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Review
. 2016 Oct 27;8(4):89-93.
doi: 10.1002/cld.578. eCollection 2016 Oct.

The transition from inflammation to cancer in the liver

Augusto Villanueva  1   2 , Tom Luedde  3
Affiliations
Review

The transition from inflammation to cancer in the liver

Augusto Villanueva et al. Clin Liver Dis (Hoboken). .
No abstract available

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Figures

Figure 1
Figure 1
Basic molecular events driving inflammatory hepatocarcinogenesis. Different forms of programmed cell death exist that are activated in a pathogen‐specific manner. Dying hepatocytes activate the immune system by the release of danger molecules termed DAMPs such as HMGB1 or S100 proteins and activate immune cell via specific receptors like RAGE. Inflammation is a key promoter driving the maladaptive wound healing response toward HCC. Type I macrophages emerge in the very early stage of the tumor microenvironment, recruiting inflammatory cells by a complex network of chemokines. These cells mediate the Th1 and Th17 response and promote hepatic compensatory proliferation by cytokines, such as tumor necrosis factor (TNF) and IL‐6, which activate antiapoptotic, proproliferative signals like NF‐κB or signal transducer and activator of transcription 3 (STAT‐3) in hepatocytes. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) produced by activated inflammatory/immune cells induce mutations and genomic alterations resulting in the appearance of premalignant cells that proliferate and survive. Type II macrophages emerge in the late stage of the tumor and are in charge of Th2 response by recruiting Th2 cells that contributed to immunosuppression. MDSCs contribute an immunosuppressive effect by secreting IL‐10 and transforming growth factor‐β (TGF‐β), and also promote angiogenesis caused by the secretion of cytokines such as VEGF. Because of immunosuppressive factors in the tumor microenvironment, antitumor immunity exerted by, for example, cytotoxic T cells cannot be activated unless the immunosuppressive factors are neutralized or eliminated.
Figure 2
Figure 2
Activation of necroptosis in human NASH. (A) For years, the term apoptosis, relying on the activation of caspases, was used synonymously with programmed cell death. However, it became evident that another form of programmed necrosis exists that is termed necroptosis and relies on the activation of RIPK1 and RIPK3. (B) In livers of human NASH patients, the necroptosis executer RIPK3 is strongly upregulated, suggesting that necroptosis might be a central regulator of liver injury and inflammation in NASH. FADD, Fas‐associated protein with death domain. Reproduced with permission from Gautheron et al.5 Copyright 2015, Jérémie Gautheron, Mihael Vucur, and Tom Luedde. Abbreviations: GAPDH, Glyceraldehyde 3‐phosphate dehydrogenase; IKK, I‐kappa‐B‐Kinase; NEMO, NF‐kappaB‐essential modulator; TAB, TAK1‐binding protein; TAK1, TGF‐beta‐activated Kinase 1.
Figure 3
Figure 3
Gene expression–based risk stratification in HCC. Robust data suggest that gene expression signatures from cirrhotic tissue enable accurate stratification of patients based on their risk for HCC development. These technologies would allow identifying those patients at higher risk, enabling chemoprevention clinical trials using enriched populations. Here, the likelihood of events is higher, and hence the time that is required to complete the trial decreases.
See this image and copyright information in PMC

References

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