Insufficient radiofrequency ablation promotes proliferation of residual hepatocellular carcinoma via autophagy

Zhao, Zizhuo; Wu, Jiayi; Liu, Xiaodi; Ming, Liang; Zhou, Xiaolin; Ouyang, Shi; Jiang, Yao; Wang, Jinquan; Luo, Baoming

doi:10.1016/j.canlet.2018.02.024

Cited by 53 publications

(58 citation statements)

References 56 publications

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“…Therefore, heat treatment at 47 C for 30 min was selected for subsequent experiments. However, in this study, we found that cell proliferation was significantly suppressed after sublethal heat stress, which contradicts previous finding [14]. This discrepancy may be due to differences in experimental models and procedures.…”

Section: Discussioncontrasting

confidence: 99%

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Targeting autophagy enhances heat stress-induced apoptosis via the ATP-AMPK-mTOR axis for hepatocellular carcinoma

Jiang

Chen

et al. 2019

International Journal of Hyperthermia

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Purpose: Radiofrequency ablation (RFA) is widely accepted as a curative treatment for small hepatocellular carcinoma (HCC). However, insufficient RFA (IRFA) can lead to rapid local recurrence. The underlying mechanisms remain poorly understood. This study aimed to elucidate the role and regulatory mechanisms of autophagy in the recurrence of HCC after IRFA. Materials and methods: SMMC7721 and Huh7 cells were exposed to sublethal heat stress to stimulate the transition zone of IRFA treatment. The levels of autophagy were measured by western blot, immunofluorescence and transmission electron microscopy. Functional assays, such as CCK-8, EdU incorporation and flow cytometry, were performed to determine the role of heat-induced autophagy. The involved signaling pathways were explored by western blot. Finally, the antitumor effects of chloroquine (CQ) on heat-treated HCC cells were evaluated via an in vivo xenograft tumor model. Results: Sublethal heat stress induced autophagy in a temperature-and time-dependent manner in HCC cells. Furthermore, the inhibition of autophagy by CQ or siRNA targeting the autophagy-related genes Beclin-1 and Atg5 enhanced heat-induced apoptosis. The combination of CQ and heat treatment significantly suppressed tumor growth both in vitro and in vivo. Mechanistically, we reported for the first time that the ATP-AMPK-mTOR signaling pathway was involved in heat-induced autophagy. Conclusions: Heat stress induced protective autophagy against heat-induced apoptosis in HCC via the ATP-AMPK-mTOR axis, suggesting that targeting autophagy may be a promising strategy for improving the efficacy of RFA treatment for HCC.

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Section: Discussioncontrasting

confidence: 99%

“…Previous studies showed that sublethal heat stress induces autophagy in several human cancer cell lines, such as HeLa and A549 cells [12]. Recent studies reported that IRFA promotes the progression of residual HCC via autophagy [13,14]. These findings strongly support a correlation between autophagy and HCC progression after IRFA.…”

Section: Introductionmentioning

confidence: 52%

Targeting autophagy enhances heat stress-induced apoptosis via the ATP-AMPK-mTOR axis for hepatocellular carcinoma

Jiang

Chen

et al. 2019

International Journal of Hyperthermia

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“…A combination of these treatments with an autophagy inhibitor (e.g. (hydroxy)chloroquine, 3-MA and Lys05) was associated with enhanced tumour cell necrosis and apoptosis, [148][149][150][151] suggesting that inhibiting autophagy to target residual tumour cells could be beneficial. Moreover, autophagy is implicated in tumour cells' resistance to systemic treatments.…”

Section: Targeting Autophagy In Hepatocellular Carcinoma: a Complex Amentioning

confidence: 99%

Autophagy in liver diseases: Time for translation?

