Abstract 3460: Overlooking the obvious - paradox of gastrointestinal carcinomas metastasis to portal vein

Abstract

Abstract All carcinomas are characterized by metastases to distant organs, accounting for 90% of cancer-associated deaths. This analysis highlights a paradox of gastrointestinal carcinomas metastasis into portal vein: colorectal, pancreatic, small bowel and gastric carcinomas invariably release cancer cells to portal vein, which is the primary dissemination route, but very rarely form intraportal metastasis. On the contrary, hepatocellular carcinoma rarely releases cancer cells into portal vein, but very often forms intraportal metastasis. This disproportional frequency of HCC portal metastasis cannot be rationalized by hepatofugal (reverse) portal blood flow due to accompanying liver cirrhosis because: 1) reverse portal flow occurs in about 10% of cirrhotic patients, while portal metastasis occurs in 40-100% of HCC cases, and 2) portal vein prevalence of HCC metastasis is also the characteristic of non-cirrhotic patients. The ‘portal paradox’ becomes a logical event in light of comparative morphology and phylogeny of the chordate lineage: the formation of the unique portal venous system preceded the appearance of liver in evolution of chordates. The analysis suggests that the appearance of the portal venous system, draining blood from caudal intestine and supplying hormones and growth factors of pancreatic family (HGFPF) to midgut diverticulum in the early evolution of ancestral chordates, promoted differentiation of the diverticulum’s enterocytes into the hepatocyte phenotype and further formation of the liver in evolution of vertebrates. These promotional-dependent interactions are conserved in the vertebrate lineage but attributed to hepatocyte-derived cells only; the rest of gastrointestinal endodermal derivatives occurred independently from portal system in chordate phylogeny. Therefore, non-HCC gastrointestinal carcinomas’ cells do not have this affinity to and dependence on portal blood and portal blood does not promote attachment and growth of non-HCC gastrointestinal carcinomas’ cells in the portal conduit. I hypothesize that selective homing and proliferation of HCC cells in the portal vein environment are due to a uniquely high concentration of HGFPF in portal blood: portal vein formed by merging superior mesenteric and pancreatic veins. HGFPF are also necessary for liver function and renewal and are extracted by hepatocytes from passing blood, creating a concentration gradient of HGFPF between the portal blood and hepatic vein outflow, making post-liver organs less favorable spaces for HCC metastasis. This also suggests that the portal vein environment (i.e., high concentration of HGFPF) promotes the differentiation and selection of more aggressive HCC clones from already-seeded portal HCC cells, explaining the worse outcome of HCC patients with portal metastasis. Citation Format: Vladimir M. Subbotin. Overlooking the obvious - paradox of gastrointestinal carcinomas metastasis to portal vein [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3460.