Activation of liver stromal cells is associated with male-biased liver tumor initiation in xmrk and Myc transgenic zebrafish.

Hepatocellular carcinoma (HCC) is more prevalent in men than in women. Previously we have found that some stromal cells, including hepatic stellate cells (HSCs), neutrophils and macrophages, play crucial roles in promoting sex disparity in kras (V12) -induced zebrafish HCC. The activation of HSCs is mediated by serotonin while activation of neutrophils and macrophages is mediated by cortisol. To ensure that these findings are also applicable to other oncogene induced tumors, stromal cell activation was compared between male and female fish during liver tumorigenesis initiated by xmrk or Myc oncogene. Consistently, we observed male-biased liver tumorigenesis in the xmrk and Myc models. In both models, there was a higher rate of HSC activation accompanied with a higher level of serotonin in male liver tumors. For tumor-infiltrated neutrophils and macrophages, significantly higher densities in male liver tumors were observed in both xmrk and Myc models. However, the male-biased increase of cortisol was observed only in xmrk- but not apparently in Myc expressing liver tumors. Overall, these observations are consistent with the observations in the kras liver tumor model, indicating that the serotonin- and cortisol-mediated pathways also play roles in sex disparity of liver tumors caused by other molecular pathways.