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

Wu, Lun; Youshun, Zhang; Ye, Mengliang; Shen, Feng; Liu, Wei; Hu, Hong-Sheng; Li, Shengwei; Wu, Huifeng; Chen, Qinhua; Zhou, Wenbo

doi:10.3892/etm.2017.4428

Cited by 10 publications

(4 citation statements)

References 41 publications

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“…VEGF, a key factor in angiogenesis, and EphA2 are associated with endothelial cell migration, paracellular permeability and tumor neovascularization (30,31). Reportedly, EphA2 is involved in VEGF-induced vascular assembly and tumor angiogenesis, which are indicators of tumor recurrence and progression (32,33). Previously, it was revealed that EphA2 activation in gastric cancer cells was triggered by VEGF release upon treatment with CAF-CM (14).…”

Section: Discussionmentioning

confidence: 99%

Role of EphA2‑PI3K signaling in vasculogenic mimicry induced by cancer‑associated fibroblasts in gastric cancer cells

et al. 2019

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Although erythropoietin-producing human hepatocellular receptor A2 (EphA2) signaling serves an important role in the tumor microenvironment, its contribution to vasculogenic mimicry (VM) formation in gastric cancer cells remains unclear. The aim of the present study was to investigate the role of EphA2 in VM formation induced by cancer-associated fibroblasts (CAFs). The conditioned medium of CAFs (CAF-CM) was prepared from 12 patients with gastric adenocarcinoma. VM was evaluated by the number of tubules and intersections in gastric cancer cells following CAF-CM treatment. The role of EphA2-phosphoinositide 3-kinase (PI3K) in VM was investigated using EphA2-targeted small interfering (si)RNAs (siEphA2), EphA2 inhibitors and PI3K-inhibitors. CAF-CM-induced VM formation was significantly associated with high protein expression levels of EphA2. EphA2 inhibitor and siEphA2 manipulation significantly decreased VM formation by CAF-CM. In siEphA2 cells, decreased expression levels of VM-associated proteins were observed. CAF-CM-induced VM formation was blocked by the PI3K-inhibitor. In conclusion, CAFs facilitate VM formation via EphA2-PI3K signaling in gastric cancer cells. Thus, EphA2-PI3K signaling may be required for CAF-promoted VM formation during gastric tumorigenesis.

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Section: Discussionmentioning

confidence: 99%

Role of EphA2‑PI3K signaling in vasculogenic mimicry induced by cancer‑associated fibroblasts in gastric cancer cells

et al. 2019

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“…Therefore, the authors suggested HIFU ablation might result in the hypoxia condition of residual tumor and induce tumor angiogenesis via HIF-1, 2α/VEGFA/EphA2 (Wu et al, 2014). Two other studies conducted by Wu et al (2017); Wu et al (2021) also demonstrated that overexpression of EphA2, VEGFA, and HIF-2α were closely associated with angiogenesis in residual HCC after HIFU ablation. Moreover, the expression of EphA2, VEGFA, and HIF-2α could be significantly inhibited by sorafenib (Wu et al, 2021).…”

Section: Clinical Implications Of Hif-1α In Hcc After Ablationmentioning

confidence: 96%

Roles of hypoxia-inducible factor in hepatocellular carcinoma under local ablation therapies

Xiao

Liu

et al. 2023

Front. Pharmacol.

