Sublethal heat treatment of hepatocellular carcinoma promotes intrahepatic metastasis and stemness in a VEGFR1-dependent manner

Tan, Li; Chen, Shu‐Ling; Wei, Guohong; Li, Yue; Liao, Junbin; Jin, Huilin; Zou, Ying; Huang, Manling; Peng, Zhenwei; Guo, Yu; Peng, Sui; Xu, Lixia; Kuang, Ming

doi:10.1016/j.canlet.2019.05.041

Cited by 50 publications

(50 citation statements)

References 43 publications

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“…Most patients still suffer from tumor recur, invasiveness, and metastasis. At present, sorafenib, a multiple tyrosine kinase inhibitor, is one of the most representative options for advanced HCC, but is sometimes limited and accompanied with reduced sensitivity and severe adverse events 3,4 . Therefore, much effort is needed on this front to uncover new anti-HCC therapeutic strategies 5 .…”

Section: Introductionmentioning

confidence: 99%

Homoharringtonine suppresses tumor proliferation and migration by regulating EphB4-mediated β-catenin loss in hepatocellular carcinoma

Zhu

Gong

et al. 2020

Cell Death Dis

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Overexpressed EphB4 conduce to tumor development and is regarded as a potential anticancer target. Homoharringtonine (HHT) has been approved for hematologic malignancies treatment, but its effect on hepatocellular carcinoma (HCC) has not been studied. This study elucidated HHT could restrain the proliferation and migration of HCC via an EphB4/β-catenindependent manner. We found that the antiproliferative activity of HHT in HCC cells and tumor xenograft was closely related to EphB4 expression. In HepG2, Hep3B and SMMC-7721 cells, EphB4 overexpression or EphrinB2 Fc stimulation augmented HHT-induced inhibitory effect on cell growth and migration ability, and such effect was abrogated when EphB4 was knocked down. The similar growth inhibitory effect of HHT was observed in SMMC-7721 and EphB4 + /SMMC-7721 cells xenograft in vivo. Preliminary mechanistic investigation indicated that HHT directly bound to EphB4 and suppressed its expression. Data obtained from HCC patients revealed increased β-catenin expression and a positive correlation between EphB4 expression and β-catenin levels. HHT-induced EphB4 suppression promoted the phosphorylation and loss of β-catenin, which triggered regulation of β-catenin downstream signaling related to migration, resulting in the reversion of EMT in TGF-β-induced HepG2 cells. Collectively, this study provided a groundwork for HHT as an effective antitumor agent for HCC in an EphB4/ β-catenin-dependent manner.

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Section: Introductionmentioning

confidence: 99%

Homoharringtonine suppresses tumor proliferation and migration by regulating EphB4-mediated β-catenin loss in hepatocellular carcinoma

Zhu

Gong

et al. 2020

Cell Death Dis

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“…Thus, a tumor with fewer microvessels is more likely to recur after a sublethal heat treatment. Furthermore, microvessel density was shown to be negatively correlated with TTP [20]; the larger the TTP, the smaller the microvessel density. A tumor with smaller TTP and larger microvessel density is less likely to recur ( Figure 5).…”

Section: Discussionmentioning

confidence: 95%

“…Time-intensity curves are analyzed to evaluate tumor response after antiangiogenic therapies [15][16][17]. However, there are few studies on the association between CEUS-assessed tumor perfusion and intrahepatic recurrence of HCC after RFA, and their results are controversial [18][19][20]. Hence, in this study, we used CEUS to evaluate the blood perfusion characteristics of HCC and analyzed perfusion parameters influencing HCC intrahepatic recurrence after RAF.…”

Section: Introductionmentioning

confidence: 99%

Quantitative dynamic contrast-enhanced ultrasound to predict intrahepatic recurrence of hepatocellular carcinoma after radiofrequency ablation: a cohort study

