The significance of graft size on tumor recurrence/metastases after liver transplantation – Activation of cell invasion and migration pathways

Abstract

Background:Although adult-to-adult LDLT has significantly relieved the crisis of donor organ shortageand allowed early transplantation for HCC patients, a liver graft from a live donor isusually small-for-size for an adult recipient. The higher potential of angiogenesis andliver regeneration in small-for-size grafts may provide a favorable environment fortumor recurrence.Objective:We aim to test the hypothesis that small-for-size grafts are more susceptible to tumorrecurrence after liver transplantation in a rat liver transplantation model, and to clarifythe mechanism of tumor recurrence.Materials and Methods:Inbred male Buffalo rats (300-350g) were used as donors and recipients. Orthotopic livertransplantation was applied using whole (100%) graft (Group W) and small-for-size(50%) graft (Group S). The recipients were injected with hepatoma cell line (CRL1601,2´105) via portal vein after reperfusion. The rats were sacrificed at days 15, 20, 25 and30 for the examination of tumor growth. The liver tumor tissues were sampled fordetection of proliferation (Ki67), angiogenesis (VEGF) and stellate cell activation (a-SMA), and cell signaling pathway related to adhesion, migration and invasion (Rac,ROCK, CAK and FAK) by immunostaining and Western Blot.Results:Early development of liver tumor and significantly larger tumor size were found inGroup S. Significant liver regeneration and tumor cell proliferation presented by Ki67staining were found in Group S. The invasive growth pattern including venous invasion ofthe liver tumor accompanied with more activated stellate cells both in tumor tissues andliver parenchyma were also presented in Group S. Severer liver injury including ballooningchanges of hepatocytes, dilation/congestion of hepatic sinusoids, and portal tractlymphocytes infiltration were found in non-tumorous tissues in Group S. Significant up-regulation of protein expression of Rac and ROCK was found in Group S. Consistently,phospho-FAK and ROCK were also activated in Group S together with higher levels ofVEGF by Western Blot.Conclusions:Significant activation of cell signaling pathways related to tumor invasion, migration andangiogenesis in small-for-size liver graft potentially promoted early and invasive tumorgrowth after liver transplantation.