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1.
Int J Cancer ; 146(5): 1383-1395, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31286509

RESUMO

Hepatocellular carcinoma (HCC) is an aggressive malignancy with increasing mortality in China. Angiogenesis is crucial for tumor formation, development and metastasis in HCC. Previous studies indicated that high expression levels of elongation factor 2 kinase (eEF2K), a protein kinase that negatively regulates the elongation stage of translation, were associated with poor prognosis of HCC. Here, we show that pharmacological inhibition or knockdown of eEF2K in highly metastatic liver cancer cells inhibits their colony forming and migratory capacities, as well as reducing their invasiveness. Importantly, knocking down eEF2K by lentiviral directed shRNA prevented tumor growth and angiogenesis of HCC in mice. Silencing of eEF2K in endothelial cells (HUVECs) led to a reduction in vascularization, evidenced by a decrease in capillary-like structures in the matrigel. Notably, knocking down eEF2K reduced the expression of angiogenesis-related growth factors in liver cancer cells and the expression of growth factor receptors on HUVECs, and thus restricted signaling crosstalk that promotes angiogenesis between HCC cells and endothelial cells. We also showed that silencing of eEF2K effectively reduced protein levels of SP1/KLF5 transcription factors and hence decreased the levels of bound SP1/KLF5 to the VEGF promoter, resulted in a decrease in VEGF mRNA expression. Knocking down eEF2K also led to a striking decrease in the phosphorylation of PI3K/Akt and STAT3, indicating inactivation of these tumorigenic pathways. Taken together, our data suggest that eEF2K contributes to angiogenesis and tumor progression in HCC via SP1/KLF5-mediated VEGF expression, as well as the subsequent stimulation of PI3K/Akt and STAT3 signaling.


Assuntos
Carcinoma Hepatocelular/irrigação sanguínea , Quinase do Fator 2 de Elongação/metabolismo , Neoplasias Hepáticas/irrigação sanguínea , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Células Hep G2 , Xenoenxertos , Células Endoteliais da Veia Umbilical Humana , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Transdução de Sinais
2.
Appl Biochem Biotechnol ; 190(1): 305-324, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31346920

RESUMO

Current estimates indicate that hepatocarcinoma is the leading cause of death globally. There is interest in utilizing nanomedicine for cancer therapy to overcome side effects of chemo-interventions. Ribavirin, an antiviral nucleoside inhibitor, accumulates inside red blood cells, causing anemia. Its analog, viramidine, can concentrate within hepatocytes and spare red blood cells, thus limiting anemia. Hepatocarcinoma cells have a large number of asialoglycoprotein receptors on their membranes that can bind galactosyl-terminating solid lipid nanoparticles (Gal-SLN) and internalize them. Here, viramidine, 5-fluorouracil, and paclitaxel-loaded Gal-SLN were characterized inside cells. Cytotoxicities of free-drug, nano-void, and drug-loaded Gal-SLN were evaluated using HepG2 cells; over 3 days, cell viability was measured. To test the mechanistic pathway, we investigated in vitro apoptosis using flow cytometry and in ovo angiogenesis using the CAM assay. Results showed that 1 and 2 µM of the viramidine-encapsulated Gal-SLN had the highest cytotoxic effect, achieving 80% cell death with a steady increase over 3 days, with induction of apoptosis and reduction of necrosis and angiogenesis, compared to free-drugs. Gal-SLN application on breast cancer MCF-7 cells confirmed its specificity against liver cancer HepG2 cells. We conclude that viramidine-encapsulated Gal-SLN has anticancer and anti-angiogenic activities against hepatocarcinoma.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Apoptose/efeitos dos fármacos , Galactose/química , Nanopartículas/química , Neovascularização Patológica/prevenção & controle , Ribavirina/análogos & derivados , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/patologia , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/patologia , Células Hep G2 , Humanos , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/patologia , Células MCF-7 , Ribavirina/administração & dosagem , Ribavirina/química , Ribavirina/farmacologia
3.
Acta Biochim Biophys Sin (Shanghai) ; 52(1): 18-25, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31828297

RESUMO

As a highly malignant tumor, hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. In most HCC patients, the development of HCC begins with hepatitis, which is followed by fibrosis and cirrhosis before progressing to HCC. Cancer-associated fibroblasts (CAFs), which are generally believed to be derived from activated hepatic stellate cells (HSCs), are highly involved in the development of HCC through the secretion of cytokines and angiogenic factors. The results of our study showed that a considerable number of CAFs highly expressed CD90 and were enriched in HCC tissues. Bioinformatics analysis of the transcriptome of HCC tissues revealed that placental growth factor (PlGF) is significantly correlated with CD90 expression. The isolated primary CAFs and activated HSCs overexpressed PlGF and CD90. In addition, the results of gene expression profiling interactive analysis based on The Cancer Genome Atlas showed that high levels of both PlGF and CD90 are correlated with tumor angiogenesis markers (CD31, CD34, and CD105) and predict poor HCC patient prognosis. In summary, our results suggest that CAFs can generate PlGF and may provide an effective target for CAFs-regulated neoangiogenesis in HCC.


