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Review
. 2021 Sep 21;13(18):4732.
doi: 10.3390/cancers13184732.

Senescence in HBV-, HCV- and NAFLD- Mediated Hepatocellular Carcinoma and Senotherapeutics: Current Evidence and Future Perspective

Vassilis G Giannakoulis  1   2 , Peter Dubovan  3   4 , Eleni Papoutsi  1   2 , Agapi Kataki  1   2 , John Koskinas  2   5
Affiliations
Review

Senescence in HBV-, HCV- and NAFLD- Mediated Hepatocellular Carcinoma and Senotherapeutics: Current Evidence and Future Perspective

Vassilis G Giannakoulis et al. Cancers (Basel). .

Abstract

Cell senescence constitutes a physiological process that serves as protection from malignant transformation of cells. However, recent scientific discoveries also identify cell senescence as pivotal in hepatocellular cancer (HCC) biology. The review herein aimed to accumulate evidence on senescence as a mediator of HCC occurrence in hepatitis B (HBV), C (HCV) virus infections, and non-alcoholic fatty liver disease (NAFLD). In HBV infection, the carcinogenic HBV X protein frequently mutates during chronic infection, and subsequently exhibits different effects on senescence. In HCV infection, senescent non-functional T-cells do not effectively clear pre-malignant hepatocytes. Furthermore, the HCV Core protein inhibits the occurrence of normal stress-induced hepatocyte senescence, allowing damaged cells to maintain their proliferative potential. In NAFLD-mediated HCC, current data point towards the gut microbiome and hepatic stellate cell senescence. Additionally, senescence contributes in the development of resistance in targeted therapies, such as sorafenib. Finally, the promising role of senotherapeutics in HCC was also explored. Overall, although we may still be at a primitive stage in fully unraveling the role of senescence in cancer, it seems that understanding and harnessing senescence may have the potential to revolutionize the way we treat hepatocellular cancer.

Keywords: cell senescence; hepatitis; hepatocellular cancer; non-alcoholic fatty liver disease; senescence-modulating agents; senomorphics; senoptotics; senotherapeutics.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Emergence and fate of senescent hepatocytes. Initially, a stress factor induces cellular damage and triggers the formation of senescent cells. Scenario 1: Activation of the immune system via the senescence-associated secretory phenotype (SASP) and clearance. Scenario 2: Abnormal overt accumulation, SASP secretome activation and carcinogenesis. Scenario 3: Pre-malignant hepatocytes evade senescence arrest and gain proliferative potential, contributing to hepatocellular cancer occurrence. Administering anti-senescence agents may enhance senescent cell elimination and ameliorate their disastrous potential. Normal hepatocytes are presented in pale brown, malignant ones in dark brown, whereas senescent ones are presented in light blue with yellow outline.
Figure 2
Figure 2
Proposed senotherapeutic strategies: (a) anti-senescent agents may be especially useful against sorafenib resistance, a condition associated with senescent cell accumulation. Sorafenib induces the formation of senescent cells, in which it is no longer effective. Thus, a combination of sorafenib with an anti-senescent agent may result in better sorafenib response. (b) Pro-senescent agents may have the potential to halt tumor growth via inducing senescence. Thus, malignant cells enter proliferative arrest, and provided that the immune system works, most senescent cells are cleared in an immune-mediated fashion. (c) The combined “one-two punch” approach. In this treatment strategy, one starts with a pro-senescence agent, to promote senescence of malignant hepatocytes. As senescent cells may start to accumulate, an anti-senescent agent is administered in the next step, in order to enhance senescent cell clearance. Normal hepatocytes are presented in pale brown, malignant ones in dark brown, whereas senescent ones are presented in light blue with yellow outline.
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