Han

Dong

Liu

et al. 2020

International Journal of Hyperthermia

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Purpose: Quantitative dynamic contrast-enhanced ultrasonography (CEUS) reflects tumor blood perfusion. There are very few studies on the relationship between intrahepatic recurrence of hepatocellular carcinoma (HCC) and tumor perfusion. We investigated the correlation of dynamic CEUS parameters with intrahepatic recurrence after radiofrequency ablation (RFA). Methods: This retrospective study enrolled 125 native HCC patients who underwent RFA between September 2017 and January 2019 with curative intent. Pre-ablation quantitative dynamic CEUS was performed. CEUS parameters were extracted from time-intensity curves. The correlation of CEUS parameters with intrahepatic recurrence was investigated. Results: The mean follow-up time was 21.6 ± 7.9 months. The recurrence rate was 33.6%. Univariate and multivariate analyses revealed that tumor peak intensity (PI) was a significant independent risk factor for intrahepatic recurrence after RFA (hazard ratio (HR), 0.3; 95% CI, 0.1-0.9). A PI of 58.8% (area under curve, 0.72; 95% CI, 0.63-0.81) was considered as the optimal cutoff level to predict the intrahepatic recurrence of HCC in patients after RFA. The recurrence-free survival rate in patients with a PI > 58.8% was 94.4% at 1 year and 77.8% at 2 years. Subgroup analysis showed that the HR of time to peak (TTP) in intrahepatic recurrence was 1.1417 (95% CI, 0.9748-1.1436; p ¼ 0.1973) in the patient group with tumor diameter > 31 mm. Conclusion: CEUS is commonly used in HCC patients who undergo RFA. The CEUS parameters PI and TTP are associated with intrahepatic recurrence after RFA, and can thus be used to identify patients at risk for intrahepatic recurrence.

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“…In addition to tumor size, incomplete RFA enhanced the invasiveness and metastasis of residual cancer in HCC cells (17,32). The aggressive biological behavior of recurrent tumors might cause poorly defined margins and irregular lesions on CEUS.…”

Section: Discussionmentioning

confidence: 99%

The Perfusion Features of Recurrent Hepatocellular Carcinoma After Radiofrequency Ablation Using Contrast-Enhanced Ultrasound and Pathological Stemness Evaluation: Compared to Initial Tumors

Bai

Wang

et al. 2020

Front. Oncol.

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Objective: To investigate the perfusion features of local recurrence in hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA) with contrast-enhanced ultrasound (CEUS) and pathological correlation, as well as to compare with those of initial HCC. Methods: From 2010 to 2018, 42 patients with recurrent HCC after RFA were enrolled in this study. The initial HCC patients included 32 males and 10 females with an average age of 58.2 ± 8.1 years. The CEUS images for initial HCC lesions and local recurrence after RFA were compared. The perfusion features were analyzed, including enhancement time, process, boundary, morphology, washout time, washout degree, feeding vessels, and internal necrosis. H&E staining and CD133/EpCAM staining were performed with biopsy samples for the stemness study. Conclusions: Recurrent HCC after RFA had more homogeneous enhancement with a poorly defined border, marked washout, and fewer less feeding vessels and inner necrosis areas compared to initial HCC. The stemness study also found upregulated stemness in recurrent HCC. These specific features might be related to the aggressive biological behavior of recurrent HCC.

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Sublethal heat treatment of hepatocellular carcinoma promotes intrahepatic metastasis and stemness in a VEGFR1-dependent manner

Cited by 50 publications

References 43 publications

Homoharringtonine suppresses tumor proliferation and migration by regulating EphB4-mediated β-catenin loss in hepatocellular carcinoma

Homoharringtonine suppresses tumor proliferation and migration by regulating EphB4-mediated β-catenin loss in hepatocellular carcinoma

Quantitative dynamic contrast-enhanced ultrasound to predict intrahepatic recurrence of hepatocellular carcinoma after radiofrequency ablation: a cohort study

The Perfusion Features of Recurrent Hepatocellular Carcinoma After Radiofrequency Ablation Using Contrast-Enhanced Ultrasound and Pathological Stemness Evaluation: Compared to Initial Tumors

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