Hepatic stellate cells limit hepatocellular carcinoma progression through the orphan receptor endosialin

Abstract

Hepatocellular carcinoma ( HCC ) is among the most common and deadliest cancers worldwide. A major contributor to HCC progression is the cross talk between tumor cells and the surrounding stroma including activated hepatic stellate cells ( HSC ). Activation of HSC during liver damage leads to upregulation of the orphan receptor endosialin ( CD 248), which contributes to regulating the balance of liver regeneration and fibrosis. Based on the established role of endosialin in regulating HSC /hepatocyte cross talk, we hypothesized that HSC ‐expressed endosialin might similarly affect cell proliferation during hepatocarcinogenesis. Indeed, the histological analysis of human HCC samples revealed an inverse correlation between tumor cell proliferation and stromal endosialin expression. Correspondingly, global genetic inactivation of endosialin resulted in accelerated tumor growth in an inducible mouse HCC model. A candidate‐based screen of tumor lysates and differential protein arrays of cultured HSC identified several established hepatotropic cytokines, including IGF 2, RBP 4, DKK 1, and CCL5 as being negatively regulated by endosialin. Taken together, the experiments identify endosialin‐expressing HSC as a negative regulator of HCC progression. image The orphan receptor endosialin ( CD 248) is expressed by activated hepatic stellate cells ( HSC ) during hepatocarcinogenesis and exerts autocrine and paracrine tumor growth‐inhibiting effects. HSC in human hepatocellular carcinoma ( HCC ) express endosialin ( CD 248). Growth of HCC in endosialin‐deficient mice is enhanced revealing a tumor‐suppressing effect of HSC during hepatocarcinogenesis. Endosialin‐silenced HSC express increased levels of HCC growth‐promoting cytokines, including IGF 2, CCL 5 and RBP 4.