Assuntos
Carcinoma Hepatocelular/irrigação sanguínea , Fibroblastos/metabolismo , Neoplasias Hepáticas/irrigação sanguínea , Neovascularização Patológica/metabolismo , Fator de Crescimento Placentário/metabolismo , Actinas/metabolismo , Antígenos CD34/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Endoglina/metabolismo , Regulação Neoplásica da Expressão Gênica , Células Estreladas do Fígado/metabolismo , Humanos , Neoplasias Hepáticas/genética , Fator de Crescimento Placentário/genética , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Prognóstico , Antígenos Thy-1/genética , Antígenos Thy-1/metabolismo , Transcriptoma/genética
4.
Curr Med Sci ; 39(5): 820-824, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31612402

RESUMO

The aim of the present study is to evaluate a method of establishing model of rabbit liver VX2 tumor using percutaneous puncture inoculation of tumor fragment guided by ultrasonography. VX2 tumor fragments were implanted into the liver of 13 New Zealand white rabbits flushed by 1 mL normal saline through percutaneous puncture needle guided by ultrasonography. Conventional ultrasonography and contrast-enhanced ultrasonography (CEUS) were performed 14 days after inoculation, and then the rabbits were sacrificed and pathologically examined. The success rate of inoculation was 100%. The average size of liver VX2 tumor was 1.7 cm×1.3 cm, CEUS of VX2 liver tumors showed the "rapid wash-in and wash-out" vascular pattern. There were significant differences between VX2 tumors and liver parenchyma in quantitative parameters of A, k and A × k (P<0.05), which meant that VX2 liver tumors were characterized by more blood flow volume and faster blood velocity than liver parenchyma. Tumor fragment flushed by normal saline into the liver through a needle may be a promising method for the induction of a hepatic tumor. And CEUS can be used for accurately assessing angiogenesis and blood perfusion of VX2 tumors.


Assuntos
Modelos Animais de Doenças , Neoplasias Hepáticas/patologia , Fígado/patologia , Neovascularização Patológica/diagnóstico por imagem , Animais , Velocidade do Fluxo Sanguíneo , Meios de Contraste/administração & dosagem , Fígado/irrigação sanguínea , Fígado/diagnóstico por imagem , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/diagnóstico por imagem , Transplante de Neoplasias , Punções , Coelhos , Cirurgia Assistida por Computador/métodos , Carga Tumoral , Ultrassonografia/métodos
5.
Jpn J Radiol ; 37(11): 781-792, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31522384

RESUMO

PURPOSE: To determine the treatment outcome and prognostic factors for survival in patients with hepatocellular carcinoma (HCC) and macrovascular tumor thrombosis (MTT). METHODS: Between January 2010 and December 2018, 66 patients diagnosed with HCC and MTT, who received specific treatment were included. Various clinical and imaging data, treatment methods, outcomes, prognostic factors, and overall survival were evaluated. Outcomes were compared with those of 24 patients treated with supportive care. RESULTS: Most patients with HCC and MTT showed disease progression (80.3%) and a low 5-year survival rate. The median survival time after treatment was 13 months (vs. supportive care group 3 months, p < 0.001). Main branch MTT (p = 0.036), extent of tumor thrombus > 1 segment (p = 0.039), presence of ascites (p = 0.009) and among treatment methods, systemic therapy alone (p = 0.007), and supportive care (p < 0.001) compared with combined local with systemic therapies were prognostic factors for poor survival. CONCLUSIONS: Although most patients with HCC and MTT showed disease progression, median survival time was significantly longer than that with supportive care. Main branch and > 1 segment involvement of MTT and presence of ascites were significant prognostic factors for poor survival. Combined local and systemic therapy over systemic therapy alone are recommended for patients with these advanced stage HCCs.


Assuntos
Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/diagnóstico por imagem , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/diagnóstico por imagem , Trombose/diagnóstico por imagem , Idoso , Carcinoma Hepatocelular/complicações , Feminino , Humanos , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Trombose/etiologia , Trombose/terapia
6.
J Surg Oncol ; 120(7): 1112-1118, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31486087

