Role of Virus-Related Chronic Inflammation and Mechanisms of Cancer Immune-Suppression in Pathogenesis and Progression of Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) can be classified as a prototypical inflammation-driven cancer that generally arises from a background of liver cirrhosis, but that in the presence of nonalcoholic steatohepatitis (NASH), could develop in the absence of fibrosis or cirrhosis. Tumor-promoting inflammation characterizes HCC pathogenesis, with an epidemiology of the chronic liver disease frequently encompassing hepatitis virus B (HBV) or C (HCV). HCC tumor onset and progression is a serial and heterogeneous process in which intrinsic factors, such as genetic mutations and chromosomal instability, are closely associated with an immunosuppressive tumor microenvironment (TME), which may have features associated with the etiopathogenesis and expression of the viral antigens, which favor the evasion of tumor neoantigens to immune surveillance. With the introduction of direct-acting antiviral (DAA) therapies for HCV infection, sustained virological response (SVR) has become very high, although occurrence of HCC and reactivation of HBV in patients with co-infection, who achieved SVR in short term, have been observed in a significant proportion of treated cases. In this review, we discuss the main molecular and TME features that are responsible for HCC pathogenesis and progression. Peculiar functional aspects that could be related to the presence and treatment of HCV/HBV viral infections are also dealt with.

Keywords: HCC; anti-viral therapies; genetic alterations; pathogenesis; progression; recurrence; tumor microenvironment.

Figure 1

Involvement of viral infections in the pathogenesis and progression of HCC. The pathogenesis of HCC is closely related to the presence of viral infections from hepatitis B and hepatitis C. Viral agents support the onset and progression of cancer through consequential events involving genetic alterations, increased reactive oxygen species and angiogenesis occurring during tumor progression from healthy liver to diseased liver.

Figure 2

Viral life cycles. (A) Hepatitis (B) virus life cycle: the virus enters through the link with Na⁺ taurocholate cotransporting polypeptide (NTCP), follows the endocytosis of the viral agent and the transport of nucleocapsid into the nucleus in which the relaxed circular DNA genome (rcDNA) is converted into covalently closed circular DNA (cccDNA). This process allows the transcription of the viral mRNA with the subsequent encapsulation of the viral protein core and the production of the double-stranded linear DNA. Through the endoplasmic reticulum, viral particles are assembled and subsequently secreted. (B) Hepatitis C virus life cycle: hepatitis C virus entry is mediated by the low density lipoprotein receptor (LDLR) with subsequent release of the viral genome that undergoes replication and transcription with production of a single polyprotein chain that allows the synthesis of viral proteins. They follow the assembly and release of viral particles.

Figure 2

Viral life cycles. (A) Hepatitis (B) virus life cycle: the virus enters through the link with Na⁺ taurocholate cotransporting polypeptide (NTCP), follows the endocytosis of the viral agent and the transport of nucleocapsid into the nucleus in which the relaxed circular DNA genome (rcDNA) is converted into covalently closed circular DNA (cccDNA). This process allows the transcription of the viral mRNA with the subsequent encapsulation of the viral protein core and the production of the double-stranded linear DNA. Through the endoplasmic reticulum, viral particles are assembled and subsequently secreted. (B) Hepatitis C virus life cycle: hepatitis C virus entry is mediated by the low density lipoprotein receptor (LDLR) with subsequent release of the viral genome that undergoes replication and transcription with production of a single polyprotein chain that allows the synthesis of viral proteins. They follow the assembly and release of viral particles.

Figure 3

Immune system involvement in the pathogenesis of HCC. Involvement and cross talk between immune cells in the creation of an immunosuppressive environment that allows the tumor to evade immunosurveillance through multiple mechanisms. These mechanisms allow the accumulation of immunosuppressive cell populations resulting in the remodeling of the TME through pathogenic immune factors that induced immuno-imbalance and the development of HCC.