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1.
Medicine (Baltimore) ; 99(40): e22350, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019411

RESUMO

BACKGROUND: Ultrasonography is the first choice for clinical diagnosis and differentiation of thyroid cancer Currently. However, due to the complexity and overlapping nature of the thyroid nodule sonograms, it remains difficult to accurately identify nodules with atypical ultrasound characteristics. Previous studies showed that superb microvascular imaging (SMI) can detect tumor neovascularization to differentiate benign from malignant thyroid nodules. However, the results of these studies have been contradictory with low sample sizes. This meta-analysis tested the hypothesis that SMI is accurate in distinguishing benign and malignant thyroid nodules. METHODS: We will search PubMed, Web of Science, Cochrane Library, and Chinese biomedical databases from their inceptions to the August 20, 2020, without language restrictions. Two authors will independently carry out searching literature records, scanning titles and abstracts, full texts, collecting data, and assessing risk of bias. Review Manager 5.2 and Stata14.0 software ((Stata Corp, College Station, TX) will be used for data analysis. RESULTS: This systematic review will determine the accuracy of SMI in distinguishing thyroid nodules. CONCLUSION: Its findings will provide helpful evidence for the accuracy of SMI in in distinguishing thyroid nodules.Systematic review registration: INPLASY202080084.


Assuntos
Processamento de Imagem Assistida por Computador/métodos , Nódulo da Glândula Tireoide/diagnóstico , Nódulo da Glândula Tireoide/patologia , Ultrassonografia/métodos , Diagnóstico Diferencial , Neovascularização Patológica/patologia , Projetos de Pesquisa , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/patologia , Nódulo da Glândula Tireoide/diagnóstico por imagem
2.
Life Sci ; 260: 118418, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32931799

RESUMO

AIMS: Stroke is a devastating event with a limited choice of intervention. Benzoinum is frequently used to treat stroke in traditional Chinese medicine. Our team has found that the neuroprotection of benzoinum may related to angiogenesis, but the exact biological mechanism is unclear. The objective of this study was to explore its biological mechanism of angiogenesis in cerebral ischemia model rats. MAIN METHODS: First, network pharmacology and molecular docking were performed to predict the possible targets and mechanisms of benzoinum in treating ischemic stroke. The best dose was then selected according to pharmacodynamic indexes such as those for neurological deficit, cerebral infarction rate, and brain histopathology in middle cerebral artery occlusion (MCAO) model rats. Finally, RT-PCR, Western Blot and immunohistochemical analysis were applied to verify the prediction results from molecular docking. KEY FINDINGS: Network pharmacology and molecular docking demonstrated that the targets of treating cerebral ischemia were PDE4D, ACE and TTR, and the mechanism may be related to the ACE-AngI-VEGF signaling pathway. Experimental verification results suggested that 0.50 g/kg and 1.00 g/kg benzoinum could significantly protect against neurological deficit and reduce cerebral infarction rate in the cerebral cortex and hippocampus in MCAO model rats. At an optimal dose, benzoinum could significantly up-regulate VEGF, SHH and ANG-1, yet down-regulate ACE expression in MCAO model rats. SIGNIFICANCE: Balsamic acid is the active ingredient of benzoinum that protects against ischemic stroke and the possible mechanism is related to the promotion of angiogenesis via regulating ACE-AngI-VEGF pathway.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Infarto da Artéria Cerebral Média/complicações , Fármacos Neuroprotetores/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Isquemia Encefálica/etiologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Masculino , Simulação de Acoplamento Molecular , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Ribonuclease Pancreático/genética , Ribonuclease Pancreático/metabolismo , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
4.
Zhonghua Zhong Liu Za Zhi ; 42(8): 624-628, 2020 Aug 23.
Artigo em Chinês | MEDLINE | ID: mdl-32867452

RESUMO

Small cell lung cancer (SCLC), a special type of lung cancer, is a highly malignant neuroendocrine tumor with strong invasiveness and rapid progression. SCLC is sensitive to radiotherapy and chemotherapy, so radiotherapy and chemotherapy have been the main first-line treatment of SCLC. However, it is easy to develop drug resistance after treatment. Therefore, the study of anti-angiogenic therapy has attracted more and more attention. At present, anti-angiogenic drugs mainly focus on four categories: monoclonal antibodies (such as bevacizumab), endogenous angiogenesis inhibitors (such as endostar), anti-angiogenic fusion protein (such as aflibercept) and small molecular tyrosine kinase inhibitors (such as anlotinib). There are still some bottlenecks in the research and clinical application of antiangiogenic drugs. It is the right direction to explore better combination therapy and effective dual-field and multi-target drugs.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Inibidores da Angiogênese/farmacologia , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/farmacologia , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Humanos , Neoplasias Pulmonares/patologia , Neovascularização Patológica/patologia , Medicina de Precisão , Carcinoma de Pequenas Células do Pulmão/patologia , Resultado do Tratamento
5.
Anticancer Res ; 40(10): 5437-5443, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988865

