Effect of a hypoxic microenvironment after radiofrequency ablation on residual hepatocellular cell migration and invasion

Abstract

Clinical observations have shown that the boundary of tumor ablation is often less than safe border and that the use of radiofrequency ablation (RFA) in the treatment of hepatocellular carcinoma (HCC) may probably accelerate its recurrence and metastasis. RFA can cause the formation of a transition zone between normal liver tissues and necrotic coagulation, where blood stagnation and thrombosis expose residual cancer cells to a hypoxic microenvironment. As the blocked vessels are slowly reperfused, the oxygen supply is gradually restored. Here, HCC cells underwent heat treatment and were cultured under hypoxic conditions to mimic the aforementioned situation, and morphological changes were observed in the surviving cells. Compared with their parental cells, hypoxic HCC cells showed changes that include enhanced invasive, metastatic, and chemoresistant abilities as well as mesenchymal characteristics. There was also a higher percentage of stem‐like cells. However, either improving the hypoxic microenvironment or silencing hypoxia inducible factor (HIF)‐1α signaling significantly reduced the invasive, metastatic, and chemoresistant potential and reversed the epithelial‐mesenchymal transition to varying degrees. Together, these results indicated that a sustained hypoxic microenvironment after RFA may exert a negative impact on the prognosis of HCC patients, and minimizing exposure to a hypoxic microenvironment and targeting HIF‐1α signaling might be effective strategies for patients who experience insufficient RFA therapy.

Amarogentin Inhibits Liver Cancer Cell Angiogenesis after Insufficient Radiofrequency Ablation via Affecting Stemness and the p53-Dependent VEGFA/Dll4/Notch1 Pathway

“…CD133 is a recognized surface marker for LCSCs [ 15 ]. The mRNA and protein expression levels of CD133 in the iRFA-liver cancer samples were higher than those in the hepatectomy-liver cancer sample (Figures 1(a) – 1(c) ).…”

“…Sublethal heat treatment promotes liver cancer cell development of a spindle-like morphology and transformation CD133-positive liver cancer cells, which are progenitor-like cancer cells that are highly proliferative [ 4 ]. Tong et al have asserted that residual liver cancer cells show a higher percentage of stem-like cells and have levels of invasiveness, metastasis, and drug resistance [ 15 ]. In addition, Wang et al have reported that downregulating the expression of CD133 suppressed proliferation, invasion, and autophagy in iRFA-treated liver cancer [ 4 ].…”

HIF-1α promotes hepatocellular carcinoma metastasis by regulating angiogenesis and epithelial-mesenchymal transition

“…HIF-1α has been implicated in regulating hepatic in ammatory progression, and associated with multiple in ammationrelated cancers or signaling pathway activation of HBV-related HCC [20,21] . The presence of hypoxia in tissues restricts HCC overgrowth because of HIF-1α regulating cellular metabolism, immune escape, angiogenesis, metastasis [22] , extracellular matrix remodeling, cancer stem cells (CSC) [23,24] or MDR via regulating PI3K/AKT/HIF-1α/MDR-1 pathway [25,26] . HIF-1α-de cient HCC cells displayed signi cantly reduced anchorage-independent growth and enhanced sensitivity toward chemotherapy [4] .…”

A new apatinib microcrystal formulation enhances the effect of radiofrequency ablation treatment on hepatocellular carcinoma

“…On the other hand, RFA may induce cellular stress and pathological changes in HCC cells. 33 , 34 Several studies suggested that the elevated EMT may account for post-RFA recurrence. 33 – 35 Therefore, inhibiting the EMT process during RFA treatment may be a useful strategy to overcome the recurrence of HCC after RFA treatment.…”