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OBJECTIVES: To compare the safety and efficacy of microwave ablation (MWA) and radiofrequency ablation (RFA) for such hemangiomas (5-9.9 cm in diameter). METHODS: This multicenter retrospective cohort study investigated the differences in technical success, ablation time, complete ablation, complications, hospital stay, and clinical response between MWA and RFA. A total of 452 patients with hepatic hemangiomas were screened. Propensity score matching was performed. Univariable and multivariate regression analyses were used. RESULTS: Among the 452 patients, 394 met the eligibility criteria and completed the follow-up. After the propensity score matching analysis, 72 pairs of patients were created. No technical failures were found. The RFA group had a longer ablation time (48.63 ± 18.11 min versus [vs.] 37.18 ± 15.86 min, p < 0.001), higher morbidity of hemoglobinuria (77.78% vs. 50.00%, p < 0.001), and longer hospital stay (5.01 ± 1.56 days vs. 4.34 ± 1.42 days, p < 0.05) than the MWA group. The treatment methods (p = 0.032, OR = 0.105, 95% CI = 0.013-0.821), size of the hemangioma (p = 0.021, OR = 5.243, 95% CI = 1.285-21.391), and time of ablation (p = 0.031, OR = 1.145, 95% CI = 1.013-1.294) were significant independent risk factors associated with hemoglobinuria. No recurrence or delayed complications were observed. There were no differences in complete ablation, clinical response, and health-related quality of life between the groups. CONCLUSIONS: MWA and RFA appear to be effective treatments for large hepatic hemangiomas. However, MWA had a shorter ablation time than RFA, and MWA was associated with fewer hemolysis-related complications and shorter hospital stays. KEY POINTS: ⢠MWA and RFA appear to be effective treatments for large hepatic hemangiomas. ⢠MWA had a shorter ablation time than RFA. ⢠MWA was associated with fewer hemolysis-related complications and shorter hospital stays.
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Carcinoma Hepatocelular , Ablación por Catéter , Hemangioma , Neoplasias Hepáticas , Ablación por Radiofrecuencia , Carcinoma Hepatocelular/terapia , Femenino , Hemangioma/cirugía , Hemoglobinuria/etiología , Hemoglobinuria/cirugía , Hemólisis , Humanos , Neoplasias Hepáticas/terapia , Masculino , Microondas/uso terapéutico , Puntaje de Propensión , Calidad de Vida , Ablación por Radiofrecuencia/métodos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: To report the safety and effectiveness of laparoscopic intratumoral resection facilitated by coagulation (LIRC) compared with laparoscopic hepatectomy (LH) in treating giant hepatic hemangioma. METHODS: From 2017 to 2020, 19 consecutive patients with giant hepatic hemangioma (≥ 10 cm) received LIRC in one center. We selected a subgroup of 103 patients treated by LH in other four centers who well matched the 19 consecutive patients treated with LIRC, in a 1:1 fashion based on the tumor location, tumor size, and body mass index. Furthermore, the differences in technical success, operative time, operative blood loss, change of laboratory indexes, hospital stays, complication and clinical responds are compared between the two groups. RESULTS: Technical success was achieved in all 38 patients. Patients in the LIRC group had a relative shorter operative time (P < 0.001) and less operative blood loss (P = 0.003). The serum levels of C-reactive protein (CRP), total bilirubin (TBil), alanine aminotransferase (ALT), and aspartate transaminase (AST) were elevated significantly (P < 0.05) 1 day after the resection and returned to normal within 7 days in both groups; however, relatively lower serum levels of those indexes were observed in the LIRC group (P < 0.05). The total complication rate was relatively lower in the LIRC group compared with the LH group (P = 0.029). Patients in the LIRC group had shorter hospital stays than those in the LH group (P = 0.010). The clinical response was similar in the two groups. CONCLUSIONS: LIRC is safe and effective for treating giant hepatic hemangioma.
