The significance of acute phase small-for-size graft injury on tumor growth and invasiveness after liver transplantation

Objective: To test the hypothesis that acute phase small-for-size graft injury may promote late phase tumor recurrence after liver transplantation. Summary Background Data: Living donor liver transplantation may provide the substantial intention-to-treat survival advantage for liver cancer patients. However, liver grafts from live donors are almost always small for size for adult recipients. Besides, tumor recurrence and metastasis after living donor liver transplantation have been reported. Method: An orthotopic Buffalo rat liver transplantation model using whole (100%, group W) and small-for-size grafts (50%, group S) was applied. Hepatoma cells were injected into the grafts after reperfusion. Comparison was made as regards acute phase graft injury and tumor growth together with cell proliferation (Ki67), angiogenesis (vascular endothelial growth factor), stellate cell activation (alpha-smooth muscle actin), and cell signaling pathway related to migration and invasion (Rac, rho-associated, coiled-coil containing protein kinase, and proline-rich tyrosine kinase 2). Invasiveness of the tumors developed was further assessed after their direct implantation into livers of nude mice. Results: Liver tumors developed earlier and faster in group S with significantly greater tumor burden [hepatic replacement area: 61%; range, 47%-72%; vs. 18%; 12%-27%; P = 0.001] and tumor cell proliferation (92% vs. 59%; P = 0.0021) in a more invasive growth pattern with a higher incidence of venous invasion (91.7% vs. 25%; P = 0.003) and more frequent hepatic stellate cell activation. There was upregulation of protein expression of Rac/rho-associated, coiled-coil containing protein kinase/proline-rich tyrosine kinase 2/vascular endothelial growth factor signaling in group S. When implanted into livers of nude mice, tumors from group S had a higher incidence of local (70% vs. 0%; P = 0.003) and lung metastasis (50% vs. 0%; P = 0.033). This phenotype was consistent with their ultrastructural features linking to angiogenesis and invasiveness. Conclusion: Significant activation of cell signaling pathways leading to tumor invasion and migration in small-for-size liver grafts promotes tumor growth and metastasis after liver transplantation.