RESUMO

BACKGROUND: The clinical importance of hypovascular liver lesions in cirrhotic patients awaiting liver transplantation (LT) has not been fully investigated. The objective of this study was to characterize the clinicopathologic features and management of these tumors and to assess their impact on post-LT outcomes. METHODS: We performed a retrospective review of cirrhotic patients with lesions suspicious for hypovascular hepatocellular carcinoma (HCC) who underwent LT at a single institution from 2011- 2017. RESULTS: We identified 22 pre-LT patients with radiologic diagnosis of a lesion(s) suspicious for hypovascular HCC. There were 28 hypovascular lesions within the 22 patient cohort; 9 lesions (32%) converted to hypervascular HCC before LT and 19 lesions remained hypovascular at LT. 88% of hypovascular lesions were HCC on explant pathology. Compared to patients with hyper-vascular HCC lesions, hypovascular HCC lesions underwent less preoperative tumor ablation (58% vs 89%; P < .01). Hypovascular HCC were more likely to be well-differentiated (67% vs 11%; P < .01), but there were no differences in the microvascular invasion, tumor recurrence, or survival post-LT. CONCLUSIONS: Hypovascular HCC has similar clinical outcomes and needs for transplantation as hypervascular HCC. The high prevalence of HCC within suspicious hypovascular lesions supports a similar monitoring and locoregional therapy strategy as for hypervascular HCC.


Assuntos
Carcinoma Hepatocelular/patologia , Cirrose Hepática/fisiopatologia , Neoplasias Hepáticas/patologia , Transplante de Fígado/mortalidade , Neovascularização Patológica , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/cirurgia , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
7.
Biomed Pharmacother ; 118: 109274, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31545220

RESUMO

This study aims to identify the feature genes associated with vascular invasion in hepatocellular carcinoma (HCC). Here, the RNA sequencing data related to vascular invasion in The Cancer Genome Atlas (TCGA) database, including 292 HCC patients with complete clinical data were included in our study as the training dataset for construction and E-TABM-36, including 41 HCC patients with complete clinical data was used as the validation dataset. Following data normalization, differentially expressed mRNA and copy number (CN) were selected between with and without vascular invasion samples. A support vector machine (SVM) classifier was constructed and validated in GSE9828 and GSE20017 datasets. Total 59 feature genes were found by the SVM classifier. Using Cox regression analysis, three clinical features, including Patholigic T, Stage and vascular invasion and 6 optimal prognostic genes, including ANO1, EPHX2, GFRA1, OLFM2, SERPINA10 and TKT were significantly correlated with prognosis. A risk score formula was developed to assess the prognostic value of 6 optimal prognostic genes, which were identified to possess the most remarkable correlation with overall survival in HCC patients. By performing in vitro experiments, we observed TKT was significantly increased, but OLFM2 was decreased in high metastatic potential HCC cell lines (SK-HEP-1 and MHCC-97 H) compared with low metastatic potential cell line Huh7 and normal human liver cell line LO2 using western blotting analysis. Knockdown of TKT in MHCC-97H or overexpression of OLFM2 in SK-HEP-1 significantly suppressed cell migration and invasion using transwell assays. Our results demonstrated that TKT and OLFM2 might be novel independent biomarkers for predicting survival based on the presence of vascular invasion in patients with HCC.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/genética , Biologia Computacional , Mineração de Dados , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/genética , Análise de Sequência de RNA , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Cromossomos Humanos/genética , Variações do Número de Cópias de DNA/genética , Feminino , Dosagem de Genes , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Polimorfismo de Nucleotídeo Único/genética , Prognóstico , Modelos de Riscos Proporcionais , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Risco , Máquina de Vetores de Suporte
8.
Int J Oncol ; 55(4): 823-832, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432158

RESUMO

The selective induction of tumor vascular thrombosis using truncated tissue factor (tTF) delivered via a target ligand is a promising novel antitumor strategy. In the present study, an anti­neuropilin­1 (NRP­1) monoclonal antibody (mAb)­streptavidin (SA):tTF­biotin (B) composite system was established. In this system, anti­NRP­1­mAb located tTF to the tumor vascular endothelial cell surface and induced vascular embolization. Due to their high binding affinity, SA and B were used to enhance thrombogenic activity. mAb was conjugated with SA using a coupling method with water­soluble 1­ethyl­3­(3­dimethylaminopropyl) carbodiimide and N­hydroxysulfosuccinimide. Biotinylated tTF (tTF­B) was prepared using a B­labeling kit subsequent to the generation and purification of fusion protein tTF. Confocal microscopy and flow cytometry indicated that the anti­NRP­1­mAb­SA conjugate retained mAb targeting activity. The preservation of B­conjugate binding capacity was confirmed using a competitive ELISA, and factor X­activation analysis revealed that tTF­B retained the procoagulant activity exhibited by tTF. Live imaging was performed to assess mAb­SA distribution and tumor­targeting capability, and this yielded promising results. The results of in vivo studies in mice with subcutaneous xenografts demonstrated that this composite system significantly induced tumor vascular thrombosis and inhibited tumor growth, whereas these histological changes were not observed in normal organs.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Neuropilina-1/imunologia , Tromboplastina/administração & dosagem , Trombose/induzido quimicamente , Animais , Antineoplásicos Imunológicos/química , Antineoplásicos Imunológicos/farmacologia , Fator X/metabolismo , Feminino , Células Hep G2 , Células Endoteliais da Veia Umbilical Humana , Humanos , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/metabolismo , Camundongos , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/farmacologia , Estreptavidina/química , Tromboplastina/química , Tromboplastina/farmacologia , Trombose/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Cardiovasc Intervent Radiol ; 42(10): 1494-1499, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31363899