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Hemangioma , Laparoscopía , Neoplasias Hepáticas , Pérdida de Sangre Quirúrgica , Estudios de Casos y Controles , Hemangioma/cirugía , Hepatectomía/efectos adversos , Humanos , Laparoscopía/efectos adversos , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/cirugía , Tempo Operativo , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
OBJECTIVES: Angiogenesis occurs during tumor progression of hepatocellular carcinoma (HCC) after insufficient radiofrequency ablation (RFA). Arsenic trioxide (ATO) shows promising therapeutic potential in advanced HCC. Whether ATO regulates angiogenesis and can be used to prevent tumor progression in HCC after insufficient RFA is still unknown. METHODS: Insufficient RFA was simulated using a water bath. MTT assay and tube formation assay were used to evaluate the effects of ATO on viability and proangiogenic abilities of SMMC7721 and HepG2 cells after insufficient RFA in vitro. The molecular changes with the treatment of ATO were evaluated through Western blot. An ectopic nude mice model was used to evaluate the effect of ATO on the tumor of SMMC7721 cells in vivo after insufficient RFA. RESULTS: In this study, HepG2 and SMMC7721 cells after insufficient RFA (named HepG2-H and SMMC7721-H, respectively) showed higher proliferation than the untreated cells and promoted tube formation of endothelial cells in a paracrine manner. ATO eliminated the difference in proliferation between untreated and RFA-treated cells and suppressed angiogenesis induced by HCC cells after insufficient RFA through the Ang-1 (angiopoietin-1)/Ang-2 (angiopoietin-2)/Tie2 pathway. Hif-1α overexpression abolished the inhibitory effect of ATO on angiogenesis in HCC after insufficient RFA. ATO inhibited tumor growth and angiogenesis in HCC after insufficient RFA. CONCLUSIONS: Our results demonstrate that ATO blocks the paracrine signaling of Ang-1 and Ang-2 by inhibiting p-Akt/Hif-1α and further suppresses the angiogenesis of HCC after insufficient RFA.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Ablación por Radiofrecuencia , Angiopoyetina 1/uso terapéutico , Angiopoyetina 2/uso terapéutico , Animales , Trióxido de Arsénico/farmacología , Trióxido de Arsénico/uso terapéutico , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Células Endoteliales/metabolismo , Células Endoteliales/patología , Neoplasias Hepáticas/patología , Ratones , Ratones Desnudos , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/patología , Ablación por Radiofrecuencia/métodosRESUMEN
Background: Platelets play important roles in tumorigenesis, angiogenesis and metastatic dissemination of tumor cells. Radiofrequency ablation (RFA) could increase the circulating tumor cells in patients with primary or metastatic lung tumors. Whether platelet lysates in hepatocellular carcinoma (HCC) after RFA promote tumor progression has not been elaborated. Methods: HCC patients within Milan Criteria and without taking anti-platelet drugs were selected in the study. MTT assay, colony formation assay, transwell assay, tube formation and western blot were used to evaluate the effect of platelet lysates on HCC cells in vitro. Lung metastatic assay was performed in vivo. Results: Platelet lysates from patients after RFA promoted cell proliferation, colony formation, migration, invasion and vasculogenic mimicry in Hep3B and HCCLM3 cells compared with those from patients before RFA. Platelet lysates after RFA significantly increased the expression of p-Akt, p-Smad3 and snail, and decreased the expression of E-cadherin compared with those before RFA in Hep3B and HCCLM3 cells. Hep3B-Luc2-tdT cells incubation with platelet lysates from patients after RFA displayed enhanced lung metastasis compared with those before RFA. Conclusions: Platelet lysates from HCC patients after RFA promoted the proliferation, migration, invasion and vasculogenic mimicry of HCC cells, which indicated that RFA in combination with anti-platelet drug may be used to improve the prognosis of HCC.
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Plaquetas/patología , Carcinoma Hepatocelular/terapia , Ablación por Catéter/efectos adversos , Neoplasias Hepáticas/terapia , Neoplasias Pulmonares/prevención & control , Inhibidores de Agregación Plaquetaria/uso terapéutico , Anciano , Animales , Plaquetas/efectos de los fármacos , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/secundario , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Terapia Combinada/métodos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Femenino , Humanos , Hígado/patología , Hígado/cirugía , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/patología , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/secundario , Masculino , Ratones , Persona de Mediana Edad , Invasividad Neoplásica/patología , Invasividad Neoplásica/prevención & control , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/prevención & control , Neovascularización Patológica/sangre , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/patología , Inhibidores de Agregación Plaquetaria/farmacología , Pronóstico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: MicroRNAs (miRNAs) is a class of functional regulator of tumorigenesis of human cancer including hepatocellular carcinoma (HCC). However, the potential clinical significance of serum exosomal miR-320d in HCC has not been elucidated. METHODS: Real-time reverse transcription PCR was used to detect the expression pattern of serum exosomal miR-320d in patients with HCC, and the correlation between the deregulation of serum exosomal miR-320d and the clinical outcome of HCC was explored. The biological function of exosomal miR-320d in HCC was also investigated. RESULTS: Our results showed that the expression levels of exosomal miR-320d were remarkably reduced in the serum samples of HCC patients and the culture medium of HCC cell lines compared with their respective controls. Serum exosomal miR-320d could differentiate the HCC patients from healthy controls with high accuracy. In addition, its level was remarkably increased in the HCC patients who had received surgical treatment. Moreover, reduced serum exosomal miR-320d was associated with advanced tumor stage, positive lymph node metastasis, and poorly differentiated tumors. HCC patients with lower serum exosomal miR-320d had shorter overall and disease-free survival. Low serum exosomal miR-320d was identified to be an independent unfavorable prognostic factor for HCC. Finally, overexpression of miR-320d inhibited the proliferation and invasion of HCC cells, and BMI1 was demonstrated to be a direct target of miR-320d. CONCLUSION: Taken together, serum exosomal miR-320d could be a potential non-invasive biomarker for the diagnosis and prognosis of HCC.
