Inflammatory Mechanisms of HCC Development

Abstract

HCC (hepatocellular carcinoma) is the second leading cause of cancer deaths worldwide, with several etiologic causes, mostly inflammation-associated. Different inflammatory responses in the liver can be triggered by different etiological agents. The inflammatory process can be resolved or be persistent, depending on the etiology and multiple other factors. Chronic inflammation, tissue remodeling, genetic alterations, and modifications in cellular signaling are considered to be key processes promoting immunosuppression. The progressive immunosuppression leads to the inactivation of anti-tumor immunity involved in HCC carcinogenesis and progression. Tumor cellular processes including DNA damage, necrosis, and ER (endoplasmic reticulum) stress can affect both immune-surveillance and cancer-promoting inflammation, supporting a mutual interdependence. Here, we review the current understanding of how chronic liver injury and inflammation is triggered and sustained, and how inflammation is linked to HCC. The identification of many hepatic microenvironmental inflammatory processes and their effector molecules, has resulted in extensive translational work and promising clinical trials of new immunomodulatory agents.

Keywords: HCC; cancer etiology; chronic inflammation; immunosuppression; immunosurveillance.

Figure 1

Role of stromal cells in the realization of premalignant microenvironment and HCC onset. HSCs (Hepatic Stellate Cells), TAMs (Tumor Associated Macrophages) and TANs (Tumor Associated Neutrophils) contribute respectively to induce liver fibrosis by matrix production, to promote tumor growth prompting the angiogenesis process and immune suppression leading to liver inflammation.

Figure 2

Platelets amplify liver damage. Growth factors released by the activated platelets can reinforce the changes induced by HBV at the level of the hepatic parenchyma as well as the formation of new vessels. Platelets create a microenvironment that opposes the action of drugs such as Sorafenib, Regorafenib and chemotherapic agents.

Figure 3

Cooperating risk factors for HCC onset. Factors with a viral and non-viral etiology may be responsible for the onset of the HCC by releasing specific mediators that lead to the formation of an inflammatory microenvironment that predisposes to the formation of fibrosis which can develop into cirrhosis which in some cases is not an essential condition for the development of HCC.