RESUMO

INTRODUCTION: Significant intratumoral shunts between tumor-supplying arteries and portal or liver veins are a contraindication for transarterial therapy of HCC because interventional treatment of these shunts is frequently insufficient. Sorafenib has anti-angiogenic effects and is indicated for palliative treatment of patients with HCC. Here, we report our experience with the use of sorafenib for the closure of intratumoral shunts in patients scheduled for transarterial therapy of HCC. MATERIALS AND METHODS: Three patients with HCC, aged 65, 82 and 79 years, exhibited a significant intratumoral shunting from tumor artery to portal (n = 1) or liver veins (n = 2). In all cases, intratumoral shunting had already been suspected based on pre-interventional CT angiography, and DSA confirmed the shunt. Oral sorafenib (800 mg/day) was administered for at least four weeks, only and specifically to occlude the shunt. Hereafter, patients were re-evaluated by CT and DSA. RESULTS: All patients tolerated the full prescribed dose for at least 4 weeks. In one case, therapy was prolonged with an adapted dose (400 mg/day) due to sorafenib-related hand-foot syndrome. After sorafenib treatment, CT and DSA confirmed a complete closure of intratumoral shunts for all patients. No tumor progression was observed. All three patients hereafter underwent successful transarterial treatment by TACE (n = 2) or TARE (n = 1) without complications. Progression-free survival according to mRECIST was 501, 397 and 599 days, respectively. CONCLUSION: Even short-term oral sorafenib seems to effectively close intratumoral shunts in patients with HCC and thus might enable transarterial treatment of these patients.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/irrigação sanguínea , Neoplasias Hepáticas/irrigação sanguínea , Neovascularização Patológica/tratamento farmacológico , Sorafenibe/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Angiografia Digital , Antineoplásicos/administração & dosagem , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/diagnóstico por imagem , Quimioembolização Terapêutica , Feminino , Humanos , Infusões Intra-Arteriais , Fígado/irrigação sanguínea , Fígado/diagnóstico por imagem , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/diagnóstico por imagem , Masculino , Neovascularização Patológica/complicações , Neovascularização Patológica/diagnóstico por imagem , Estudos Retrospectivos , Sorafenibe/administração & dosagem , Tempo , Tomografia Computadorizada por Raios X , Resultado do Tratamento
10.
Asian Pac J Cancer Prev ; 20(8): 2303-2310, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31450899

RESUMO

Background: There is no doubt that hyperthermia is one of the powerful radiosensitizers. Finding a proper mechanism working in hyperthermia/radiation combination is still pronounced challenge. Objectives: This study is focusing on the anti-cancer activities (anti-proliferative, anti-angiogenic and antiapoptotic) of thermoradiotherapy. Materials and Methods: Liver cancer cell line (HepG2) was treated by 37oC, 40oC and 43oC hyperthermia degrees combined with three radiation doses (2 Gy, 4 Gy and 8 Gy) for 24, 48 and 72 hrs. Cell viability, apoptotic/necrotic cell screening, apoptotic (BAX and FasL) and antiapoptotic (BCL-2 and GRP78) genes, and pro-angiogenic mediators [vascular endothelial- (VEGF) and Platelet derived-growth factors (PDGF) ware investigated. Results: Our data showed that 40oC temperature combined with 4 Gy radiation gives a significant decrease (p<0.05) in cell viability. Maximum cytotoxicity was reported 48 hr post-treatment followed by slight restoration of cell viability after 72 hr. Compared with untreated cells, only 5% of viable cells with a high percentage of apoptotic (31%) and necrotic (63%) cells were demonstrated in 40oC/4 Gy/48 hr group. Expression of pro-apoptotic genes (BAX and FasL) were increased after hyperthermia with apparent elevation in 40oC/4 Gy/48 hr group coincides with moderate expression of antiapoptotic BCL-2 and GRP78 genes. A significant reduction (p<0.001; p<0.05) in VEGF and PDGF levels; respectively was shown at 40oC/4 Gy/48 hr group. Conclusions: This pilot study proposed 40oC mild temperature hyperthermia as a favorable hyperthermal condition with 4 Gy radiotherapy in HCC treatment. A further research has to be performed considering an application of more than one session of radiothermal therapy at 40oC/4 Gy for total abrogation of cancer cells.