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Carcinoma Hepatocelular/mortalidad , Exosomas/genética , Neoplasias Hepáticas/mortalidad , MicroARNs/sangre , Anciano , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/cirugía , Estudios de Casos y Controles , Línea Celular Tumoral , Proliferación Celular/genética , Ácidos Nucleicos Libres de Células/sangre , Supervivencia sin Enfermedad , Regulación hacia Abajo/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/cirugía , Masculino , MicroARNs/genética , Persona de Mediana Edad , PronósticoRESUMEN
This study investigated the relationship between endothelial pyroptosis and the occurrence of systemic inflammatory response (SIR) after radiofrequency (RF) ablation of hepatic hemangiomas. Thirty-two patients with hepatic hemangiomas were treated with RF ablation and blood samples of the patients were collected at different time points. Immunohistochemistry staining was performed to evaluate the expression of caspase-1, gasdermin D (GSDMD), IL-1ß and IL-18 in hepatic hemangioma and subablated hemangioma tissue. In vitro experiments, human umbilical vein endothelial cells (HUVECs) were treated with sub-ablative hyperthermia with or without the addition of caspase-1 inhibitor, Ac-YVAD-CMK in the medium. Lactate dehydrogenase (LDH), IL-18, IL-1ß, caspase-1 and GSDMD were measured by enzyme-linked immunosorbent assay, real-time PCR and Western blot methods. An elevation of general SIR parameters (CRP and WBC), pyroptosis-related inflammatory cytokines (IL-1ß and IL-18) and LDH were observed 1-day post-RF ablation and their peak values were significantly correlated with ablated volume (p < .001) and ablation time (p < .001). Moreover, levels of pyroptosis-related inflammatory cytokines correlated well with general SIR parameters, respectively (p < .001). Immunohistochemical analysis showed the increased expression of caspase-1, GSDMD, IL-18 and IL-1ß in the endothelial cells of subablated hemangioma. In vitro experiments showed that subablative hyperthermia induced the caspase-1-associated endothelial pyroptosis and Ac-YVAD-CMK attenuated pyroptosis. In conclusion, SIR in patients treated by RF ablation for hepatic hemangiomas was significantly associated with the ablated volume and ablation time and endothelial pyroptosis may involve in the occurrence of SIR following RF ablation of hepatic hemangiomas.
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Hemangioma/terapia , Células Endoteliales de la Vena Umbilical Humana/patología , Inflamación/patología , Neoplasias Hepáticas/terapia , Piroptosis , Ablación por Radiofrecuencia/efectos adversos , Adulto , Anciano , Caspasa 1/metabolismo , Inhibidores de Caspasas/farmacología , Citocinas/metabolismo , Femenino , Hemangioma/patología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Piroptosis/efectos de los fármacos , Factores de TiempoAsunto(s)
Hemangioma , Neoplasias Hepáticas , Bleomicina/uso terapéutico , Aceite Etiodizado/uso terapéutico , Hemangioma/terapia , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/terapia , Soluciones Esclerosantes/uso terapéutico , Escleroterapia , Resultado del TratamientoRESUMEN
BACKGROUND: The mechanisms and prevention of progression of hepatocellular carcinoma (HCC) after insufficient radiofrequency ablation (RFA) has been preliminarily investigated, therefore, new strategy needs to be investigated to prevent the process. Whether metformin could be used to inhibit the growth of HCC after insufficient RFA and further prevent the progression of residual HCC remains unclearly. METHODS: MTT assay, colony formation assay and transwell assay were used to observe the cell viability, migration and invasion. Western blot and immunohistochemistry methods were used to observe the expression of proteins. Xenograft model was used to evaluate the growth of HCC cells in vivo. RESULTS: Metformin inhibited the enhanced proliferation, migration and invasion of HepG2 and SMMC7721 cells after insufficient RFA (named as HepG2-H and SMMC7721-H). Metformin deregulated the expression of p-Akt in HepG2 and SMMC7721 cells after insufficient RFA through AMPK/PTEN pathway. HepG2-H cells also exhibited larger tumor size in vivo. Higher expression of Ki-67 and CD31 and lower expression of E-cadherin were observed in HepG2-H tumors. Metformin blocked the enhanced growth of HepG2 cells in vivo after insufficient RFA. Metformin had no apparent toxicity on nude mice. CONCLUSIONS: Metfromin inhibited the growth of HCC cells after insufficient RFA, and may be used to prevent the progression of HCC after RFA.
