Establishing a novel mouse model of tacrolimus-induced post-transplant hepatocellular carcinoma pulmonary recurrence for transplant oncology.

[BACKGROUND] Long-term immunosuppression following transplantation places recipients at a high risk of malignancy. Hepatocellular carcinoma (HCC) recurrence after transplantation poses significant challenges to long-term survival of recipients. Several studies in transplant oncology have established cancer-transplant models to support the development of therapies for reducing the risk of post-transplant cancer recurrence. However, existing models fail to recapitulate the complex immune status of recipients and the authentic tumor microenvironment after transplantation.

[METHODS] C57BL/6 recipient mice were injected intravenously with luciferase-expressing Hepa1-6 cells 7 days before receiving Balb/c cardiac allografts, followed by post-transplant immunosuppression with tacrolimus. On day 7 post-transplantation, the immune state of recipients was assessed by measuring serum inflammatory cytokines, and allograft rejection was evaluated by hematoxylin-eosin staining. Cancer progression was evaluated using imaging and measurements of serum alpha-fetoprotein levels, with subsequent histological confirmation.

[RESULTS] Allogeneic cardiac transplantation resulted in a significant increase in serum levels of pro-inflammatory cytokines accompanied by a marked reduction in cancer burden. Marked lymphocytic infiltration, hemorrhage, and structural disintegration were observed in the grafts of untreated animals. In contrast, tacrolimus treatment effectively attenuated both the inflammatory cytokine response and acute allograft rejection but, conversely, resulted in a significant increase in tumor burden. Histological analysis confirmed that malignancies were exclusively localized to the lungs, mirroring the most common site of clinical HCC recurrence post-transplantation.

[CONCLUSION] This model effectively simulates the elevated risk of cancer recurrence under post-transplant immunosuppression and faithfully recapitulates lung metastasis of HCC mediated by circulating cancer cells-the most common site of clinical recurrence following liver transplantation for HCC. It thus provides a reliable tool for basic research aimed at reducing risk of post-transplant cancer recurrence.