Abstract
Activation of hepatic stellate cells (HSC) plays a crucial role in the liver disease progression from liver fibrosis/cirrhosis to cancer. Here, we found a rapid change of microenvironment after krasV12-induction in zebrafish liver with progressively increased stromal cell number and enlarged liver size. Neutrophils and macrophages exhibited a faster response than HSCs. By manipulating the numbers of neutrophils and macrophages through morpholino knockdown, we found that macrophages contributed to both HSC survival and activation while neutrophils appear to be only required for HSC activation. Serotonin, which is essential for HSC survival and activation, was found up-regulated in hepatocytes and macrophages, but not in neutrophils after krasV12 induction. Serotonin receptor was highly expressed in HSCs; increase of the receptor activity by an agonist stimulated HSCs and oncogenic growth of the liver while an opposite effect was observed with an antagonist. Activated HSCs promoted the pro-tumorigenesis functions of neutrophils and macrophages through secretion of Tgfb1. Overall, these observations elucidated a cellular interaction in microenvironment where that upregulated serotonin in hepatocytes and macrophages activated HSCs. Since the microenvironment crosstalk plays a vital role in manipulation of liver carcinogenesis, the underlying mechanism may provide potential therapeutic targets for liver diseases.
Highlights
Tumor microenvironment is important in tumor initiation and progression
In human hepatocellular carcinoma (HCC) patients, there are high densities of tumor associated neutrophils (TANs), tumor associated macrophages (TAMs) and hepatic stellate cells (HSC) in the liver tumors and these correlate to poor prognosis[8,9,10,11]
Quantification of glial fibrillary acidic protein (Gfap) and α-smooth muscle actin (α-Sma) staining is shown in Fig. 1E and it appeared that both total HSC density and the ratio of activated HSCs were increased significantly in krasV12-expressing livers, compared to wildtype livers at 24 hpi
Summary
Tumor microenvironment is important in tumor initiation and progression. Hepatic stellate cells (HSCs), liver-specific mesenchymal cells, are an important component of tumor microenvironment and the stromal dynamics is a key determinant of liver cancer progression[1]. TAMs and TANs are simultaneously activated to a pro-tumor gene expression profile during carcinogenesis and could affect each other[12] Both TAMs and TANs have been demonstrated to be able to influence HSCs in a non-neoplastic context. Our laboratory has generated several inducible HCC models by transgenic expression of an oncogene in hepatocytes in zebrafish[16,17,18,19]. The transparent nature of zebrafish larvae and the availability of various transgenic reporter zebrafish with expression of a fluorescence protein marker in specific cell lineage such as HSCs, neutrophils or macrophages provide excellent tools to elucidate interactions of different microenvironment components in a neoplastic context[22,23,24]. HSC activation resulted in up-regulation of Tgfb[1] expression, which in turn maintained pro-tumor gene expression in TANs and TAMs and thereby promoted carcinogenesis
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