Assuntos
Apoptose , Carcinoma Hepatocelular/patologia , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Hipertermia Induzida/métodos , Neoplasias Hepáticas/patologia , Radioterapia/métodos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/terapia , Terapia Combinada , Humanos , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/terapia , Projetos Piloto , Células Tumorais Cultivadas
11.
Biomed Res Int ; 2019: 9264137, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31428651

RESUMO

Background: Numerous studies have shown that hepatocellular carcinoma (HCC) without microvascular invasion (MVI) may have better outcomes. This study established a preoperative MVI risk nomogram mainly incorporating three related risk factors of MVI in BCLC 0/A HCC after surgery. Methods: Independent predictors for the risk of MVI were investigated, and an MVI risk nomogram was established based on 60 patients in the training group who underwent curative hepatectomy for BCLC 0/A HCC and validated using a dataset in the validation group. Results: Univariate analysis in the training group showed that hepatitis viral B (HBV) DNA (P=0.034), tumor size (P<0.001), CT value in the venous phase (P=0.039), CT value in the delayed phase (P=0.017), peritumoral enhancement (P=0.013), visible small blood vessels in the arterial phase (P=0.002), and distance from the tumor to the inferior vena cava (IVC) (DTI, P=0.004) were risk factors significantly associated with the presence of MVI. According to multivariate analysis, the independent predictive factors of MVI, including tumor size (P=0.002), CT value in the delayed phase (P=0.018), and peritumoral enhancement (P=0.057), were incorporated in the corresponding nomogram. The nomogram displayed an unadjusted C-index of 0.851 and a bootstrap-corrected C-index of 0.832. Calibration curves also showed good agreement on the presence of MVI. ROC curve analyses showed that the nomogram had a large AUC (0.851). Conclusions: The proposed nomogram consisting of tumor size, CT value in the delayed phase, and peritumoral enhancement was associated with MVI risk in BCLC 0/A HCC following curative hepatectomy.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Microvasos , Neovascularização Patológica , Nomogramas , Adulto , Idoso , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Feminino , Humanos , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Masculino , Microvasos/patologia , Microvasos/cirurgia , Pessoa de Meia-Idade , Invasividade Neoplásica , Neovascularização Patológica/patologia , Neovascularização Patológica/cirurgia , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Risco
12.
Mar Drugs ; 17(7)2019 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-31337016

RESUMO

Chitooligosaccharides (COS), the only cationic oligosaccharide in nature, have been demonstrated to have anti-tumor activity. However, the inhibitory effects of COS on different stages of tumor metastasis are still unknown, and it is not clear what stage(s) of tumor metastasis COS targeted. To study the inhibitory effects of a new partially acetylated chitooligosaccharide (paCOS) with fraction of acetylation (FA) 0.46 on each phase of liver cancer cell metastasis, a dynamic tumor-vessel microsystem undergoing physiological flow was leveraged. paCOS (FA = 0.46) significantly inhibited proliferation of HepG2 cells through vascular absorption on the chip, and inhibited migration of HepG2 cells by inhibiting the formation of pseudopod in liver tumor cells. It was also found that paCOS at 10 µg/mL had a stronger inhibitory effect on liver tumor cells invading blood vessels than that of paCOS at 100 µg/mL, and paCOS at 100 µg/mL, which had a significant destructive effect on tumor vascular growth and barrier function. Moreover, paCOS reduced the number of liver tumor cells adhering onto the surface of HUVECs layer after 3 h of treatment. Therefore, the results revealed that paCOS had considerable potential as drugs for anti-tumor metastasis.


Assuntos
Quitina/análogos & derivados , Neoplasias Hepáticas/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Acetilação , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quitina/química , Quitina/farmacologia , Quitina/uso terapêutico , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/patologia , Técnicas Analíticas Microfluídicas , Invasividade Neoplásica/patologia , Invasividade Neoplásica/prevenção & controle
13.
Anticancer Res ; 39(6): 2739-2747, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31177109

RESUMO

BACKGROUND/AIM: The aim of the present study was to investigate the vascular normalization effect of traditional Chinese medicine Astragalus membranaceus (AM) and Curcuma wenyujin (CW) on tumor-derived endothelial cells (TECs). MATERIALS AND METHODS: TECs were isolated from the xenografted HCC cell line HepG2 expressing red fluorescent protein (RFP). The effect of AM and CW on TECs proliferation was measured using the CCK8 assay. The vascular normalization potential of AM and CW was assessed using a tube formation assay. Immunocytochemistry was performed to assess the effect of AM and CW on the expression of angiogenic maker CD34 and hypoxia-inducible factor HIF1a. RESULTS: The isolated TECs and endothelioma (EOMA) cells did not differ with regard to the expression levels of endothelial markers CD34, VEGFR-1, VEGFR-2, PDGFR-α and PDGFR-ß. All AM, CW, AM+CW and Nintedanib (Nin) showed a dose-dependent increasing inhibition effect on either TECs or EOMA cells. AM, CW and AM+CW significantly reduced HIF1a expression, increased CD34 expression and enhanced endothelial network formation in TECs or EOMA cells compared to the control. CONCLUSION: AM and CW promoted vascular normalization in tumor-derived endothelial cells of HCC, through increased expression of CD34 and reduced expression of HIF1a.