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BACKGROUND: Epithelial-mesenchymal transition (EMT) played an important role in the progression of hepatocellular carcinoma (HCC) after insufficient radiofrequency ablation (RFA). However, whether sorafenib could be used to suppress the EMT of HCC after insufficient RFA and further prevent the progression of residual HCC remains poorly unknown. METHODS: Insufficient RFA was simulated using a water bath (47 °C 5, 10, 15, 20 and 25 min gradually). MTT assay and transwell assay were used to evaluate the effects of sorafenib on viability, migration and invasion of HepG2 and SMMC7721 cells after insufficient RFA in vitro. After insufficient RFA, the molecular changes in HCC cells with the treatment of sorafeinb were evaluated using western blot and ELISAs. An ectopic nude mice model was used to evaluate the effect of sorafenib on the growth of HepG2 cells in vivo after insufficient RFA. RESULTS: HepG2 and SMMC7721 cells after insufficient RFA (named as HepG2-H and SMMC7721-H) exhibited enhanced viability, migration and invasion in vitro. Sorafenib inhibited the enhanced viability, migration and invasion of HepG2 and SMMC7721 cells after insufficient RFA. Molecular changes of EMT were observed in HepG2-H and SMMC7721-H cells. Sorafenib inhibited the EMT of HepG2-H and SMMC7721-H cells. HepG2-H cells also exhibited larger tumor size in vivo. Higher expression of PCNA, Ki67, N-cadherin, MMP-2 and MMP-9, was also observed in HepG2-H tumors. Sorafenib blocked the enhanced growth of HepG2 cells in vivo after insufficient RFA. CONCLUSIONS: Sorafenib inhibited the EMT of HCC cells after insufficient RFA, and may be used to prevent the progression of HCC after RFA.
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Antineoplásicos/administración & dosificación , Carcinoma Hepatocelular/tratamiento farmacológico , Transición Epitelial-Mesenquimal/efectos de los fármacos , Neoplasias Hepáticas/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/administración & dosificación , Animales , Antineoplásicos/farmacología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/cirugía , Ablación por Catéter , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/cirugía , Ratones , Invasividad Neoplásica , Niacinamida/administración & dosificación , Niacinamida/farmacología , Compuestos de Fenilurea/farmacología , Sorafenib , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Traditional systemic chemotherapy does not provide survival benefits in patients with hepatocellular carcinoma (HCC). Molecular targeted therapy shows promise for HCC treatment, however, the duration of effectiveness for targeted therapies is finite and combination therapies offer the potential for improved effectiveness. METHODS: Sorafenib, a multikinase inhibitor, and YC-1, a soluble guanylyl cyclase (sGC) activator, were tested in HCC by proliferation assay, cell cycle analysis and western blot in vitro and orthotopic and ectopic HCC models in vivo. RESULTS: In vitro, combination of sorafenib and YC-1 synergistically inhibited proliferation and colony formation of HepG2, BEL-7402 and HCCLM3 cells. The combination also induced S cell cycle arrest and apoptosis, as observed by activated PARP and caspase 8. Sorafenib and YC-1 respectively suppressed the expression of phosphorylated STAT3 (p-STAT3) (Y705) in a dose- and time-dependent manner. Combination of sorafenib and YC-1 significantly inhibited the expression of p-STAT3 (Y705) (S727), p-ERK1/2, cyclin D1 and survivin and SHP-1 activity compared with sorafenib or YC-1 used alone in all tested HCC cell lines. In vivo, sorafenib-YC-1 combination significantly suppressed the growth of HepG2 tumor xenografts with decreased cell proliferation and increased apoptosis observed by PCNA and PARP. Similar results were also confirmed in a HCCLM3 orthotopic model. There was a reduction in CD31-positive blood vessels and reduced VEGF expression, which suggested a combinational effect of sorafenib and YC-1 on angiogenesis. The reduced expression of p-STAT3, cyclin D1 and survivin was also observed with the combination of sorafenib and YC-1. CONCLUSIONS: Our data show that sorafenib-YC-1 combination is a novel potent therapeutic agent that can target the STAT3 signaling pathway to inhibit HCC tumor growth.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma Hepatocelular/metabolismo , Indazoles/administración & dosificación , Neoplasias Hepáticas/metabolismo , Factor de Transcripción STAT3/antagonistas & inhibidores , Animales , Apoptosis/efectos de los fármacos , Western Blotting , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Niacinamida/administración & dosificación , Niacinamida/análogos & derivados , Compuestos de Fenilurea/administración & dosificación , Sorafenib , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVE: Radiofrequency (RF) ablation is an accepted nonsurgical treatment of hepatic hemangiomas, but with an appreciable complication rate. Our study aimed to assess the safety and efficacy of RF ablation, administered with either multitined expandable electrodes or with internally cooled cluster electrodes, in the treatment of large (≥10 cm diameter) hepatic hemangiomas. METHODS: We retrospectively reviewed our sequential experience of treating 43 large hepatic hemangiomas in 42 patients with RF ablation/multitined expandable electrodes or with RF ablation/internally cooled electrodes. Twenty-two hemangiomas in 21 patients were treated with expandable electrode (multitined electrode group), and 21 hemangiomas in 21 patients were treated with internally cooled cluster electrode (internally cooled electrode group). RESULTS: Among the 43 large hepatic hemangiomas, 27 subcapsular lesions were treated by a laparoscopic approach, and 16 lesions located in liver parenchyma were treated by a computed tomography-guided percutaneous approach. In the multitined electrode group, RF ablation treatment was performed in all 21 patients in 1 session. In the internally cooled electrode group, 18 patients were treated by RF ablation in 1 session, and 3 patients, with ≥14.0-cm single hemangioma, were treated with RF ablation in 2 sessions. Complete ablation was achieved in 81.8% (18/22) and 90.5% (19/21) in the multitined electrode group and the internally cooled electrode group, respectively (P>0.05). Ablation time for single hemangioma was shorter with the internally cooled electrode than with the multitined electrode (P<0.05). There were 79 complications related to ablation (2 major and 77 minor) in 31 patients. All 21 patients in the multitined electrode group experienced complications, compared with 10 of 21 patients (47.6%) in the internally cooled electrode group (P<0.05). Both of the 2 major complications occurred in the multitined electrode group. All the complications were treated successfully with conservative measures. CONCLUSIONS: RF ablation is a safe and effective treatment for large hepatic hemangiomas. Use of the internally cooled cluster electrodes and a more defensive treatment algorithm can reduce the complications.
