The significance of acute phase graft injury on tumor recurrene/metastases in live donor liver transplantation

Abstract

Objective: This study aims to investigate the significance of cell signaling pathways related to acute phase injury and angiogenesis, tumor cell invasion and migration on liver tumor recurrence in small-for-size liver grafts after LDLT. Patients and Methods: From May 2000 to Dec 2005, 121 adult-to-adult liver transplants were included in the current study. Eighty-seven patients received grafts from living donors and 34 received deceased donor grafts. Liver biopsies were taken in the donors before graft harvesting and 2 hours after reperfusion in the recipients. The hepatic stellate cell activation and intragraft protein expression of Rac, FAK and CAK after reperfusion were investigated by immunostaining. The intragraft mRNA expressions of VEGF, ROCK, RhoA, Egr-1 and FAK were also detected by real time RT-PCR. Liver tumor recurrence and metastases were compared. Results According to the ratio of the graft weight to standard liver vulume (graft ratio), the patients were grouped to Group 1 (n=80) with graft ratio less than 0.6; and Group 2 (n=41) with graft ratio great than 0.6. Twenty-two recipients (27.5%) in Group 1 and 9 recipients (22%) in Group 2 were diagnosed with hepatocellular carcinoma. Among the HCC recipients, there was no difference of the incidence of higher tumor staging (8/22 vs 4/9, p=0.704) and tumor vascular permeation (7/22 vs 1/9, p=0.379) between the two groups. The incidence of liver tumor recurrence together with lung metastasis was 36.4% (8/22) in Group 1. Most of the patients with recurrence had hepatic sinusoidal injury at early phase after LDLT. There was no liver tumor recurrence in Group 2 (p=0.068). Significant activation of hepatic stellate cells was found in Group 1 together with stronger intragraft protein expression of FAK and CAK compared to that of Group 2. Intragraft mRNA levels of Egr-1, RhoA, FAK and VEGF was significantly higher in Group 1 compared to Group 2. Conclusion: Significant activation of signaling pathways of acute phase injury and angiogenesis, cell invasion and migration in small-for-size liver grafts after LDLT might contribute to the higher incidence of liver tumor recurrence and metastases. Elucidating the mechanism of liver tumor recurrence after liver transplantation will lay the foundation for the development of therapeutic strategies to target small-for-size graft injury and to reduce the likelihood of tumor recurrence after liver transplantation.