LAUSR

erotonin (also known as 5-hydroxytryptamine S[5-HT]) is a small-molecule neurotransmitter that was identified in a series of studies conducted between 1935 and 1953 because of its capacity to induce contractions in the intestine and blood vessels. A plethora of functions for the serotonin system have been described, including regulation of mood, blood clotting, gut motility, systemic energy homeostasis, and tissue repair. Serotonin is synthesized from the essential amino acid tryptophan via tryptophan hydroxylase (TPH) in the brain and enterochromaffin cells of the gastrointestinal tract. Gutproduced serotonin then actively is taken up by platelets and travels in the blood stream where it can be released on demand. Seminal studies in the past decade have identified several important roles for the serotonin system in liver homeostasis and disease. An elegant study in 2006 introduced a new paradigm for platelet-derived serotonin in promoting liver regeneration by acting directly on hepatocytes (via the hepatocyte 5-HT2A receptor). 1 A subsequent study in 2011 established a more complex model, showing the antiregenerative and profibrogenic function of serotonin in normal and diseased liver through 5-HT2B receptor activation in stellate cells and production of transforming growth factor (TGF)-b1. These studies described an integral role for the serotonin system in controlling the balance between hepatic regeneration and fibrosis. Given that inflammation and fibrosis provide a permissive microenvironment for the emergence of tumorigenic hepatocytes and that hepatocellular carcinoma is the third-leading cause of cancer death with a poor prognosis and very limited therapeutic options, a key follow-up study was to interrogate the role of serotonin-related pathways in the development of hepatocellular carcinoma in models with progressive liver fibrosis. This is even more important in light of recent findings about the reliability of serum serotonin as a potential clinical biomarker for the diagnosis and staging of liver cancer. In this issue of Cellular and Molecular Gastroenterology and Hepatology, Yang et al have described a new positive feedback circuit for serotonin system components in fueling the fibrosis–cancer axis in diseased liver. The authors also have reported that this loop is essential for sexual dimorphism in liver cancer. To investigate this topic, they used a transgenic zebrafish model with the kras mutation and showed accelerated fibrosis and cancer in males. Subsequently, through a series of pharmacologic interventions, they discovered a 2-way intercellular communication loop between hepatocytes and