Thermal Injury–induced Hepatic Parenchymal Hypoperfusion: Risk of Hepatocellular Carcinoma Recurrence after Radiofrequency Ablation

Lee, Dong Hoon; Lee, Jeong Min; Yoon, Jung Hwan; Kim, Yoon Jun; Han, Joon Koo

doi:10.1148/radiol.2016152322

“…A chronically hypoxic tissue zone can be generated following thermal ablation, where the microenvironment of any residual viable cells may be altered . The development of RFA‐induced hepatic parenchymal hypoxia is associated with an increased risk of recurrence . Moreover RFA could accelerate the outgrowth of colorectal liver metastases in a hypoxia‐driven manner .…”

Section: Discussionmentioning

confidence: 99%

“…(20) The development of RFA-induced hepatic parenchymal hypoxia is associated with an increased risk of recurrence. (21) Moreover RFA could accelerate the outgrowth of colorectal liver metastases in a hypoxia-driven manner. (22) Fig.…”

Section: Discussionmentioning

confidence: 99%

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

Tong

¹

,

Yang

²

,

Xu

³

et al. 2017

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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.

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“…(20) The development of RFA-induced hepatic parenchymal hypoxia is associated with an increased risk of recurrence. (21) Moreover RFA could accelerate the outgrowth of colorectal liver metastases in a hypoxia-driven manner. The expression levels of HIF-1a in MHCC97H and SMMC7721 cells were examined by western blot.…”

Section: Discussionmentioning

confidence: 99%

Effect of a Hypoxic Microenvironment after Radiofrequency Ablation on Residual Hepatocellular Cell Migration and Invasion

Tong

¹

,

Luo

²

2017

Ultrasound in Medicine & Biology

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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) ...

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“…The changes of those molecules in a time-dependent manner were confirmed by Western blotting (Figure 1(C)). RFA treatment not only induces tumor necrosis, but also disrupts the blood supply [21]. To mimic the poorly vascular microenvironment following RFA [21], heat-treated residual HCC cells were incubated in culture media with 1% FBS representative of ischemic condition.…”

Section: Hcc Cells Survived Sublethal Heat Treatment Via Autophagymentioning

confidence: 99%

“…RFA treatment not only induces tumor necrosis, but also disrupts the blood supply [21]. To mimic the poorly vascular microenvironment following RFA [21], heat-treated residual HCC cells were incubated in culture media with 1% FBS representative of ischemic condition. As shown in Figure 1(D), growth kinetics of heat-treated residual HCC cells were further slowdowned in ischemic condition (1% FBS) compared with standard condition (10% FBS).…”

Section: Hcc Cells Survived Sublethal Heat Treatment Via Autophagymentioning

confidence: 99%

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

Zhang

¹

,

Lin

²

,

Liu

³

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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Thermal Injury–induced Hepatic Parenchymal Hypoperfusion: Risk of Hepatocellular Carcinoma Recurrence after Radiofrequency Ablation

Cited by 17 publications

References 30 publications

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

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

Effect of a Hypoxic Microenvironment after Radiofrequency Ablation on Residual Hepatocellular Cell Migration and Invasion

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

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