Insufficient Radiofrequency Ablation Promotes Angiogenesis of Residual Hepatocellular Carcinoma via HIF-1α/VEGFA

Kong, Jian; Kong, Jinge; Pan, Bing; Shi, Ke; Dong, Shuying; Li, Xiuli; Zhou, Aimin; Zheng, Lemin; Sun, Wen

doi:10.1371/journal.pone.0037266

Cited by 114 publications

(139 citation statements)

References 48 publications

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“…Of note, previously untreated patients had more advanced-stage intrahepatic tumors compared to previously treated patients. Previous studies suggested that residual HCC following various treatments is associated with increased malignant potential compared to untreated HCC (16)(17)(18). Therefore, we suggest that aggressive treatment may result in earlier extrahepatic metastasis, despite a less advanced intrahepatic tumor stage, in previously treated patients.…”

Section: Discussionmentioning

confidence: 65%

Clinical characteristics and prognostic factors for advanced hepatocellular carcinoma with extrahepatic metastasis

Aino

Sumie

Nishizaki

et al. 2014

Molecular and Clinical Oncology

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Abstract. Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. The aim of this study was to evaluate whether there are differences in the clinical characteristics and survival between patients with advanced HCC with extrahepatic metastasis who received and those who did not receive previous treatment. Between April, 1998 and April, 2012, a total of 419 HCC patients with extrahepatic metastasis (81 previously untreated and 338 previously treated) were enrolled in this study. The differences in the clinical characteristics, including metastatic sites, were compared between the two groups. In addition, the prognostic predictors among all the patients and among the 81 previously untreated patients were analyzed. The distribution of the major metastatic sites was similar in the two groups; the most frequent site of extrahepatic metastasis was the lungs, followed by the bones, lymph nodes and adrenal glands. The median survival time (MST) among the 419 patients was 6.8 months. The 1-, 2-, 3-and 5-year survival rates were 31.6, 15.3, 9.5 and 2.3%, respectively. No significant differences in survival were observed between patients who received and those who did not receive previous treatment. The multivariate analysis revealed that the Child-Pugh classification, white blood cell count, neutrophil-lymphocyte ratio (NLR) and primary tumor stage were independent predictors of survival for all the patients and for the 81 previously untreated patients. Differences in the clinical characteristics of patients with advanced HCC with extrahepatic metastasis were identified between patients who received and those who did not receive previous treatment. Furthermore, intrahepatic tumor status, Child-Pugh classification, white blood cell count and NLR were demonstrated to be independent predictors of survival in HCC patients with extrahepatic metastasis. IntroductionHepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Recent advances in imaging technology and implementation of surveillance programs for high-risk patients have led to increased detection of early-stage HCC, making curative therapies possible in some patients (1,2). However, the long-term survival of HCC patients remains unsatisfactory, due to the high frequency of intra-and extrahepatic recurrence (3,4). In particular, the development of advanced HCC with extrahepatic metastasis hinders the use of curative therapies, such as surgical resection or radiofrequency ablation, therefore contributing to poor survival. Prior to the approval of sorafenib, several systemic chemotherapeutic regimens had been evaluated for patients with advanced HCC, although no effective therapeutic protocols were identified (5,6). Two randomized placebo-controlled trials demonstrated a survival benefit associated with sorafenib for patients with advanced HCC, including those with extrahepatic metastasis (7,8). As a result, sorafenib is currently considered to be the standard treatment for advanced HCC in the United States, Europe, Japan ...

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Section: Discussionmentioning

confidence: 65%

Clinical characteristics and prognostic factors for advanced hepatocellular carcinoma with extrahepatic metastasis

Aino

Sumie

Nishizaki

et al. 2014

Molecular and Clinical Oncology

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“…Resistance to therapy, and tumor progression, is increased by the ability of HCC cells to resist adverse environmental conditions, such as hypoxia. Locoregional therapies, such as transarterial embolization, which result in ischemic necrosis but tumor cell survival within hypoxic regions, might contribute to incomplete eradication or tumor recurrence (Shim et al, 2008;Gadaleta and Ranieri, 2011;Kong et al, 2012). Although the ability of tumors to survive during hypoxia is a crucial determinant of therapeutic response and tumor progression, the cellular mechanisms by which tumor cells respond to, and survive during, hypoxia are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Modulation of hypoxia-signaling pathways by extracellular long non-coding RNA regulator of reprogramming