RESUMO

BACKGROUND: Neuropilin-1 (NRP1) is a receptor for vascular endothelial growth factor A (VEGFA), and has been reported to be overexpressed in several malignancies. Since angiogenesis plays an important role in pathogenesis of multiple myeloma (MM) and the role of NRP1 in MM has not been studied yet, we characterized the expression of NRP1 in this disease. MATERIALS AND METHODS: The expression level of NRP1 was measured in 140 patients newly diagnosed with MM and 28 healthy controls by flow cytometry and quantitative reverse transcriptase polymerase chain reaction. RESULTS: Expression of NRP1 was significantly reduced on plasma cells (median=2.05%) compared to that on B-cells (median=10.05%, p<0.0001) in bone marrow of patients with MM. In MM, the expression of NRP1 was high on plasmacytoid dendritic cells (median=85.85%) and low on regulatory T-cells (median=0.6%). CONCLUSION: In MM, NRP1 is regulated differentially as compared to other B-cell malignancies at both the RNA and protein level.


Assuntos
Mieloma Múltiplo/genética , Neovascularização Patológica/genética , Neuropilina-1/genética , Fator A de Crescimento do Endotélio Vascular/genética , Adulto , Linfócitos B/metabolismo , Feminino , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/patologia , Neovascularização Patológica/sangue , Neovascularização Patológica/patologia , Neuropilina-1/sangue , Transdução de Sinais/genética
6.
Anticancer Res ; 40(10): 5463-5469, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988868

RESUMO

BACKGROUND/AIM: Periostin exists as an extracellular matrix protein in several carcinomas and is related to metastasis and poor prognosis. It is mainly secreted from cancer associated fibroblasts, and not from carcinoma cells. As a tumor microenvironment component, periostin usually mediates tumor cell stemness, metastasis, angiogenesis and lymphangiogenesis. This study aimed to examine the role of periostin in chondrosarcoma. MATERIALS AND METHODS: To evaluate the effect of periostin on the proliferation of chondrosarcoma cells, MTT assay was performed on SW1353 cells and periostin knockdown SW1353 cells. Migration activity was examined using Boyden chamber. RESULTS: Periostin, secreted from chondrosarcoma cells, was found to support proliferation, and maintain stemness and migration of chondrosarcoma cells. Periostin also induced proliferation and migration of lymphatic endothelial cells. CONCLUSION: Periostin plays an important role in chondrosarcoma development and disease progression.


Assuntos
Moléculas de Adesão Celular/genética , Proliferação de Células/genética , Condrossarcoma/genética , Neovascularização Patológica/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Sobrevivência Celular/genética , Condrossarcoma/patologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Humanos , Linfangiogênese/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Neovascularização Patológica/patologia , Microambiente Tumoral/genética
7.
PLoS One ; 15(9): e0226450, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32911509

RESUMO

Triple negative tumors are more aggressive than other breast cancer subtypes and there is a lack of specific therapeutic targets on them. Since muscarinic receptors have been linked to tumor progression, we investigated the effect of metronomic therapy employing a traditional anti-cancer drug, paclitaxel plus muscarinic agonists at low doses on this type of tumor. We observed that MDA-MB231 tumor cells express muscarinic receptors, while they are absent in the non-tumorigenic MCF-10A cell line, which was used as control. The addition of carbachol or arecaidine propargyl ester, a non-selective or a selective subtype 2 muscarinic receptor agonist respectively, plus paclitaxel reduces cell viability involving a down-regulation in the expression of ATP "binding cassette" G2 drug transporter and epidermal growth factor receptor. We also detected an inhibition of tumor cell migration and anti-angiogenic effects produced by those drug combinations in vitro and in vivo (in NUDE mice) respectively. Our findings provide substantial evidence about subtype 2 muscarinic receptors as therapeutic targets for the treatment of triple negative tumors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Agonistas Colinérgicos/administração & dosagem , Paclitaxel/administração & dosagem , Receptor Muscarínico M2/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Administração Metronômica , Animais , Arecolina/administração & dosagem , Arecolina/análogos & derivados , Carbacol/administração & dosagem , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Receptores ErbB/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Proteínas de Neoplasias/metabolismo , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , RNA Interferente Pequeno/metabolismo , Receptor Muscarínico M2/agonistas , Receptor Muscarínico M2/genética , Neoplasias de Mama Triplo Negativas/irrigação sanguínea , Neoplasias de Mama Triplo Negativas/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Int J Nanomedicine ; 15: 6451-6468, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922011