Assuntos
Antígenos CD34/metabolismo , Carcinoma Hepatocelular/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Células Endoteliais/citologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Hepáticas/metabolismo , Animais , Astragalus propinquus/química , Carcinoma Hepatocelular/irrigação sanguínea , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Curcuma/química , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/irrigação sanguínea , Medicina Tradicional Chinesa , Camundongos , Transplante de Neoplasias , Transdução de Sinais/efeitos dos fármacos
14.
World J Gastroenterol ; 25(19): 2365-2372, 2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31148907

RESUMO

BACKGROUND: Lenvatinib is one of the first-line tyrosine kinase inhibitors used for unresectable hepatocellular carcinoma (HCC). In the present study, we evaluated the potential of early changes in the time-intensity curve (TIC) of arterial phase on contrast-enhanced ultrasound (CEUS) as early imaging biomarkers of lenvatinib efficacy. AIM: To evaluate the potential of the early changes in the TIC of CEUS as early imaging biomarkers of lenvatinib efficacy in patients with unresectable HCC. METHODS: We analyzed 20 consecutive patients with unresectable HCC treated with lenvatinib from March to November 2018. Tumor response at 8 wk was assessed by computed tomography using the modified Response Evaluation Criteria in Solid Tumors (mRECIST). CEUS was performed at baseline before treatment (Day 0) and on day 7 (Day 7), and the images were analyzed in the arterial phase for 20 seconds after the contrast agent arrived at the target tumor. Three perfusion parameters were extracted from the TICs: the slope of wash-in (Slope), time to peak (TTP) intensity, and the total area under the curve (AUC) during wash-in. The rate of change in the TIC parameters between Day 0 and Day 7 was compared between treatment responders and non-responders based on mRECIST. RESULTS: The rate of change for all TIC parameters showed significant differences between the responders (n = 9) and non-responders (n = 11) (Slope, P = 0.025; TTP, P = 0.004; and AUC, P = 0.0003). The area under the receiver operating curve values for slope, TTP, and AUC for the prediction of responders were 0.805, 0.869, and 0.939, respectively. CONCLUSION: CEUS may be useful for the early prediction of tumor response to lenvatinib therapy in patients with unresectable HCC.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Imagem de Perfusão/métodos , Compostos de Fenilureia/uso terapêutico , Quinolinas/uso terapêutico , Idoso , Artérias/diagnóstico por imagem , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/diagnóstico por imagem , Meios de Contraste/administração & dosagem , Feminino , Humanos , Fígado/irrigação sanguínea , Fígado/diagnóstico por imagem , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Critérios de Avaliação de Resposta em Tumores Sólidos , Tomografia Computadorizada por Raios X , Ultrassonografia/métodos
15.
World J Gastroenterol ; 25(20): 2524-2538, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31171895

RESUMO

BACKGROUND: Neoangiogenesis is one of the key pathogenetic mechanisms in hepatocellular carcinoma (HCC). Modulation of the renin-angiotensin system (RAS) by angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) seems to be a possible adjuvant therapy for HCC, due to the anti-angiogenic and anti-fibrogenic activity of these drugs. AIM: To elucidate the role of ARBs and ACE-Is in HCC. METHODS: We performed an electronic search of the literature using the most accessed online databases (PubMed, Cochrane library, Scopus and Web of Science), entering the query terms "angiotensin-converting enzyme inhibitors" OR "ACE inhibitors" OR "ACE-I" AND "hepatocarcinoma*" OR "hepatocellular carcinoma; moreover "angiotensin II type 1 receptor blockers" OR "ARBs" AND "hepatocarcinoma*" OR "hepatocellular carcinoma". Eligibility criteria were: (1) prospective or retrospective clinical studies; (2) epidemiological studies; and (3) experimental studies conducted in vivo or in vitro. Abstracts, conference papers, and reviews were excluded a priori. We limited our literature search to articles published in English, in peer-reviewed journals. RESULTS: Thirty-one studies were selected. Three interventional studies showed that ACE-Is had a significant protective effect on HCC recurrence only when used in combination with vitamin K or branched chain aminoacids, without a significant increase in overall survival. Of six retrospective observational studies, mainly focused on overall survival, only one demonstrated a prolonged survival in the ACE-Is group, whereas the two that also evaluated tumor recurrence showed conflicting results. All experimental studies displayed beneficial effects of RAS inhibitors on hepatocarcinogenesis. Numerous experimental studies, conducted either on animals and cell cultures, demonstrated the anti-angiogenetic and antifibrotic effect of ACE-Is and ARBs, thanks to the suppression of some cytokines such as vascular endothelial growth factor, hypoxia-inducible factor-1a, transforming growth factor-beta and tumor necrosis factor alpha. All or parts of these mechanisms were demonstrated in rodents developing fewer HCC and preneoplastic lesions after receiving such drugs. CONCLUSION: In humans, RAS inhibitors - alone or in combination - significantly suppressed the cumulative HCC recurrence, without prolonging patient survival, but some limitations intrinsic to these studies prompt further investigations.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , Recidiva Local de Neoplasia/prevenção & controle , Neovascularização Patológica/prevenção & controle , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/mortalidade , Quimioterapia Adjuvante/métodos , Modelos Animais de Doenças , Quimioterapia Combinada/métodos , Hepatectomia , Humanos , Fígado/irrigação sanguínea , Fígado/efeitos dos fármacos , Fígado/cirurgia , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/mortalidade , Recidiva Local de Neoplasia/epidemiologia , Estudos Observacionais como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Sistema Renina-Angiotensina/efeitos dos fármacos , Resultado do Tratamento
16.
Biomed Res Int ; 2019: 8350926, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31211142

