Serotonin in liver tumor: Friend or foe?

We read with great interest the recent HEPATOLOGY article by Starlinger et al., in which they proved that low preoperative platelet-derived 5-hydroxytryptamine (5-HT; serotonin; <73 ng/mL) would result in high incidence of postoperative liver dysfunction and morbidity. It seemed that 5-HT was a beneficial factor in patients with liver tumor. Thus, they concluded “involvement of 5-HT might represent a novel therapeutic target to accelerate [liver regeneration] LR after hepatectomy.” We want to point out that in contrast to the data by Starlinger et al., Soll et al. highlighted that 5-HT could promote cell survival and growth of hepatocellular carcinoma (HCC) cells by the activation of the 5-HT2B receptor. In addition, they found that there was a significant decrease in hepatic tumor formation rate in tryptophan hydroxylase 1-deficient mice (lacking peripheral 5-HT) chronically fed with CCl4. In another article, Buergy et al. 3 demonstrated that thrombocytosis (high 5-HT level) at the time of diagnosis was associated with a shorter survival in many solid tumors, including HCC. In addition to the relationship between 5-HT and promotion of HCC, other reports investigated the relationship between 5-HT and hepatitis virus infection and subsequent cirrhosis, which are predominant prognostic factors for HCC. Lang et al. found that treatment with 5-HT in infected mice aggravated liver damage by delaying virus clearance. In contrast, mice lacking serotonin accelerated virus clearance and reduced liver damage. Moreover, the article by Ruddell et al. pointed out that 5-HT played a profibrogenic role by mediating proliferation and apoptosis of hepatic stellate cells. In conclusion, 5-HT can produce both beneficial and detrimental effects in basic liver diseases as well as HCC. Therefore, more clinical and experimental studies are needed to determine the complicated relationships between 5-HT and HCC before considering it as a novel therapeutic target.