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.

Activation of EGFR‐KLF4 positive feedback loop results in acquired resistance to sorafenib in hepatocellular carcinoma

“…Here, we further measured the IC 50 values of sorafenib in four HCC cell lines, including Hep3B, Huh7, pHCC1, and pHCC2. pHCC2 was the other human primary HCC cell lines established by us previously . As shown in Figure A, the IC 50 value of pHCC2 was up to 15 μM, which was more than the value of sorafenib concentration (10 μM) for inducing SR; the IC 50 values of Hep3B, Huh7, and pHCC1 were less than 5 μM.…”

“…Hep3B, Huh7, and a primary HCC cell line (pHCC1) established previously by Liu et al were used to produce three SR human HCC cell lines. MTT assay determined that 10 μM sorafenib treatment significantly reduced the viability of three wild‐type cell lines, but failed to reduce the viability of three SR cell lines (Figure A).…”

“…pHCC2 was the other human primary HCC cell lines established by us previously. 7 As shown in Figure 6A, the IC 50 value of pHCC2 was up to 15 μM, which was more than the value of sorafenib concentration (10 μM) for inducing SR; the IC 50 values of Hep3B, Huh7, and pHCC1 were less than 5 μM. Compared with Hep3B, Huh7, and pHCC1 cells, the expression levels of EGFR and KLF4 were dramatically increased in pHCC2, suggesting that high F I G U R E 5 EGFR induces KLF4 transcription by binding to its promoter.…”

Cancer Stem Cells: A Potential Breakthrough in HCC-Targeted Therapy

“…The recurrence rate of patients with a high CD133 expression is higher than that of a low CD133 expression (Song et al, 2008). The process of CD133 + CSCs promoting the recurrence of HCC is closely associated with VEGF (Liu et al, 2017a). Other studies have shown that CD44 expressions in nontumor tissues may predict HCC recurrence (Tovuu et al, 2013).…”

miRNA122a regulation of gene therapy vectors targeting hepatocellular cancer stem cells

“…Cancer stem cells (CSCs) represent a subpopulation of cancer cells with innate resistance to radio and chemotherapies and are vital for tumor progression and recurrence after therapy [ 6 , 7 ]. Accumulating evidences suggest that a small subset of HCC possess these stem like properties and thus are important targets for therapeutic interventions [ 8 ].…”