Pathophysiology of recurrent hepatocellular carcinoma after radiofrequency ablation

Abstract

Radiofrequency ablation (RFA) is effective for the local control of hepatocellular carcinoma (HCC), particularly when a patient's liver functional reserve does not allow radical resection. There is controversy regarding the superiority of surgical resection compared with RFA for such patients, particularly those with three or fewer tumors with diameters ≤3 cm. Moreover, HCC often recurs after RFA, and the tumor cells show distinct phenotypic changes. Incomplete ablation accounts for tumor recurrence, and recent studies provide new insights into the biological mechanisms responsible for the pathological changes of HCC after RFA. This review focuses on the roles of epithelial-mesenchymal transition and cancer stemness that are driven by a mechanism that involves microRNA-mediated upregulation of hypoxia-inducible factor-1. The studies reviewed here provide compelling evidence that complete ablation of HCC is required to prevent recurrence and indicate that further research is urgently required to develop a new systematic strategy to prevent tumor recurrence by targeting hypoxia-inducible factor-1.

Novel approaches for molecular targeted therapy against hepatocellular carcinoma

“…Hepatocellular carcinoma occurs in the background of chronic hepatitis or cirrhosis, which leads to frequent recurrence after curative therapy. In fact, patients with HCC have a high risk of tumor recurrence even after local curative treatment by either surgical resection or RFA . The recurrence rate of HCC is 15–30% within 1 year, and approximately 80% in 5 years, even after curative therapy .…”

Activation of extracellular signal‐regulated kinase is associated with hepatocellular carcinoma with aggressive phenotypes

“…A subset of HCC; that is, tumors expressing biliary/stem cell markers (including keratin 19 [KRT19, also known as cytokeratin 19, K19, or CK19] and sal‐like protein 4) or those with a high proliferative activity, shows rapid tumor growth and a high metastatic rate, whereas most HCCs grow relatively slowly and are often treatable even after disease recurrence. Sorafenib, a multikinase inhibitor, is widely used as the first‐line treatment for advanced HCC, especially HCC with extrahepatic spread or vascular invasion, although the antitumor effects are insufficient for controlling large and multinodular HCC, and for preventing tumor recurrence in the surrounding inflamed liver after treatment . Other types of multikinase inhibitors have also proven effective against unresectable HCC, thereby underscoring the importance of signaling pathways triggered by tyrosine kinase receptors in the progression of HCC, which has a potential for promising new targeting therapies for HCC .…”

“…Sorafenib, a multikinase inhibitor, is widely used as the first-line treatment for advanced HCC, especially HCC with extrahepatic spread or vascular invasion, [5][6][7] although the antitumor effects are insufficient for controlling large and multinodular HCC, and for preventing tumor recurrence in the surrounding inflamed liver after treatment. 8,9 Other types of multikinase inhibitors have also proven effective against unresectable HCC, 10-12 thereby underscoring the importance of signaling pathways triggered by tyrosine kinase receptors in the progression of HCC, which has a potential for promising new targeting therapies for HCC. 13 However, biomarkers that can predict the response of HCC to these targeted therapies are currently unavailable.…”

<b>DEC1 promotes hypoxia-induced epithelial-mesenchymal transition (EMT) in human hepatocellular carcinoma </b><b>cells </b>

“…Intratumoral hypoxia followed by stabilization of hypoxia-inducible factor (HIF)-1α promotes acquisition of EMT-like features in various kinds of carcinomas (2, 9, 11, 18) as well as hematopoietic tumors (1). Several studies have reported that HIF-1α overexpression is positively correlated with EMT induction in hepatocellular carcinoma (HCC) cell lines and surgical resection specimens (7,8,20). In addition, hypoxia-induced EMT resulted in multidrug resistance in HCC cells (16), tumor metastasis after transcatheter arterial embolization (TAE) (4), and poor prognosis in HCC patients (6).…”