Abstract
Background & AimsChronic inflammation is a major etiological factor for hepatocellular carcinoma (HCC), but how immune cells respond in the initiation of hepatocarcinogenesis remains uncharacterized. This study aims to investigate the response and roles of neutrophils in early hepatocarcinogenesis.MethodsBy inducible expression of oncogenic krasV12 in hepatocytes in transgenic zebrafish combined with live imaging of neutrophils in transparent larvae, the response of neutrophils to oncogenic liver was characterized and their roles investigated by pharmaceutical and genetic manipulations.ResultsWe found a rapid recruitment of neutrophils to the liver upon induction of krasV12 expression. Pharmaceutical stimulation of neutrophils resulted in further increases of neutrophils in oncogenic livers, liver size and tumor severity, while inhibition of neutrophils caused decreases of liver-associated neutrophils and liver size. Time-lapse video indicated that neutrophils had a stagnant migratory pattern meandering along the tumor edge but became relatively stationary upon entering the krasV12-expressing liver. Both oncogenic hepatocytes and tumor-associated neutrophils (TANs) were isolated via fluorescence-activated cell sorting. Molecular analyses indicated a pro-inflammatory microenvironment, as marked by increased tgfβ1a expression in krasV12-expressing hepatocytes and a loss of anti-tumor activities in TANs. Depletion of Tgf-β significantly reduced the number of TANs and the size of oncogenic liver.ConclusionsAn inflammatory cue from oncogenic hepatocytes upon induction of krasV12 expression causes a rapid recruitment of neutrophils to oncogenic liver and the neutrophils play a promoting role in early hepatocarcinogenesis.
Highlights
In the past decade, increasing evidence has indicated a dual role of neutrophils in a variety of tumors [1]
Tumor-associated neutrophils (TANs) have long been observed to correlate to tumor progression in chronic colitis-associated carcinogenesis or gastric adenocarcinoma [4,5,6]. These alternatively behaved neutrophils are capable of releasing growth-stimulating signals, matrix-degrading proteases, and angiogenesis mediators [1,7], favoring tumor progression. It has been reported the existence of subtypes N1 and N2 neutrophils; the neutrophil plasticity appears to be regulated by transforming growth factor-beta (Tgf-b), which is often found to be secreted by cancer cells [4]
The gene expression pattern indicated that the oncogenic kras+ hepatocytes favored a pro-inflammatory environment, consistent with a previous report of liver tumors arising from inflammation due to chronic injury [42]
Summary
In the past decade, increasing evidence has indicated a dual role of neutrophils in a variety of tumors [1]. Tumor-associated neutrophils (TANs) have long been observed to correlate to tumor progression in chronic colitis-associated carcinogenesis or gastric adenocarcinoma [4,5,6] These alternatively behaved neutrophils are capable of releasing growth-stimulating signals, matrix-degrading proteases, and angiogenesis mediators [1,7], favoring tumor progression. Time-lapse video indicated that neutrophils had a stagnant migratory pattern meandering along the tumor edge but became relatively stationary upon entering the krasV12-expressing liver Both oncogenic hepatocytes and tumor-associated neutrophils (TANs) were isolated via fluorescence-activated cell sorting. Conclusions: An inflammatory cue from oncogenic hepatocytes upon induction of krasV12 expression causes a rapid recruitment of neutrophils to oncogenic liver and the neutrophils play a promoting role in early hepatocarcinogenesis
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