The liver microenvironment : a driver of hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a major health problem and is the third leading cause of cancer-related mortality worldwide. The prevalence of non-alcoholic fatty liver diseases (NAFLD) is on the rise, and the possibility for the development of HCC in NAFLD patients is increasing in the western countries. HCC driver mutations are not druggable and the median improvement of life expectancy in treated HCC patients doesn’t exceed, at best, 2 years. Therefore, novel rewarding targets should be identified, from whom the components of the liver microenvironment represent a fertile field of research and drug discovery. SULFATASE 2 (SULF2), an extracellular sulfatase, was markedly upregulated in the cancer associated fibroblasts (CAFs) in more than half of HCC biopsies, and CAF-SULF2 expression was associated with poor prognosis and sorafenib tolerance in HCC patients. In vitro, stromal SULF2 induced the proliferation, migration, invasion and therapy evasion of HCC cell lines. Stromal SULF2 activated JNK/IL6 pathway in the fibroblast cell lines, while SULF2-rich secretome activated NF-kB/CD44 stemness pathway in the tumour cells justifying the aggressive, SULF2-dependent tumour cell phenotype. In a mouse model of NAFLD-induced HCC, Sulf2, as well as other targets, was upregulated in the non-tumour liver tissue of the dietary-challenged mice compared to matched controls. Pathway analysis and immunohistochemistry (IHC) validation in mouse and human tissue supported the profound role of different immune cells in the process of tumour development. We have identified a novel Cd44-positive macrophage phenotype that worked in concert with certain T cell subsets to develop HCC in mice. The number of CD44 positive macrophages in the non-tumour liver biopsies of NAFLD patients who developed HCC was higher than CD44 positive macrophages in patients who didn’t develop malignancy. In conclusion, non-parenchymal cell compartments play an essential role in HCC development and progression. Therapeutics targeting the activities of these cells represent a novel strategy for disease prevention/management.