Takahashi

Yan

Haga

et al. 2014

Journal of Cell Science

219

189

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Resistance to adverse environmental conditions, such as hypoxia, contributes to the reduced efficacy of anticancer therapies and tumor progression. Although deregulated expression of many long noncoding RNA (lncRNA) occurs in human cancers, the contribution of such RNA to tumor responses to hypoxia are unknown. RNA expression profiling identified several hypoxiaresponsive lncRNAs, including the long intergenic noncoding RNA, regulator of reprogramming (linc-RoR), which is also increased in expression in malignant liver cancer cells. Linc-RoR expression was increased in hypoxic regions within tumor cell xenografts in vivo. Tumor cell viability during hypoxia was reduced by small interfering RNA (siRNA) to linc-RoR. Compared with controls, siRNA to linc-RoR decreased phosphorylation of p70S6K1 (RPS6KB1), PDK1 and HIF-1a protein expression and increased expression of the linc-RoR target microRNA-145 (miR-145). LincRoR was highly expressed in extracellular RNA released by hepatocellular cancer (HCC) cells during hypoxia. Incubation with extracellular vesicle preparations containing extracellular RNA increased linc-RoR, HIF-1a expression and cell survival in recipient cells. These studies show that linc-RoR is a hypoxia-responsive lncRNA that is functionally linked to hypoxia signaling in HCC through a miR-145-HIF-1a signaling module. Furthermore, this work identifies a mechanistic role for the extracellular transfer of linc-RoR in intercellular signaling to promote cell survival during hypoxic stress.

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“…VEGFA is among the most potent angiogenic factors expressed in various human cancers, including HCC (28). VEGFA is a hexose-modified multifunctional protein that acts specifically on vascular endothelial cells, whereby it induces micro-angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Overexpression and correlation of HIF-2α, VEGFA and EphA2 in residual hepatocellular carcinoma following high-intensity focused ultrasound treatment: Implications for tumor recurrence and progression

Youshun

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. Rapid growth of residual tumors can occur as a result of their recurrence and progression. The present study aimed to investigate the expression of hypoxia inducible factor-2 subunit α (HIF-2α), vascular endothelial growth factor A (VEGFA), erythropoietin-producing hepatocellular A2 (EphA2) and angiogenesis in residual hepatocellular carcinoma (HCC), following treatment with high-intensity focused ultrasound (HIFU) ablation, in order to investigate the association between protein expression and tumor recurrence and growth. Athymic BALB/c (nu/nu) mice were subcutaneously inoculated with the HCC cell line HepG2, in order to create xenograft tumors. Approximately 30 days post-inoculation, eight mice were treated with HIFU, whereas eight mice received no treatment and acted as the control group. Residual tumor tissues were obtained from the experimental groups after one month. Levels of HIF-2α, VEGFA, EphA2 and cluster of differentiation 31 (CD31) expression was measured by immunohistochemical staining. CD31-positive vascular endothelial cells were counted to calculate microvascular density (MVD), and western blot analysis was performed to determine levels of HIF-2α, VEGFA, and EphA2 protein. It was found that the expression levels of HIF-2α, VEGFA, EphA2, and MVD proteins in residual HCC tissues were significantly higher than in the control group tissues (P<0.05). Tumor MVD was strongly correlated with VEGFA (R=0.957, P<0.01) and EphA2 (R=0.993, P<0.01) protein expression levels. Furthermore, there was a significant positive correlation between HIF-2α and EphA2 expression (R=0.991, P<0.01). The correlation between VEGFA and EphA2 expression was also positive (R=0.985, P<0.01). These data suggest that overexpression of HIF-2α, VEGFA and EphA2 is related to angiogenesis in residual HCC following HIFU ablation, potentially via their association with key mediators of recurrence.

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Insufficient Radiofrequency Ablation Promotes Angiogenesis of Residual Hepatocellular Carcinoma via HIF-1α/VEGFA

Cited by 114 publications

References 48 publications

Clinical characteristics and prognostic factors for advanced hepatocellular carcinoma with extrahepatic metastasis

Clinical characteristics and prognostic factors for advanced hepatocellular carcinoma with extrahepatic metastasis

Modulation of hypoxia-signaling pathways by extracellular long non-coding RNA regulator of reprogramming

Overexpression and correlation of HIF-2α, VEGFA and EphA2 in residual hepatocellular carcinoma following high-intensity focused ultrasound treatment: Implications for tumor recurrence and progression

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