Chronic Inflammation-elicited Liver Progenitor Cell Conversion to Liver Cancer Stem Cell with Clinical Significance

Abstract

The substantial heterogeneity and hierarchical organization in liver cancer supports the theory of liver cancer stem cell (LCSC). However, the relationship between chronic hepatic inflammation and LCSC generation remains obscure. Here we observed a close correlation between aggravated inflammation and liver progenitor cell (LPC) propagation in the cirrhotic liver of rats exposed to diethylnitrosamine. LPCs isolated from the rat cirrhotic liver initiated subcutaneous liver cancers in NOD/SCID mice, suggesting the malignant transformation of LPC toward LCSC. Interestingly, depletion of Kupffer cells in vivo attenuated the LCSC properties of transformed LPCs and suppressed CK19⁺OV6⁺ tumor occurrence. Conversely, LPCs co-cultured with macrophages exhibited enhanced LCSC properties. We further demonstrated that macrophage-secreted TNF-α triggered chromosomal instability in LPCs via the deregulation of ubiquitin D and Checkpoint kinase 2, and enhanced the self-renewal of LPCs through TNFR1/Src/STAT3 pathway, which synergistically contributed to the conversion of LPCs to LCSCs. Clinical investigation revealed that CK19⁺OV6⁺ liver cancer patients displayed a worse prognosis and exhibited superior response to sorafenib treatment. In conclusion, our results not only clarified the cellular and molecular mechanism underlying the inflammation-mediated LCSC generation, but also provided a novel molecular classification for the individualized treatment of liver cancer. This article is protected by copyright. All rights reserved.

http://ift.tt/2u0kyNy