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Ablación por Catéter/métodos , Hemangioma/cirugía , Neoplasias Hepáticas/cirugía , Adulto , Anciano , Ablación por Catéter/instrumentación , Electrodos , Diseño de Equipo , Femenino , Hemangioma/patología , Humanos , Laparoscopía/métodos , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/epidemiología , Estudios Retrospectivos , Factores de Tiempo , Tomografía Computarizada por Rayos X/métodos , Resultado del TratamientoRESUMEN
Purpose: Systemic inflammatory response syndrome (SIRS) is a common complication of radiofrequency ablation (RFA) for hepatic hemangiomas. RFA can cause hemolytic reactions during hepatic hemangioma ablation. However, the mechanisms underlying RFA-induced SIRS remain unclear. Methods: We established an orthotopic liver hemangioma model and performed radiofrequency ablation. The levels of interleukin (IL)-1ß and IL-18 and the production of ROS were measured. The wet-to-dry lung ratio, inflammation score, and in vivo endothelial cell permeability were examined. GSDMD-/- mice were used to investigate the effect of heme-inducing SIRS. RNA sequencing (RNA-seq) was performed to identify the main pathways underlying heme-induced SIRS. Western blotting and immunoprecipitation were used to determine the changes and interactions of associated proteins. Results: The levels of heme, IL-1ß, and IL-18 were significantly increased after RFA. The wet-to-dry lung ratio increased in hepatic hemangiomas after RFA, indicating that SIRS occurred. Heme induced increased levels of IL-1ß and IL-18, cell death, wet-to-dry lung radio, and inflammation score in vitro and in vivo, indicating that heme induced SIRS and pyroptosis. Furthermore, GSDMD participates in heme-induced SIRS in mice, and GSDMD deletion in mice reverses the effect of heme. Heme regulates NLRP3 activation through the NOX4/ROS/TXNIP-TRX pathway, and an N-acetyl-L-cysteine (NAC) or NOX4 inhibitor (GLX351322) reverses heme-induced SIRS. Conclusion: Our findings suggest that heme induces endothelial cell pyroptosis and SIRS in mice and decreasing heme levels and ROS scavengers may prevent SIRS in hepatic hemangioma after RFA.
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BACKGROUND: Residual tumor progression after insufficient radiofrequency ablation (RFA) has been recently reported. However, whether epithelial-mesenchymal transition (EMT), which is a key process that drives cancer metastasis, is involved in the tumor progression after insufficient RFA is not well understood. METHODS: Human hepatocellular carcinoma (HCC) cell lines SMMC7721 and Huh7 were used. Insufficient RFA was simulated using a water bath (47°C 5 min, 10 min, 15 min, 20 min and 25 min gradually). MTT assay was used to evaluate the proliferation of HCC cells in vitro. Migration and invasion of HCC cells were determined by transwell assay. The molecular changes in HCC cells after insufficient RFA were evaluated by western blot. LY294002 and PD98059 were used to treat HCC cells. An ectopic nude mice model and a tail vein metastatic assay were used to evaluate the growth and metastatic potential of SMMC7721 cells in vivo after insufficient RFA. RESULTS: SMMC7721 and Huh7 cells after insufficient RFA (named as SMMC7721-H and Huh7-H respectively) exhibited enhanced proliferation, migration and invasion (6.4% and 23.6%, 33.2% and 66.1%, and 44.1% and 57.4% increase respectively) in vitro. Molecular changes of EMT were observed in SMMC7721-H and Huh7-H cells. LY294002 and PD98059 inhibited the EMT of SMMC7721-H and Huh7-H cells. SMMC7721-H cells also exhibited larger tumor size (1440.8±250.3 mm3 versus 1048.56±227.6 mm3) and more lung metastasis (97.4% increase) than SMMC7721 cells in vivo. Higher expression of PCNA, N-cadherin and MMP-2 and MMP-9, was also observed in SMMC7721-H tumors. CONCLUSIONS: Insufficient RFA could directly promote the invasiveness and metastasis of HCC cells. Insufficient RFA may promote the EMT of HCC cells through Akt and ERK signaling pathways.
