Abstract
Metabolic rewiring in tumor cells is a major hallmark of oncogenesis. Some of the oncometabolites drive suppressive and tolerogenic signals from the immune system, which becomes complicit to the advent and the survival of neoplasia. Tryptophan (TRP) catabolism through the kynurenine (KYN) pathway was reported to play immunosuppressive actions across many types of cancer. Extensive debate of whether the culprit of immunosuppression was the depletion of TRP or rather KYN accumulation in the tumor microenvironment has been ongoing for years. Results from clinical trials assessing the benefit of inhibiting key limiting enzymes of this pathway such as indoleamine 2,3-dioxygenase (IDO1) or tryptophan 2,3-dioxygenase (TDO2) failed to meet the expectations. Bearing in mind the complexity of the tumoral terrain and the existence of different cancers with IDO1/TDO2 expressing and non-expressing tumoral cells, here we present a comprehensive analysis of the TRP global metabolic hub and the driving potential of the process of oncogenesis with the main focus on liver cancers.
Highlights
In addition to being a component of proteins, TRP is metabolized through the kynurenine (KYN) or the serotonin (5-HT) pathway to lead to the production of physiologically active metabolites, such as kynurenic acid (KYNA) and NAD+ or serotonin (5-HT) and melatonin [31] (Figure 1)
Other drugs targeting the key enzyme of the kynurenine pathway IDO1 have been used in vitro and/or in vivo and are listed in Table 2. 1-MT exists as two stereoisomers, 1-D-MT and 1- L -MT and IDO1 is the preferential target of 1- L -MT, while 1-D-MT, which has been used in clinical trials, preferentially inhibits IDO2 [65,66]
TDO2 promotes tumor progression through the production of kynurenine, which is an endogenous ligand of the aryl hydrocarbon receptor (AHR), known to be involved in increased tumor cell survival and motility, and reduced anti-tumor immune responses
Summary
The liver is an essential organ involved in digestion and in many other functions, among them immunotolerance [1]. It is continuously exposed to antigens from food intake, gut microbiome, and possibly from pathogens. Any dysfunction of the liver can lead to important metabolic or immunological disorders, eventually threatening the survival of the organism and/or leading to liver tumorigenesis. In 2020, liver cancer ranked 6th in the world in terms of incidence 906,000 new cases) and 3rd in terms of mortality (around 830,000 deaths), with disparities between men and women as incidence and mortality rates were 2–3 times higher in men [2]. Liver cancer is expected to increase by 50% in the 20 years with major geographical disparities in prevalence worldwide [3]
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