title: CD133+cancer stem cells promoted by VEGF accelerate the recurrence of hepatocellular carcinoma.
abstract: The role of cancer stem cells (CSCs) in inducing the recurrence of hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA) remains unclear. Here, we found that a dramatic increase in plasma vascular endothelial growth factor (VEGF) and an induction of local CD133+CSCs are associated with early HCC recurrence, suggesting that VEGF expression and tumour stemness contribute to the relapse. In vitro studies demonstrated that VEGF, via activation of VEGFR2, increased the number of CD133+CSCs and enhanced their capacity for self-renewal by inducing the expression of Nanog. In vivo studies further demonstrated that VEGF-treated CD133+CSCs formed tumours larger than those developing from unstimulated cells and VEGF pre-treatment increased the tumorigenic cell frequency of primary HCC cells dependently on the presence of Nanog and VEGFR2. In HCC tissue derived from patients with early recurrence, almost all CD133+cells were Nanog and p-VEGFR2 positive, suggesting that activation of VEGFR2 is critical for RFA-induced tumour stemness in HCC. In summary, RFA-induced VEGF promotes tumour stemness and accelerates tumourigenesis in HCC in a manner dependent on Nanog and VEGFR2, which is valuable for the prediction of HCC recurrence after RFA and the development of novel therapeutics.
authors.affiliation: Capital Medical University affiliated Beijing You An Hospital, Beijing, 100069, China.|Beijing Institute of Hepatology, Beijing, 100069, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Liu
authors.affiliation: Capital Medical University affiliated Beijing You An Hospital, Beijing, 100069, China.
authors.forename: Meijun
authors.initials: M
authors.lastname: Hao
authors.affiliation: Capital Medical University affiliated Beijing You An Hospital, Beijing, 100069, China.|Beijing Institute of Hepatology, Beijing, 100069, China.
authors.forename: Yabo
authors.initials: Y
authors.lastname: Ouyang
authors.affiliation: Capital Medical University affiliated Beijing You An Hospital, Beijing, 100069, China.
authors.forename: Jiasheng
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Capital Medical University affiliated Beijing You An Hospital, Beijing, 100069, China.|Beijing Institute of Hepatology, Beijing, 100069, China.|Organ Transplantation Center, the Affiliated Hospital of Qingdao University, Qingdao City, Shandong Province, 266003, China.
authors.forename: Dexi
authors.initials: D
authors.lastname: Chen
mesh_terms: D000071916:AC133 Antigen / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005434:Flow Cytometry; D015870:Gene Expression; D020869:Gene Expression Profiling; D064593:Heterografts; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D000071317:Nanog Homeobox Protein / Q000235:genetics / Q000378:metabolism; D009364:Neoplasm Recurrence, Local; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D042442:Vascular Endothelial Growth Factors / Q000097:blood / Q000378:metabolism*
chemical_list: D000071916:AC133 Antigen; D015415:Biomarkers; D016207:Cytokines; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D042442:Vascular Endothelial Growth Factors; D040301:Vascular Endothelial Growth Factor Receptor-2