Allaire

Rautou

Codogno

et al. 2019

Journal of Hepatology

299

222

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Autophagy is a self-eating catabolic pathway that contributes to liver homeostasis through its role in energy balance and in the quality control of the cytoplasm, by removing misfolded proteins, damaged organelles and lipid droplets. Autophagy not only regulates hepatocyte functions but also impacts on non-parenchymal cells, such as endothelial cells, macrophages and hepatic stellate cells. Deregulation of autophagy has been linked to many liver diseases and its modulation is now recognized as a potential new therapeutic strategy. Indeed, enhancing autophagy may prevent the progression of a number of liver diseases, including storage disorders (alpha-1 antitrypsin deficiency, Wilson's disease), acute liver injury, non-alcoholic steatohepatitis and chronic alcohol-related liver disease. Nevertheless, in some situations such as fibrosis, targeting specific liver cells must be considered, as autophagy displays opposing functions depending on the cell type. In addition, an optimal therapeutic time-window should be identified, since autophagy might be beneficial in the initial stages of disease, but detrimental at more advanced stages, as in the case of hepatocellular carcinoma. Finally, identifying biomarkers of autophagy and methods to monitor autophagic flux in vivo are important steps for the future development of personalized autophagy-targeting strategies. In this review, we provide an update on the regulatory role of autophagy in various aspects of liver pathophysiology, describing the different strategies to manipulate autophagy and discussing the potential to modulate autophagy as a therapeutic strategy in the context of liver diseases.

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“…Autophagy is a fundamentally protective mechanism of cell survival against various stresses [35,36]. Recently, two studies have shown that activation of autophagy is induced by incomplete RFA [18,37]. In this study, we add to the growing body of knowledge by focusing on activated HSCs in tumor microenvironment that modulates autophagic survival and proliferation of heat-treated residual HCC cells, leading to residual HCC recurrence and progression.…”

Section: Discussionmentioning

confidence: 95%

“…Autophagy is an evolutionarily conserved protective mechanism to recycle energy for cell homeostasis in response to various stresses including anticancer therapies (e.g., chemotherapy, radiation, heat) [14][15][16][17][18]. Therefore, it could be speculated that autophagy of HCC cells took place under thermal treatment, leading to survival of microscopic residual HCC cells undetected by radiological imaging but eventually converted to active growth under appropriate conditions.…”

Section: Introductionmentioning

confidence: 99%

Activated hepatic stellate cells promote progression of post-heat residual hepatocellular carcinoma from autophagic survival to proliferation

Zhang

Lin

Liu

et al. 2019

International Journal of Hyperthermia

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Background: Microscopic residual tumor often occurs after thermal ablation for medium-large hepatocellular carcinoma (HCC), leading to early aggressive recurrence or late relapse during follow-up. The mechanism how microscopic residual HCC cells survive sublethal heat stress and develop rapid outgrowth remains poorly understood. Methods: HCC cells were exposed to sublethal heat treatment and co-cultured with conditioned media from activated HSCs (HSC-CM). Changes of cell proliferation, parameters of cell autophagy and activation of signaling pathways in heat-treated residual HCC cells were analyzed. An HCC orthotopic model was subjected to partial thermal ablation and antitumor effects of a combined treatment regimen were studied. Results: HCC cells survived sublethal heat stress via activation of autophagy. HSC-CM enhanced autophagic survival within 24 h and then promoted proliferation of heat-treated residual HCC cells through HGF/c-Met signaling. Inhibition of autophagy or c-Met increased apoptosis of heat-treated residual HCC cells and reversed the protective effect of HSC-CM. HGF modulated biological status in autophagic survival or proliferation of heat-treated residual HCC through HGF/c-Met/ERK signaling and downstream components of ATG5/Beclin1 or cyclinD1. In an animal model, inhibiting autophagy in combination with c-Met inhibitor significantly thwarted tumor progression of residual HCC after incomplete thermal ablation via the suppressed autophagy, the decreased proliferation and the increased apoptosis. Conclusions: Activated HSCs promote progression of residual HCC cells after sublethal heat treatment from autophagic survival to proliferation via HGF/c-Met signaling. A combined treatment regimen of inhibiting autophagy and c-Met signaling could be used to suppress tumor progression of residual HCC after incomplete thermal ablation. ARTICLE HISTORY

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Insufficient radiofrequency ablation promotes proliferation of residual hepatocellular carcinoma via autophagy

Cited by 53 publications

References 56 publications

Targeting autophagy enhances heat stress-induced apoptosis via the ATP-AMPK-mTOR axis for hepatocellular carcinoma

Targeting autophagy enhances heat stress-induced apoptosis via the ATP-AMPK-mTOR axis for hepatocellular carcinoma

Autophagy in liver diseases: Time for translation?

Activated hepatic stellate cells promote progression of post-heat residual hepatocellular carcinoma from autophagic survival to proliferation

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