Role of cytokines in hepatocellular carcinoma

Abstract

Liver cancer ranks No. 5 in the world among all types of cancer and takes 3rd position among cancer-related deaths. Hepatocellular carcinoma (HCC) is a primary malignancy which does not include liver metastases from other sites. It is the most common form of liver cancers, and one of the leading causes of cancer-related deaths worldwide. HCC includes genetically and morphologically heterogeneous group of malignant tumors. HCC is characterized by a gender predisposition, namely, it occurs in men 1.5-fold more often, than in women. Viral infections such as hepatitis B and C are major risk factors for HCC. Moreover, non-alcoholic steatohepatitis (NASH) associated with metabolic syndrome and type 2 diabetes also becomes an increasingly common risk factor in developed countries. The mechanisms underlying the development of HCC are based on genetic changes in tumor cells and their microenvironment. Recently, the role of changes in the tumor microenvironment has drawn more attention, thus becoming the key characteristic in the HCC pathogenesis at all stages of the malignant process. Hepatocytes have a close relationship with immune cells, since in the liver, in addition to hepatocytes, there are Kupffer cells, myeloid cells (dendritic cells, monocytes and neutrophils) and other types of immune cells (T and B lymphocytes, NK and NKT, etc.). Cytokines released by various immune cells in the liver may influence liver processes, e.g., inflammation and carcinogenesis. Chronic inflammation results from persistent stimulation, or deficiencies of anti-inflammatory mechanisms. Its key features include immune cell infiltration, presence of inflammatory mediators, and imbalance of pro- and antiinflammatory cytokines leading to aggressive angiogenesis and tissue remodeling which, in turn, promotes the malignant process. Currently, there are several approaches to the HCC treatment which depend on the stage of the disease. Immunotherapy and its combinations have shown positive advances, and further research in this area will provide therapeutic options at the terminal stages of HCC. A variety of cytokines and their functions in HCC development are discussed in the present review article.