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.
Highlights
Autocrine and paracrine VEGF signalling occurs in some tumour cells, contributing to induction of cancer stem cells (CSCs), independent of any role that VEGF may have in angiogenesis[12,22]
CSCs are localized in a perivascular niche, and VEGF secreted from these cells functions in a paracrine manner to stimulate angiogenesis in nascent tumours; simultaneously, autocrine VEGF signalling can promote dedifferentiation and an epithelial-mesenchymal transition (EMT) resulting in increased migration and invasion into the stroma[12]
radiofrequency ablation (RFA)-induced microvascular and tissue injury promotes angiogenesis to relieve ischaemia in local areas[23], and this VEGF-induced angiogenesis may act synergistically with VEGF-induced tumour stemness to accelerate Hepatocellular carcinoma (HCC) recurrence, as shown by our results that VEGF signalling enhances the tumourigenicity of CD133+ CSCs isolated from patients with an increased risk for early recurrence
Summary
The exact effects of VEGF on the promotion of HCC stemness are still unclear. CD133+, VEGFR2+ cells were identified as endothelial progenitor cells[14]. VEGFR2 is preferentially expressed on the cell surface of CD133+ human glioma CSCs, whose viability, self-renewal, and tumourigenicity rely, at least in part, on signalling through the VEGF-VEGFR2–Neuropilin-1 axis[15]. These data suggest that CD133 and the VEGF/VEGFR2 pathway cooperate to regulate stemness, angiogenesis and tumourigenesis. We uncover a new role of VEGF in the acceleration of HCC recurrence via induction of CD133+ CSCs development
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