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Carcinoma Hepatocelular/terapia , Ablación por Catéter/métodos , Transición Epitelial-Mesenquimal , Neoplasias Hepáticas/terapia , Sistema de Señalización de MAP Quinasas , Proteínas Proto-Oncogénicas c-akt/metabolismo , Animales , Carcinoma Hepatocelular/enzimología , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Cromonas/farmacología , Progresión de la Enfermedad , Flavonoides/farmacología , Humanos , Neoplasias Hepáticas/enzimología , Neoplasias Hepáticas/patología , Ratones , Ratones Desnudos , Morfolinas/farmacología , Metástasis de la NeoplasiaRESUMEN
Metformin has shown great promise in the treatment of HCC. Radiofrequency ablation (RFA) deficiency results in recurrence and metastasis of remaining HCC tumors. Here, we aimed to investigate the role and mechanism of metformin in HCC after RFA deficiency. HCC cell line Hep-G2 was selected to simulate RFA deficiency and named HepG2-H cells. After treating cells with different concentrations of metformin (2.5, 5, 10 µM) or transfecting related plasmids, cell proliferation, migration, invasion, apoptosis and angiogenesis were detected, in vitro permeability test was performed, and an angiogenesis-related protein VEGFA was analyzed. The residual HCC model after RFA deficiency was established in mice. Metformin was administered by gavage to detect changes in tumor volume and weight, and CD31 staining was used to observe microvessels. The targeting relationship between miR-302b-3p and TXNIP was demonstrated by the bioinformatics website, dual-luciferase reporter assay, and RNA pull-down assay. The results found that metformin inhibited RFA deficiency-induced growth and angiogenesis of HCC cells in vitro. miR-302b-3p counteracted the therapeutic effect of metformin on RFA deficiency. miR-302b-3p targeted regulation of TXNIP. The up-regulation of TXNIP reversed the effects of overexpression of miR-302b-3p on RFA-deficient HCC cells. Metformin inhibited RFA-deficiency-induced HCC growth and tumor vascular abnormalities in vivo. Overall, metformin promotes the normalization of abnormal blood vessels after RFA deficiency in HCC by miR-302b-3p targeting TXNIP, which can be used to prevent the progression of HCC after RFA.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Metformina , MicroARNs , Ablación por Radiofrecuencia , Animales , Ratones , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Metformina/farmacología , Metformina/uso terapéutico , Línea Celular Tumoral , Proliferación Celular/genética , Tiorredoxinas/genética , Regulación Neoplásica de la Expresión GénicaRESUMEN
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-associated death worldwide. Angiogenesis, the process of formation of new blood vessels, is required for cancer cells to obtain nutrients and oxygen. HCC is a typical hypervascular solid tumor with an aberrant vascular network and angiogenesis that contribute to its growth, progression, invasion, and metastasis. Current anti-angiogenic therapies target mainly tyrosine kinases, vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR), and are considered effective strategies for HCC, particularly advanced HCC. However, because the survival benefits conferred by these anti-angiogenic therapies are modest, new anti-angiogenic targets must be identified. Several recent studies have determined the underlying molecular mechanisms, including pro-angiogenic factors secreted by HCC cells, the tumor microenvironment, and cancer stem cells. In this review, we summarize the roles of pro-angiogenic factors; the involvement of endothelial cells, hepatic stellate cells, tumor-associated macrophages, and tumor-associated neutrophils present in the tumor microenvironment; and the regulatory influence of cancer stem cells on angiogenesis in HCC. Furthermore, we discuss some of the clinically approved anti-angiogenic therapies and potential novel therapeutic targets for angiogenesis in HCC. A better understanding of the mechanisms underlying angiogenesis may lead to the development of more optimized anti-angiogenic treatment modalities for HCC.
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Inhibidores de la Angiogénesis , Carcinoma Hepatocelular , Neoplasias Hepáticas , Neovascularización Patológica , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Células Endoteliales , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Microambiente Tumoral , Factor A de Crecimiento Endotelial Vascular/metabolismo , Inhibidores de la Angiogénesis/uso terapéuticoRESUMEN
BACKGROUND: Thermal ablation, currently used extensively for liver tumors, also has been applied. successfully to hepatic hemangioma; however, it is still considered experimental because previous studies have comprised small sample sizes with short follow-up periods. PURPOSE: We aimed to investigate the effectiveness, safety, and long-term outcomes of thermal ablation for hepatic hemangioma. MATERIALS AND METHODS: From October 2011 to February 2021, the data of 357 patients with 378 hepatic hemangiomas treated by thermal ablation at six hospitals were analyzed in this retrospective study. The technical success, safety, and long-term follow-up results were analyzed. RESULTS: A total of 252 patients (mean age, 49.2 ± 10.5 years) with 273 subcapsular hemangiomas underwent laparoscopic thermal ablation, whereas 105 patients with 105 hemangiomas located in the liver parenchyma underwent CT-guided percutaneous ablation. Of the 378 hepatic hemangiomas (5.0-21.2 cm), 369 lesions were subjected to one session of ablation, while 9 lesions were subjected to two sessions of ablation. Technical success was achieved in 100.0% of cases. Complete ablation was achieved in 361 of 378 hemangiomas (95.5%), while 17 hemangiomas (4.5%) were incompletely ablated, showing subtle enhancement at the peripheral rim. The major complication rate was 2.0% (7/357). The median follow-up period was 67 months (range, 12-124 months). Of the 224 patients with hemangioma-related symptoms, 216 demonstrated complete disappearance of symptoms (96.4%), while 8 were ameliorated (3.6%). Ablated lesion shrinkage was progressive, and 11.4% of hemangiomas almost completely disappeared over time (P < 0.01). CONCLUSION: With a reasonable ablation strategy and comprehensive treatment measurements, thermal ablation could be a safe, feasible, and effective treatment option for hepatic hemangioma.
