Insufficient Radiofrequency Ablation Promotes Angiogenesis of Residual Hepatocellular Carcinoma via HIF-1α/VEGFA

Abstract

BackgroundThe mechanism of rapid growth of the residual tumor after radiofrequency (RF) ablation is poorly understood. In this study, we investigated the effect of hyperthermia on HepG2 cells and generated a subline with enhanced viability and dys-regulated angiogenesis in vivo, which was used as a model to further determine the molecular mechanism of the rapid growth of residual HCC after RF ablation.Methodology/Principal FindingsHeat treatment was used to establish sublines of HepG2 cells. A subline (HepG2 k) with a relatively higher viability and significant heat tolerance was selected. The cellular protein levels of VEGFA, HIF-1α and p-Akt, VEGFA mRNA and secreted VEGFA were measured, and all of these were up-regulated in this subline compared to parental HepG2 cells. HIF-1α inhibitor YC-1 and VEGFA siRNA inhibited the high viability of the subline. The conditioned media from the subline exerted stronger pro-angiogenic effects. Bevacizumab, VEGFA siRNA and YC-1 inhibited proangiogenic effects of the conditioned media of HepG2 k cells and abolished the difference between parental HepG2 cells and HepG2 k cells. For in vivo studies, a nude mouse model was used, and the efficacy of bavacizumab was determined. HepG2 k tumor had stronger pro-angiogenic effects than parental HepG2 tumor. Bevacizumab could inhibit the tumor growth and angiogenesis, and also eliminate the difference in tumor growth and angiogenesis between parental HepG2 tumor and HepG2 k tumor in vivo.Conclusions/SignificanceThe angiogenesis induced by HIF1α/VEGFA produced by altered cells after hyperthermia treatment may play an important role in the rapid growth of residual HCC after RF ablation. Bevacizumab may be a good candidate drug for preventing and treating the process.

Clinical characteristics and prognostic factors for advanced hepatocellular carcinoma with extrahepatic metastasis

“…Of note, previously untreated patients had more advanced-stage intrahepatic tumors compared to previously treated patients. Previous studies suggested that residual HCC following various treatments is associated with increased malignant potential compared to untreated HCC (16)(17)(18). Therefore, we suggest that aggressive treatment may result in earlier extrahepatic metastasis, despite a less advanced intrahepatic tumor stage, in previously treated patients.…”

Modulation of hypoxia-signaling pathways by extracellular long non-coding RNA regulator of reprogramming

“…Resistance to therapy, and tumor progression, is increased by the ability of HCC cells to resist adverse environmental conditions, such as hypoxia. Locoregional therapies, such as transarterial embolization, which result in ischemic necrosis but tumor cell survival within hypoxic regions, might contribute to incomplete eradication or tumor recurrence (Shim et al, 2008;Gadaleta and Ranieri, 2011;Kong et al, 2012). Although the ability of tumors to survive during hypoxia is a crucial determinant of therapeutic response and tumor progression, the cellular mechanisms by which tumor cells respond to, and survive during, hypoxia are poorly understood.…”

Overexpression and correlation of HIF-2α, VEGFA and EphA2 in residual hepatocellular carcinoma following high-intensity focused ultrasound treatment: Implications for tumor recurrence and progression

“…VEGFA is among the most potent angiogenic factors expressed in various human cancers, including HCC (28). VEGFA is a hexose-modified multifunctional protein that acts specifically on vascular endothelial cells, whereby it induces micro-angiogenesis.…”