RESUMO

Objective: It is difficult to control small hepatocellular carcinoma (HCC) nodules adjacent to the Glisson sheath (GS) by trans-arterial chemoembolization (TACE) probably due to multiple small tumor feeders directly branching from the trunk artery. The purpose of this study was to conduct a retrospective evaluation of a new TACE technique called the repeated alternate infusion of cisplatin solution and gelatin slurry distal to balloon occlusion (RAIB-TACE), for the treatment of small HCC nodules adjacent to GS. Materials and Methods: Small nodules less than 4 cm attached to proximal portion of the subsegmental to lobar level portal branch were retrospectively selected. Between January 2011 and April 2014, 29 nodules in 29 patients were treated by super-selective lipiodol TACE/balloon-occluded TACE (B-TACE) (Lip-TACE group). Since April 2014, treatment protocols for small nodules adjacent to GS were changed, and 14 nodules in 12 patients were treated by RAIB-TACE (RAIB-TACE group). In RAIB-TACE group, alternate infusion of cisplatin solution and sparse gelatin slurry (mixture of 80 mg of gelatin fragments and 20 mL of contrast medium) were repeated until arterial flow was ceased. In Lip-TACE group, lipiodol was used as drug carrier and dense gelatin slurry (mixture of 80 mg of gelatin fragments and 2 mL of contrast medium) as embolization material. Dynamic CT/MRI was obtained 1-3 months after TACE, and response of each nodule was evaluated basing on modified RECIST criteria. Results: In RAIB-TACE group, all 14 nodules (100%) were diagnosed as CR or PR. In Lip-TACE group, 18 of 29 (62.1%) were diagnosed as CR or PR. There was a statistically significant difference in objective response ratio between the groups (p=0.008, Fisher's test). Biloma (n=1) and benign stricture of the right hepatic duct (n=1) were seen in RAIB-TACE group. The biloma shrunk without treatment and the patient had no symptom, but the patient with biliary stricture repeated cholangitis and was treated by administration of antibiotics. Conclusion: The study results show that RAIB-TACE is more effective than lipiodol TACE/B-TACE for small hepatocellular carcinoma adjacent to GS. We speculate that one of the reasons to explain why Lip-TACE is inferior to RAIB-TACE is that viscous lipiodol or dense gelatin slurry could not flow into small tumor feeders effectively.


Assuntos
Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica , Cisplatino/administração & dosagem , Óleo Etiodado/administração & dosagem , Gelatina/administração & dosagem , Neoplasias Hepáticas/terapia , Idoso , Idoso de 80 Anos ou mais , Oclusão com Balão , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/patologia , Feminino , Humanos , Fígado/irrigação sanguínea , Fígado/patologia , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
18.
Semin Nucl Med ; 49(3): 204-210, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30954186

RESUMO

In order to evaluate the role of angiogenesis in 90Y-radioembolization for colorectal cancer liver metastasis an overview was provided of angiogenic growth factors and their function, the angiogenic mechanisms in colorectal cancer, the role of hypoxia, and the advances in antiangiogenic therapy. Last, the use of circulating angiogenic growth factors in 90Y-radioembolization was reviewed. Two literature searches were conducted. A search query in PubMed on angiogenesis in colorectal cancer, and a systematic search in PubMed (Medline), Embase, and the Cochrane Library (October 2018) with synonyms for "radioembolization" and "angiogenic growth factor." The first search yielded 3 relevant publications on the role of angiogenic growth factors in colorectal cancer, hypoxia, and antiangiogenic therapy. The second search yielded two prospective studies on circulating angiogenic factors and their relationship with response and survival after 90Y-radioembolization for colorectal cancer liver metastases. Rises in circulating angiogenic growth factors after radioembolization were seen in both studies. High baseline values of Ang-2 and IL-8 correlated with shorter survival and post 90Y-radiembolization rises in Ang-2 and HGF correlated with early progression. Various angiogenic growth factors play a role in the development and progression of colorectal cancer. Several factors show correlation with poor outcomes after 90Y-radioembolization and might be used for patient selection in the future, however, validation in larger comparative studies is required.


