ALPPS procedure in an experimental colorectal liver metastases model: hero or villain?

Abstract

Background: Associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) has been raised as a potential therapy for bilobar metastatic liver disease, although the potential tumor progression (TP) that this technique may induce is still not well established. Methods: The aim of this report was to study tumor hepatic progression induced by the first step of ALPPS in a WAG/Rij rat syngenic model of metastatic colorectal carcinoma by subcapsular inoculation of CC531 cell line. We analyzed the effect of hypoxia and immune response induced by ALPPS on liver metastases. Results: ALLPS seems to induce not only tumor progression, but also metastases independently of the site of inoculation. Immunohistochemical analisys revealed that ALPPS induced expression of hepatic vasculogenic factors and a dramatic increase of intrahepatic macrophages in comparison with non-operated groups. Interestingly, hepatic macrophages strongly expressed COX-2, while tumor-infiltrating macrophages expressed mainly arginase-1. ALPPS also induced a decrease of tumor-infiltrating lymphocytes and increase of intrahepatic T-lymphocytes. Conclusion: ALPPS technique may induce hypoxic environment which enhance hepatic HIF1alpha and VEGF expression. Additionally, the regenerative stimulus seems to be driven by a pro-inflammatory environment, in which M1 intrahepatic macrophages, which expressed COX-2 may develop a key role. These facts may be related with the tumor progression observed in inoculated and operated animals.