TREM-2 defends the liver against hepatocellular carcinoma through multifactorial protective mechanisms.

Abstract

Hepatocellular carcinoma (HCC) is a prevalent and aggressive cancer usually arising on a background of chronic liver injury involving inflammatory and hepatic regenerative processes. The triggering receptor expressed on myeloid cells 2 (TREM-2) is predominantly expressed in hepatic non-parenchymal cells and inhibits Toll-like receptor signalling, protecting the liver from various hepatotoxic injuries, yet its role in liver cancer is poorly defined. Here, we investigated the impact of TREM-2 on liver regeneration and hepatocarcinogenesis. TREM-2 expression was analysed in liver tissues of two independent cohorts of patients with HCC and compared with control liver samples. Experimental HCC and liver regeneration models in wild type and <i>Trem-2^-/-</i> mice, and <i>in vitro</i> studies with hepatic stellate cells (HSCs) and HCC spheroids were conducted. <i>TREM-2</i> expression was upregulated in human HCC tissue, in mouse models of liver regeneration and HCC. <i>Trem-2^-/-</i> mice developed more liver tumours irrespective of size after diethylnitrosamine (DEN) administration, displayed exacerbated liver damage, inflammation, oxidative stress and hepatocyte proliferation. Administering an antioxidant diet blocked DEN-induced hepatocarcinogenesis in both genotypes. Similarly, <i>Trem-2^-/-</i> animals developed more and larger tumours in fibrosis-associated HCC models. <i>Trem-2^-/-</i> livers showed increased hepatocyte proliferation and inflammation after partial hepatectomy. Conditioned media from human HSCs overexpressing TREM-2 inhibited human HCC spheroid growth <i>in vitro</i> through attenuated Wnt ligand secretion. TREM-2 plays a protective role in hepatocarcinogenesis via different pleiotropic effects, suggesting that TREM-2 agonism should be investigated as it might beneficially impact HCC pathogenesis in a multifactorial manner.