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Ablación por Catéter , Hemangioma , Neoplasias Hepáticas , Humanos , Adulto , Persona de Mediana Edad , Estudios Retrospectivos , Ablación por Catéter/métodos , Hemangioma/diagnóstico por imagen , Hemangioma/cirugía , Hemangioma/patología , Resultado del Tratamiento , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/patologíaRESUMEN
BACKGROUND: The mechanism regarding rapid progression of residual hepatocellular carcinoma (HCC) after insufficient radiofrequency ablation (RFA) has been preliminarily discussed. However, most studies have mainly focused on RFA-induced changes in the tumor cells. The present study was designed to determine whether tumor-associated endothelial cells (TAECs) could contribute to the invasiveness of HCC after insufficient RFA. METHODS: TAECs were isolated from fresh HCC tissue and characterized. Morphological changes were observed in TAECs after heat treatment for 10 min. TAEC proliferation, migration and tube formation after heat treatment for 10 min at 37°C (control group), and 42 and 47°C (insufficient RFA groups) were examined. The differences in TAECs interactions with HepG2-GFP or HCCLM3-GFP cells among the two insufficient RFA groups and control group were evaluated. The expression of E-selectin, ICAM-1 and VCAM-1 in TAECs was measured. The effects of TAECs on the invasiveness of HepG2-GFP or HCCLM3-GFP cells after insufficient RFA were analyzed. The IL-6, IL-8, MCP-1 and GRO-α concentrations in conditioned medium from TAECs were measured after insufficient RFA. The associated signaling pathways of Akt, ERK1/2, STAT3 and NF-κB were analyzed in TAECs after insufficient RFA. RESULTS: TAECs expressed the EC-specific markers and took up complexes of Dil-Ac-LDL. Relative to the control group, the proliferation of TAECs was significantly inhibited and their migration and tube formation were significantly enhanced in the insufficient RFA groups. Significantly more HepG2-GFP or HCCLM3-GFP cells adhered to TACEs in these groups than in the control group (all P<0.001), via up-regulated expression of E-selectin, ICAM-1 and VCAM-1. TAECs promoted the invasiveness of HepG2-GFP or HCCLM3-GFP cells after insufficient RFA via the up-regulation of IL-6, IL-8, MCP-1 and GRO-α in conditioned medium (all P<0.05). Insufficient RFA enhanced the activities of Akt, ERK1/2 and NF-κB signaling pathways and inhibited STAT3 signaling pathways. CONCLUSIONS: Insufficient RFA enhanced TAEC migration and tube formation, and this may play a key role in the rapid growth of residual HCC. Increased expression of metastasis-related molecules in TAECs after insufficient RFA may be a potential mechanism for the metastasis of residual HCC.
