Privileged portal metastasis of hepatocellular carcinoma in light of the coevolution of a visceral portal system and liver in the chordate lineage: a search for therapeutic targets.

Hepatocellular carcinoma (HCC) disseminates systemically, but metastases occur in distant organs only in minority of patients, whereas HCC routinely metastasizes to liver and its vessels. HCC cells disseminate via hepatic veins, but portal veins are affected by metastasis more frequently than are hepatic veins, and correlates with poor prognosis. In this review, I suggest that privileged HCC portal metastasis occurs because of high levels of pancreatic family hormones and growth factors (PHGFs) in the portal blood. The analysis suggests that the appearance of the portal system carrying PHGFs in the evolution of invertebrate chordate (Amphioxus) led to the evolution of the liver in vertebrate; given that the portal pattern of HCC metastasis and selection of more-aggressive clones are PHGF dependent, PHGFs and their ligands constitute therapeutic targets.