Assuntos
Neoplasias Colorretais/patologia , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/radioterapia , Neovascularização Patológica/radioterapia , Radioisótopos de Ítrio/uso terapêutico , Humanos , Neoplasias Hepáticas/secundário
19.
Cancer Invest ; 37(4-5): 185-198, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31006280

RESUMO

High expression of vascular endothelial growth factor (VEGF) in patients with hepatocellular carcinoma (HCC) is associated with poor prognosis. Here, we investigated the antitumor activity of lenvatinib, a multiple receptor tyrosine kinase inhibitor, in VEGF-overexpressing HCC models. In human umbilical vein endothelial cells, lenvatinib showed potent inhibitory activities against VEGF-induced proliferation and VEGF/basic fibroblast growth factor-induced tube formation. In VEGF-overexpressing HCC xenograft models, characterized by aggressive tumor growth and hypervascularity, lenvatinib had significant antitumor and antiangiogenic activities. These results suggest that potent activity of lenvatinib against VEGF signaling underlies its antitumor and antiangiogenic activities in the hypervascular HCC models.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Compostos de Fenilureia/farmacologia , Quinolinas/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/patologia , Camundongos , Neovascularização Patológica/patologia , Compostos de Fenilureia/uso terapêutico , Quinolinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Med Hypotheses ; 126: 109-128, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31010487

RESUMO

Unlike other carcinomas, hepatocellular carcinoma (HCC) metastasizes to distant organs relatively rarely. In contrast, it routinely metastasizes to liver vasculature/liver, affecting portal veins 3-10 times more often than hepatic veins. This portal metastatic predominance is traditionally rationalized within the model of a reverse portal flow, due to accompanying liver cirrhosis. However, this intuitive model is not coherent with facts: 1) reverse portal flow occurs in fewer than 10% of cirrhotic patients, while portal metastasis occurs in 30-100% of HCC cases, and 2) portal vein prevalence of HCC metastasis is also characteristic of HCC in non-cirrhotic livers. Therefore, we must assume that the route for HCC metastatic dissemination is the same as for other carcinomas: systemic dissemination via the draining vessel, i.e., via the hepatic vein. In this light, portal prevalence versus hepatic vein of HCC metastasis appears as a puzzling pattern, particularly in cases when portal HCC metastases have appeared as the sole manifestation of HCC. Considering that other GI carcinomas (colorectal, pancreatic, gastric and small bowel) invariably disseminate via portal vein, but very rarely form portal metastasis, portal prevalence of HCC metastasis appears as a paradox. However, nature does not contradict itself; it is rather our wrong assumptions that create paradoxes. The 'portal paradox' becomes a logical event within the hypothesis that the formation of the unique portal venous system preceded the appearance of liver in evolution of chordates. The analysis suggests that the appearance of the portal venous system, supplying hormones and growth factors of pancreatic family, which includes insulin, glucagon, somatostatin, and pancreatic polypeptide (HGFPF) to midgut diverticulum in the early evolution of chordates (in an Amphioxus-like ancestral animal), promoted differentiation of enterocytes into hepatocytes and their further evolution to the liver of vertebrates. These promotional-dependent interactions are conserved in the vertebrate lineage. I hypothesize that selective homing and proliferation of malignant hepatocytes (i.e., HCC cells) in the portal vein environment are due to a uniquely high concentration of HGFPF in portal blood. HGFPF are also necessary for liver function and renewal and are significantly extracted by hepatocytes from passing blood, creating a concentration gradient of HGFPF between the portal blood and hepatic vein outflow, making post-liver vasculature and remote organs less favorable spaces for HCC growth. It also suggested that the portal vein environment (i.e., HGFPF) promotes the differentiation of more aggressive HCC clones from already-seeded portal metastases, explaining the worse outcome of HCC with the portal metastatic pattern. The analysis also offers new hypothesis on the phylogenetic origin of the hepatic diverticulum of cephalochordates, with certain implications for the modeling of the chordate phylogeny.


Assuntos
Evolução Biológica , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/patologia , Veias Hepáticas/patologia , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/patologia , Veia Porta/patologia , Animais , Hepatócitos/patologia , História do Século XIX , História do Século XX , Humanos , Anfioxos , Fígado/patologia , Cirrose Hepática/patologia , Neoplasias Hepáticas/secundário , Oncologia/história , Modelos Anatômicos , Modelos Biológicos , Metástase Neoplásica , Obstetrícia/história , Filogenia , Ratos
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