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Hepatocellular carcinoma (HCC) is one of the most common digestive malignancies. HCC It ranges as the fifth most common cause of cancer mortality worldwide. While The prognosis of metastatic or advanced HCC is still quite poor. Recently, locoregional treatment, especially local ablation therapies, plays an important role in the treatment of HCC. Radiofrequency ablation (RFA) and high-intensity focused ultrasound (HIFU) ablation are the most common-used methods effective and feasible for treating HCC. However, the molecular mechanisms underlying the actions of ablation in the treatments for HCC and the HCC recurrence after ablation still are poorly understood. Hypoxia-inducible factor (HIF), the key gene switch for adaptive responses to hypoxia, has been found to play an essential role in the rapid aggressive recurrence of HCC after ablation treatment. In this review, we summarized the current evidence of the roles of HIF in the treatment of HCC with ablation. Fifteen relevant studies were included and further analyzed. Among them, three clinical studies suggested that HIF-1α might serve as a crucial role in the RAF treatment of HCC or the local recurrence of HCC after RFA. The remainder included experimental studies demonstrated that HIF-1, 2α might target the different molecules (e.g., BNIP3, CA-IX, and arginase-1) and signaling cascades (e.g., VEGFA/EphA2 pathway), constituting a complex network that promoted HCC invasion and metastasis after ablation. Currently, the inhibitors of HIF have been developed, providing important proof of targeting HIF for the prevention of HCC recurrence after IRFA and HIFU ablation. Further confirmation by prospective clinical and in-depth experimental studies is still warranted to illustrate the effects of HIF in HCC recurrence followed ablation treatment in the future.

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“…However, at lower intensities (0.1–1.0 W/cm 2 ), FUS is not cytotoxic and has, in fact, been shown to stimulate cell proliferation, as demonstrated in studies with bone marrow stem cells and peripheral neuronal cells [ 18 , 19 ]. In addition, recent evidence shows that standalone HIFU may promote tumor recurrence and progression in aggressive liver cancer [ 20 ] and cannot prevent rapid tumor recurrence in ~50% of patients with intermediate-risk (T2b) or high-risk (T2c-T4), localized PCa [ 21 , 22 ]. Therefore, it is envisioned that the utility of moderate FUS doses (0.1–0.9 kW/cm 2 ) may have profound clinical application towards a targeted elimination of localized PCa, and novel strategies to enhance the anticancer efficacy of FUS are clearly warranted.…”

Section: Introductionmentioning

confidence: 99%

Pre-Exposure to Stress-Inducing Agents Increase the Anticancer Efficacy of Focused Ultrasound against Aggressive Prostate Cancer Cells

et al. 2022

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Despite the initial success in treatment of localized prostate cancer (PCa) using surgery, radiation or hormonal therapy, recurrence of aggressive tumors dictates morbidity and mortality. Focused ultrasound (FUS) is being tested as a targeted, noninvasive approach to eliminate the localized PCa foci, and strategies to enhance the anticancer potential of FUS have a high translational value. Since aggressive cancer cells utilize oxidative stress (Ox-stress) and endoplasmic reticulum stress (ER-stress) pathways for their survival and recurrence, we hypothesized that pre-treatment with drugs that disrupt stress-signaling pathways in tumor cells may increase FUS efficacy. Using four different PCa cell lines, i.e., LNCaP, C4-2B, 22Rv1 and DU145, we tested the in vitro effects of FUS, alone and in combination with two clinically tested drugs that increase Ox-stress (i.e., CDDO-me) or ER-stress (i.e., nelfinavir). As compared to standalone FUS, significant (p < 0.05) suppressions in both survival and recurrence of PCa cells were observed following pre-sensitization with low-dose CDDO-me (100 nM) and/or nelfinavir (2 µM). In drug pre-sensitized cells, significant anticancer effects were evident at a FUS intensity of as low as 0.7 kW/cm2. This combined mechanochemical disruption (MCD) approach decreased cell proliferation, migration and clonogenic ability and increased apoptosis/necrosis and reactive oxygen species (ROS) production. Furthermore, although activated in cells that survived standalone FUS, pre-sensitization with CDDO-me and/or nelfinavir suppressed both total and activated (phosphorylated) NF-κB and Akt protein levels. Thus, a combined MCD therapy may be a safe and effective approach towards the targeted elimination of aggressive PCa cells.

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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

Cited by 10 publications

References 41 publications

Role of EphA2‑PI3K signaling in vasculogenic mimicry induced by cancer‑associated fibroblasts in gastric cancer cells

Role of EphA2‑PI3K signaling in vasculogenic mimicry induced by cancer‑associated fibroblasts in gastric cancer cells

Roles of hypoxia-inducible factor in hepatocellular carcinoma under local ablation therapies

Pre-Exposure to Stress-Inducing Agents Increase the Anticancer Efficacy of Focused Ultrasound against Aggressive Prostate Cancer Cells

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