•HCC disseminates systemically via hepatic veins but paradoxically metastasizes more often to portal veins.•The “portal paradox” becomes a logical event in light of co-evolution of a portal system and the liver in chordate lineage.•The portal system carrying pancreatic family hormones/growth factors (PHGFs) occurs prior to the liver in chordate evolution.•Acquiring liver, hepatocyte differentiation, HCC portal metastasis and selection more aggressive clones are PHGFs-dependent.•PHGFs of portal blood and their ligands constitute therapeutic targets for prevention/cure of HCC metastatic dissemination.
Drug Discovery Today – Elsevier
Published: Mar 1, 2018
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