Incomplete radiofrequency ablation enhances invasiveness and metastasis of residual cancer of hepatocellular carcinoma cell HCCLM3 via activating β-catenin signaling.

Terence Lee,Dong-Mei Gao,Zong-Tao Chai,Zhao-You Tang,Ning Zhang,Yi-Ming Zhao,Hui-Chuan Sun,Zi-Man Zhu,Zheng-Gang Ren,Xiao-Dong Zhu,Lu Wang,Jian-Yang Ao,Miao Wang,De-Ning Ma,Qiang-Bo Zhang

doi:10.1371/journal.pone.0115949

Abstract

BackgroundRadiofrequency ablation (RFA) is one of the curative therapies for hepatocellular carcinoma (HCC), however, accelerated progression of residual HCC after incomplete RFA has been reported more frequently. The underlying molecular mechanism of this phenomenon remains to be elucidated. In this study, we used an incomplete RFA orthotopic HCC nude mouse model to study the invasive and metastatic potential of residual cancer as well as the correlated mechanism.MethodsThe incomplete RFA orthotopic nude mouse models were established using high metastatic potential HCC cell line HCCLM3 and low metastatic potential HCC cell line HepG2, respectively. The changes in cellular morphology, motility, metastasis and epithelial–mesenchymal transition (EMT), and HCC cell molecular markers after in vitro and in vivo incomplete RFA intervention were observed.ResultsPulmonary and intraperitoneal metastasis were observed in an in vivo study. The underlying pro-invasive mechanism of incomplete RFA appeared to be associated with promoting EMT, including down-regulation of E-cadherin and up-regulation of N-cadherin and vimentin. These results were in accordance with the in vitro response of HCC cells to heat intervention. Further studies demonstrated that β-catenin was a pivotal factor during this course and blocking β-catenin reduced metastasis and EMT phenotype changes in heat-treated HCCLM3 cells in vitro.ConclusionIncomplete RFA enhanced the invasive and metastatic potential of residual cancer, accompanying with EMT-like phenotype changes by activating β-catenin signaling in HCCLM3 cells.

Highlights

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third leading cause of cancer-related death [1]
A growing number of clinical studies have identified the rapid progression of residual cancer after incomplete radiofrequency ablation (RFA) in treating HCC [32, 33]
Hyperthermia may play an important role in the rapid growth of residual HCC after RFA by promoting angiogenesis of residual HCC via HIF-1a/VEGFA [34]

Summary

Introduction

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third leading cause of cancer-related death [1]. Liver transplantation provides an alternative treatment for small unresectable HCC, the shortage of liver grafts limits the applicability of this approach [4] Due to these circumstances, several non-surgical techniques have been introduced for HCC treatment, such as radiofrequency ablation (RFA), percutaneous ethanol injection (PEI) and microwave coagulation therapy (MCT) [5, 6]. The underlying pro-invasive mechanism of incomplete RFA appeared to be associated with promoting EMT, including down-regulation of E-cadherin and upregulation of N-cadherin and vimentin. These results were in accordance with the in vitro response of HCC cells to heat intervention.

Methods

Results

Conclusion