RESUMO

Background: Non-small cell lung cancer (NSCLC) is one of the most lethal types of cancer with highly infiltrating. Chemotherapy is far from satisfactory, vasculogenic mimicry (VM) and angiogenesis results in invasion, migration and relapse. Purpose: The objective of this study was to construct a novel CPP (mmp) modified vinorelbine and dioscin liposomes by two new functional materials, DSPE-PEG2000-MAL and CPP-PVGLIG-PEG5000, to destroy VM channels, angiogenesis, EMT and inhibit invasion and migration. Methods and Results: The targeting liposomes could be enriched in tumor sites through passive targeting, and the positively charged CPP was exposed and enhanced active targeting via electrostatic adsorption after being hydrolyzed by MMP2 enzymes overexpressed in the tumor microenvironment. We found that CPP (mmp) modified vinorelbine and dioscin liposomes with the ideal physicochemical properties and exhibited enhanced cellular uptake. In vitro and in vivo results showed that CPP (mmp) modified vinorelbine and dioscin liposomes could inhibit migration and invasion of A549 cells, destroy VM channels formation and angiogenesis, and block the EMT process. Pharmacodynamic studies showed that the targeting liposomes had obvious accumulations in tumor sites and magnificent antitumor efficiency. Conclusion: CPP (mmp) modified vinorelbine plus dioscin liposomes could provide a new strategy for NSCLC.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Microambiente Tumoral , Células A549 , Animais , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Morte Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Galinhas , Endocitose/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Hidrólise , Lipossomos , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Microambiente Tumoral/efeitos dos fármacos , Vinorelbina/farmacologia , Vinorelbina/uso terapêutico
9.
Proc Natl Acad Sci U S A ; 117(35): 21598-21608, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32817421

RESUMO

We tested cis-Apc Δ716 /Smad4 +/- and cis-Apc Δ716 /Smad4 +/- Kras G12D mice, which recapitulate key genetic abnormalities accumulating during colorectal cancer (CRC) tumorigenesis in humans, for responsiveness to anti-VEGF therapy. We found that even tumors in cis-Apc Δ716 /Smad4 +/- Kras G12D mice, although highly aggressive, were suppressed by anti-VEGF treatment. We tested the hypothesis that inflammation, a major risk factor and trigger for CRC, may affect responsiveness to anti-VEGF. Chemically induced colitis (CIC) in cis-Apc Δ716 /Smad4 +/- and cis-Apc Δ716 /Smad4 +/- Kras G12D mice promoted development of colon tumors that were largely resistant to anti-VEGF treatment. The myeloid growth factor G-CSF was markedly increased in the serum after induction of colitis. Antibodies blocking G-CSF, or its target Bv8/PROK2, suppressed tumor progression and myeloid cell infiltration when combined with anti-VEGF in CIC-associated CRC and in anti-VEGF-resistant CRC liver metastasis models. In a series of CRC specimens, tumor-infiltrating neutrophils strongly expressed Bv8/PROK2. CRC patients had significantly higher plasma Bv8/PROK2 levels than healthy volunteers and high plasma Bv8/PROK2 levels were inversely correlated with overall survival. Our findings establish Bv8/PROK2 as a translational target in CRC, in combination with anti-VEGF agents.


