Effect of liver regeneration on malignant hepatic tumors

Table 1 Sum-up of signal molecules involved in liver regeneration

Regeneration Phases	Molecular factors	Origin	Targets and Effects	Involved Signalling pathways
Priming stage	Nitric oxide, prostaglandins, tumor necrosis factor, interleukin 6	NPLCs	Trigger of liver regeneration, sensitizing hepatocytes to growth factors for replication	NF-κB, JAK/STAT3 and MAPK signaling pathway
Proliferation stage	HGF	HSCs and other NPLCs, hepatocytes; mesenchymal cells	Cooperative effects allow the hepatocytes to overcome cell-cycle	HGF/cMet signaling pathway
	TGF-α	Hepatocytes, HSCs	Checkpoint-controls and transition of hepatocytes from G0, through G1, to the S phase of the cell cycle, leading to DNA synthesis and cell proliferation	EGFR signaling pathway IGF-1R and insulin receptor
	EGF	Salivary glands in intestine and pancreas
	IGF	Hepatocytes, NPLCs
	PDGF	Hepatocytes	Mitosis in NPLCs, remodelling of ECM	PDGFR in HSCs
	VEGF			VEGF receptor in endothelial cells
Termination stage	TGF-β	HSCs, other NPLCs, mesenchymal cells	Inhibition of hepatocyte DNA synthesis, remodeling of ECM, restoration at the end of regeneration	TGF-β signaling pathway
Others	Wnt/β-catenin plays a supportive role in liver regeneration; metalloproteinase play a pivotal role in ECM degradation, generation and degradation of active growth factor and signaling molecules in the ECM

Nonparenchymal liver cells: Kupffer cell, sinusoidal endothelial cells and hepatic stellate cells. HGF: Hepatocyte growth factor; TGF-α: Transforming growth factor α; EGF: Epidermal growth factor; IGF: Insulin-like growth factor; PDGF: Platelet-derived growth factor; VEGF: Vascular endothelial growth factor; TGF-β: Transforming growth factor β; HSCs: Hepatic stellate cells; NPLCs: Nonparenchymal liver cells; ECM: Extracellular matrix.

Table 2 Sum-up of signal pathways in hepatocellular carcinoma

Signaling pathways		Cell survival	Cell proliferation	Cell differentiation	Cell migration	Angiogenesis
Receptor tyrosine kinase signaling pathways	HGF/c-MET	√	√		√	√
	EGF(TGF-α)/EGFR	√	√
	IGF/IGFR	√	√		√
	VEGF/VEGFR					√
	PDGF/PDGFR					√
	TGF-β1/SMAD			√	√
Intercellular kinase signaling pathways	RAF/MEK/ERK	√	√	√		√
	PI3K/AKT/mTOR	√	√			√
	Wnt/β-catenin	√	√	√		√
	Hedgehog		√	√	√
	NK-κB, JAK/STAT3	√	√	√	√	√

HGF: Hepatocyte growth factor; EGF: Epidermal growth factor; TGF-α: Transforming growth factor alpha; IGF: Insulin-like growth factor; VEGF: Vascular endothelial growth factor; PDGF: Plate differentiation growth factor receptor; TGF-β: Transforming growth factor beta.