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)-1a signaling significantly reduced the invasive, metastatic, and chemoresistant potential and reversed the epithelialmesenchymal 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-1a signaling might be effective strategies for patients who experience insufficient RFA therapy.H epatocellular carcinoma (HCC) ranks as the third most frequent cause of cancer-related death.(1) Although surgical operation and transplantation have been recognized as the primary curative therapies for patients with HCC, the advanced neoplastic stage, severe liver dysfunction and shortage of available liver grafts restrict their application.(2) Radiofrequency ablation (RFA) therapy has emerged as an alternative due to its minimal invasiveness, safety, and shorter hospital stays. The survival of patients with HCC <3 cm treated by RFA competes with that of surgical candidates.(3) However, suboptimal RFA treatment of HCC has been reported as a risk factor of early diffuse recurrence, (4) and large tumor size is an independent risk factor of local recurrence because of its poorly defined margins.(5) The necrotic lesion generated by RFA is surrounded by a rim of chronically hypoxic liver tissue, where aggressive outgrowth of residual hepatic micro-metastases has been observed.(6) A hypoxic microenvironment contributes to the development of a malignant phenotype, which includes local invasion, metastatic progression, and chemoresistance. Hypoxia inducible factor (HIF)-1a is a key mediator of cellular adaption to hypoxia (8) and can facilitate the progression of various cancer cells by promoting cell migration, tumor angiogenesis, and metastasis.(9) The epithelial-mesenchymal transition (EMT) has long been recognized as an important step in the progression of primary tumors to distant metastasis.(10) ...

Melittin Inhibits Hypoxia-Induced Vasculogenic Mimicry Formation and Epithelial-Mesenchymal Transition through Suppression of HIF-1α/Akt Pathway in Liver Cancer

“…It has been shown that hypoxia may facilitate the metastasis of liver cancer cells [20]. CoCl 2 treatment significantly elevated the numbers of migrated and invaded SMMC-7721, Huh7, and HepG2 cells (Figures 1(c)–1(f)).…”

“…Liver cancer is a typical malignant tumor with rich blood supply. However, many treatment methods for liver cancer usually induce a hypoxia microenvironment, including TACE and radiofrequency ablation [20, 31], and thereafter promote tumor angiogenesis and metastasis, in part related to the accumulation of HIF-1 α [32]. Overexpression of HIF-1 α promotes the growth, migration, and invasion of liver cancer cells and induces the upregulation of VEGF, which is one of the most potent angiogenic factors presented in various human cancers [33].…”

HIF‐1α downregulation of miR‐433‐3p in adipocyte‐derived exosomes contributes to NPC progression via targeting SCD1

“…A lot of research has shown that the hypoxic tumor microenvironment could cooperate to regulate malignant biological functions of tumor stromal cells and cancer cells. 5,6 Increasing evidence shows that almost all primary NPC tissues contain hypoxic regions which contribute to more and more distant metastases. 29 Adipocytes used to be considered to be one of the major sources for inflammatory cytokines such as IL-6 and several complement factors.…”

“…One critically essential, yet frequently ignored, part of cancer progression is the hypoxic microenvironment, 5 which includes tumor cells and stromal cells. Adipocytes are abundant cancer stromal cells 6 .…”

Thermal ablation in non-small cell lung cancer: a review of treatment modalities and the evidence for combination with immune checkpoint inhibitors

“…Aggressive outgrowth of residual hepatic micro-metastasis had been seen in the surrounding tissue of patients undergoing RFA of HCC (127). A hypoxic microenvironment that occurs in HCC post RFA has been shown to enhance the invasive, chemo-resistant and metastatic abilities of the tumour cells, these changes had been seen in patients that underwent incomplete ablation (128). Perhaps in contrast to lung cancer, a chronic inflammatory state in HCC patients may favour a tumour microenvironment that would enhance tumour growth, as suggested by the Th2 cell dominance pre and post RFA in hepatocellular carcinoma in patients with hepatitis C (129).…”