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Carcinoma Hepatocelular/irrigación sanguínea , Carcinoma Hepatocelular/patología , Ablación por Catéter , Células Endoteliales/patología , Neoplasias Hepáticas/irrigación sanguínea , Neoplasia Residual/patología , Neovascularización Patológica/patología , Carcinoma Hepatocelular/enzimología , Carcinoma Hepatocelular/cirugía , Adhesión Celular , Comunicación Celular , Línea Celular Tumoral , Proliferación Celular , Separación Celular , Forma de la Célula , Células Endoteliales/enzimología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Hipertermia Inducida , Neoplasias Hepáticas/enzimología , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/cirugía , FN-kappa B/metabolismo , Invasividad Neoplásica , Neoplasia Residual/enzimología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Reproducibilidad de los Resultados , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Regulación hacia ArribaRESUMEN
BACKGROUND: Previous studies suggest that oxidative stress plays an important role in the development of breast cancer. There is a significant inverse relationship between HDL and the risk and mortality of breast cancer. However, it is well known that under conditions of oxidative stress, such as breast cancer, HDL can be oxidatively modifiedand these modifications may have an effect on the functions of HDL. The purpose of this study is to determine the different effects of normal and oxidized (caused by hypochlorite-induced oxidative stress) HDL on breast cancer cell metastasis. METHODS: Human breast cancer cell lines were treated with normal and hypochlorite-oxidized HDL, and then cell metastasis potency in vivo and the abilities of migration, invasion, adhesion to HUVEC and ECM in vitro were examined. Integrin expression and PKC activity were evaluated, and PKC inhibitor and PKC siRNA was applied. RESULTS: We found hypochlorite-oxidized HDL dramatically promotes breast cancer cell pulmonary metastasis (133.4% increase at P < 0.0 l for MDA-MB-231 by mammary fat pad injection; 164.3% increase at P < 0.01 for MCF7 by tail vein injection) and hepatic metastasis (420% increase at P < 0.0 l for MDA-MB-231 by mammary fat pad injection; 1840% fold increase at P < 0.001 for MCF7 by tail vein injection) in nude mice, and stimulates higher cell invasion (85.1% increase at P < 0.00 l for MDA-MB-231; 88.8% increase at P < 0.00 l for MCF7;), TC-HUVEC adhesion (43.4% increase at P < 0.00 l for MDA-MB-231; 35.2% increase at P < 0.00 l for MCF7), and TC-ECM attachment (41.0% increase at P < 0.00 l for MDA-MB-231; 26.7% increase at P < 0.05 for MCF7) in vitro compared with normal HDL. The data also shows that the PKC pathway is involved in the abnormal actions of hypochlorite-oxidized HDL. CONCLUSIONS: Our study demonstrated that HDL under hypochlorite-induced oxidative stress stimulates breast cancer cell migration, invasion, adhesion to HUVEC and ECM, thereby promoting metastasis of breast cancer. These results suggest that HDL-based treatments should be considered for treatment of breast cancer patients.
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Ácido Hipocloroso/toxicidad , Lipoproteínas HDL/metabolismo , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Estrés Oxidativo/efectos de los fármacos , Animales , Adhesión Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/metabolismo , Femenino , Silenciador del Gen/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Integrinas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/secundario , Ratones , Ratones Endogámicos BALB C , Invasividad Neoplásica , Metástasis de la Neoplasia , Proteína Quinasa C/antagonistas & inhibidores , Proteína Quinasa C/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , ARN Interferente Pequeño/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Circular RNAs (circRNAs) are endogenous non-coding RNAs, some of which have pathological roles. The current study aimed to explore the role of circRNA BTG3-associated nuclear protein (circ-BANP) binding with let-7f-5p and its regulation of the toll-like receptor 4 (TLR4)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in residual hepatocellular carcinoma (HCC) after insufficient radiofrequency ablation (RFA). METHODS: Circ-BANP, let-7f-5p, and TLR4 expressions in HCC samples were assessed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blotting. Bioinformatics prediction, RNA pull-down assay, and dual luciferase reporter gene assay were used to analyze the relationships among circ-BANP, let-7f-5p, and TLR4. Huh7 cells were used to generate an in vitro model of residual HCC, defined as Huh7-H cells, which were transfected with either a plasmid or the sequence of circ-BANP, let-7f-5p, or TLR4. Expression of circ-BANP, let-7f-5p, and TLR4 mRNA was determined by RT-qPCR. TLR4, STAT3, p-STAT3, vascular endothelial growth factor A, vascular endothelial growth factor receptor-2, and epithelial-mesenchymal transformation (EMT)-related factors proteins were determined by Western blotting. Cell proliferation was determined by cell counting kit-8 and 5-Ethynyl-2'-deoxyuridine (EdU) assay and cell migration and invasion by Transwell assay. Animal studies were performed by inducing xenograft tumors in nude mice. RESULTS: Circ-BANP and TLR4 mRNAs were upregulated in HCC tissues (the fold change for circ-BANP was 1.958 and that for TLR4 was 1.736 relative to para-tumors) and expression further increased following insufficient RFA (fold change for circ-BANP was 2.407 and that of TLR4 was 2.224 relative to para-tumors). Expression of let-7f-5p showed an opposite tendency (fold change for let-7f-5p in HCC tissues was 0.491 and that in tumors after insufficient RFA was 0.300 relative to para-tumors). Competitive binding of circ-BANP to let-7f-5p was demonstrated and TLR4 was identified as a target of let-7f-5p (Pâ<â0.01). Knockdown of circ-BANP or elevation of let-7f-5p expression inhibited the TLR4/STAT3 signaling pathway, proliferation, invasion, migration, angiogenesis, and EMT in Huh7 and Huh7-H cells (Pâ<â0.01). The effects induced by circ-BANP knockdown were reversed by let-7f-5p inhibition. Overexpression of TLR4 reversed the impact of let-7f-5p upregulation on the cells (Pâ<â0.01). Silencing of circ-BANP inhibited the in vivo growth of residual HCC cells after insufficient RFA (Pâ<â0.01). CONCLUSIONS: Knockdown of circ-BANP upregulated let-7f-5p to inhibit proliferation, migration, and EMT formation in residual HCC remaining after insufficient RFA. Effects occur via regulation of the TLR4/STAT3 signaling pathway.