Chronic Inflammation-elicited LPC Conversion To Liver CSC And Its Relavence To Sorafenib Therapy

The substantial heterogeneity and hierarchical organization in liver cancer favors the theory of liver cancer stem cell(LCSC).Increasing evidence has indicated that the occurrence of liver cancer is attributed to the propagation of liver cancer stem cells(LCSCs).LCSCs possess unlimited self-renewal capacity and is critical in the initiation,progression,chemo-resistance and postsurgical recurrence of PLC.In comparison with stem cells,progenitor cells in adult organ exhibit limited self-renewal capability and reduced differentiation potential.Liver progenitor cells(LPCs),also termed oval cells in rodents,are small normal epithelial cells located in the canals of Hering,which could be distinguished by specific cell surface markers such as OV6 or CK19.LPC activation was reported to be associated with the tissue damage and inflammation,but the compensatory expansion of LPC only occurred in case that hepatocyte regeneration is largely restricted in the liver with severe chronic injury.A most recent study showed that reactivation of the generative capacity in adult LPCs markedly increased their susceptibility to transformation,which provides direct evidence that cell generative capacity can be a major determinant of organ cancer risk.Nevertheless,whether LPCs are involved in LCSCs generation during inflammation-elicited hepatocarcinogenesis deserves exploration.The relation between chronic hepatic inflammation and LCSC generation remains obscure.The current conventional treatments of hepatocellular carcinoma involve liver resection,liver transplantation,radiofrequency ablation and TACE.These treatments can not effectively eliminate the liver cancer stem cells.Therefore,the liver cancer recurrence rate is still high.With the development of small molecule targeted drugs,more and more targeted drugs have been used in the treatment of tumors.Sorafenib,a small molecule targeted drug that can be used in the treatment of advanced liver cancer,can be widely used in the clinical treatment.According to the reports of kinase inhibition experiment in vitro,Sorafenib can inhibit the vascular endothelial growth factor receptor 1-3(VEGFR1-3),platelet derived growth receptor beta(PDGFR-beta),stem cell factor(C-kit)and type III receptor tyrosine kinase(Flt3)and so on.Recently,various studies indicate that sorafenib can inhibit the phosphorylation of STAT3,thereby inhibiting the occurrence of cholangiocarcinomaTo explore the contribution of chronic inflammation in the conversion of LPC to LCSC,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.Intriguingly,depletion of Kupffer cells in vivo suppressed CK19+OV6+ tumor occurrence.We further demonstrated that TNF-α triggered chromosomal instability via the deregulation of ubiquitin D and Checkpoint kinase 2 which induced the transformation of LPCs into LCSCs.Clinical investigation revealed that CK19+OV6+ liver cancer patients displayed a worse prognosis and exhibited superior response to Sorafenib therapy.Thus,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.