Clinicopathological insights and management of liver metastases: Current advances and future perspectives

Table 1 Key ligands and their receptors in primary liver neoplasms and hepatic metastases

Ligand	Receptor(s)	Functional role	Tumor association
HGF	c-MET (HGF receptor)	Facilitates cellular proliferation, migration, and invasive behavior	Highly expressed in HCC and iCCA; generally low in metastatic lesions
VEGF	VEGFR-1, VEGFR-2, VEGFR-3	Mediates angiogenesis and increases vascular permeability	Elevated in poorly differentiated HCC, iCCA, and certain metastases such as colorectal carcinoma
TGF-β	TGF-β receptors 1 and 2	Regulates EMT, fibrotic processes, and immune suppression	Upregulated in HCC and iCCA, contributing to fibrosis and EMT induction
PDGF	PDGFR-α, PDGFR-β	Activates stromal components and induces desmoplastic reactions	Predominantly expressed in iCCA and select metastatic adenocarcinomas (e.g., pancreatic, breast origin)
EGF	EGFR (human epidermal growth factor receptor 1)	Promotes cell growth, survival, and motility	EGFR signaling is active in iCCA, some HCC cases, and also in colorectal and pulmonary metastases
FGF	FGFR1 to FGFR4	Involved in angiogenesis and cellular proliferation	FGFR2 gene fusions are characteristic of iCCA (especially small-duct subtype); less frequent in HCC
Wnt ligands (e.g., Wnt3a, Wnt5a)	Frizzled receptors and lipoprotein receptor-related protein 5/6 co-receptors	Regulates Wnt/β-catenin pathway affecting cell differentiation and proliferation	Aberrant Wnt/β-catenin activation is common in HCC; expression in metastases is variable
Notch ligands (Jagged1, DLL1)	Notch receptors 1 to 4	Controls cellular differentiation and angiogenic processes	Notch signaling is upregulated in iCCA but less prominent in HCC or metastatic tumors
CXCL12 (stromal cell-derived factor 1)	CXCR4	Directs chemotaxis, promotes metastasis and angiogenesis	High CXCR4/CXCL12 axis activity is observed in metastases from colorectal, breast, and pancreatic cancers
IL-6	IL-6 receptor (via gp130/Janus kinase/signal transducer and activator of the transcription pathway)	Mediates inflammatory responses, proliferation, and survival	Elevated levels noted in HCC and metastatic colorectal carcinoma
Mucin-1	Cell surface protein without classic receptor (functions as ligand)	Involved in tumor progression and immune evasion	Overexpressed in iCCA and certain metastatic adenocarcinomas, especially of breast and pancreatic origin

CXCL: C-X-C motif ligand; CXCR: C-X-C chemokine receptor; EGF: Epidermal growth factor; EMT: Epithelial-mesenchymal transition; FGF: Fibroblast growth factor; iCCA: Intrahepatic cholangiocarcinoma; IL-6: Interleukin-6; HCC: Hepatocellular carcinoma; HGF: Hepatocyte growth factor; PDGF: Platelet-derived growth factor; TGF-β: Transforming growth factor beta; VEGF: Vascular endothelial growth factor.