor; TNFα: TNF alpha; TNFαR: TNF alpha receptor; CtR: Complement receptor; ICAM1: Intercellular adhesion molecule 1; ICAM1R: Intercellular adhesion molecule 1 receptor; LTXα: Lymphotoxin alpha; LTXαR: Lymphotoxin alpha receptor.

Figure 2 Summary of ligand binding to epidermal growth factor receptor in liver regeneration. Endocrine EGFR signalling by EGF from Brunner’s glands and salivary glands. Paracrine EGFR signalling by HB EGF from LSEC and Kupffer cells, autocrine EGFR signalling by amphiregulin and TGFα from hepatocytes. LSEC: Liver sinusoidal endothelial cell; EGF: Epidermal growth factor; EGFR: Epidermal growth factor receptor; HB EGF: Heparin bound EGF-like growth factor; TGFα: Transforming growth factor α.

Figure 3 Intracellular signal transduction map. A: Intracellular signal transduction in liver regeneration; B: Ligand overlap and receptor binding redundancy; C: Intracellular cross talk between signalling pathways. HGF: Hepatocyte growth factor; FGF: Fibroblast growth factor; VEGF: Vascular endothelial cell growth factor; EGFR: Epidermal growth factor receptor; IL6: Interleukin 6; TNF: Tumour necrosis factor; LPS: Lipopolysaccharide; RTK: Receptor tyrosine kinase family (including HGF receptor, FGF receptor, VEGF receptor, EGF receptor); GPCR: G protein coupled receptor; IL6R: Interleukin 6 receptor; TNFR: Tumour necrosis factor receptor; TLR: Toll like receptor; RAS/RAF/MEK/ERK: signalling components downstream of receptor tyrosine kinase; PI3K: Phosphatidylinositol 3’-kinase; AKT: Akt kinase (also known as protein kinase B); mTOR: Mammalian target of rapamycin; JAK: Janus Kinase; STAT3: Signal Transducer And Activator Of Transcription 3; YAP: Yes-associated protein; NFκb: Nuclear factor kappa B.