Assuntos
Neoplasias Colorretais/genética , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Indutores da Angiogênese/metabolismo , Animais , Anticorpos/imunologia , Neoplasias do Colo/metabolismo , Neoplasias Colorretais/metabolismo , Feminino , Fator Estimulador de Colônias de Granulócitos/metabolismo , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Genéticos , Células Mieloides/metabolismo , Neovascularização Patológica/patologia , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/imunologia , Fator A de Crescimento do Endotélio Vascular/metabolismo
10.
Life Sci ; 258: 118163, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32738363

RESUMO

The tumor microenvironment (TME) provides a guarantee for the survival and development of solid tumors. In recent years, treatment strategies for TME have set off a great upsurge in the field of cancer research. Tumor angiogenesis and tumor immune microenvironment are two important research branches of TME, and antiangiogenic therapy and immunotherapy have gradually become one important focus of cancer treatment research. More interestingly, increasing number of studies have indicated that there are complex regulatory interactions between the two treatment strategies, with multiple regulatory mechanisms involved. Based on these findings, clinical studies on the combination of immunotherapy and antiangiogenic therapy have also been carried out gradually. This combination strategy has shown good results in many types of tumors, but it also faces many challenges. The paper analysed the potential mechanism of the immunotherapy and antiangiogenic therapy combination, discussed the latest significant clinical trial progress and the existing challenges and problems, aiming to offer some available insights on the effective clinical application of this combination pattern.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Imunoterapia/métodos , Neoplasias/terapia , Neovascularização Patológica/terapia , Animais , Terapia Combinada , Humanos , Neoplasias/complicações , Neoplasias/imunologia , Neoplasias/patologia , Neovascularização Patológica/complicações , Neovascularização Patológica/imunologia , Neovascularização Patológica/patologia , Microambiente Tumoral/efeitos dos fármacos
11.
Nat Commun ; 11(1): 3653, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32694534

RESUMO

The vasculature represents a highly plastic compartment, capable of switching from a quiescent to an active proliferative state during angiogenesis. Metabolic reprogramming in endothelial cells (ECs) thereby is crucial to cover the increasing cellular energy demand under growth conditions. Here we assess the impact of mitochondrial bioenergetics on neovascularisation, by deleting cox10 gene encoding an assembly factor of cytochrome c oxidase (COX) specifically in mouse ECs, providing a model for vasculature-restricted respiratory deficiency. We show that EC-specific cox10 ablation results in deficient vascular development causing embryonic lethality. In adult mice induction of EC-specific cox10 gene deletion produces no overt phenotype. However, the angiogenic capacity of COX-deficient ECs is severely compromised under energetically demanding conditions, as revealed by significantly delayed wound-healing and impaired tumour growth. We provide genetic evidence for a requirement of mitochondrial respiration in vascular endothelial cells for neoangiogenesis during development, tissue repair and cancer.


Assuntos
Mitocôndrias/metabolismo , Neoplasias/patologia , Neovascularização Patológica/patologia , Neovascularização Fisiológica , Cicatrização/fisiologia , Trifosfato de Adenosina/metabolismo , Alquil e Aril Transferases/genética , Alquil e Aril Transferases/metabolismo , Animais , Linhagem Celular Tumoral/transplante , Respiração Celular , Modelos Animais de Doenças , Embrião de Mamíferos , Desenvolvimento Embrionário/fisiologia , Células Endoteliais/fisiologia , Endotélio Vascular/citologia , Endotélio Vascular/fisiologia , Feminino , Técnicas de Inativação de Genes , Humanos , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Mitocôndrias/genética , Neoplasias/irrigação sanguínea , Fosforilação Oxidativa
12.
Adv Cancer Res ; 148: 27-67, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32723566

RESUMO

Vascular mimicry is induced by a wide array of genes with functions related to cancer stemness, hypoxia, angiogenesis and autophagy. Vascular mimicry competent (VM-competent) cells that form de novo blood vessels are common in solid tumors facilitating tumor cell survival and metastasis. VM-competent cells display increased levels of vascular mimicry selecting for stem-like cells in an O2-gradient-dependent manner in deeply hypoxic tumor regions, while also aiding in maintaining tumor cell metabolism and stemness. Three of the principal drivers of vascular mimicry are EphA2, Nodal and HIF-1α, however, directly or indirectly many of these molecules affect VE-Cadherin (VE-Cad), which forms gap-junctions to bind angiogenic blood vessels together. During vascular mimicry, the endothelial-like functions of VM-competent cancer stem cells co-opt VE-Cad to bind cancer cells together to create cancer cell-derived blood conducting vessels. This process potentially compensates for the lack of access to blood and nutrient in avascular tumors, simultaneously providing nutrients and enhancing cancer invasion and metastasis. Current evidence also supports that vascular mimicry promotes cancer malignancy and metastasis due to the cooperation of oncogenic signaling molecules driving cancer stemness and autophagy. While a number of currently used cancer therapeutics are effective inhibitors of vascular mimicry, developing a new class of vascular mimicry specific inhibitors could allow for the treatment of angiogenesis-resistant tumors, inhibit cancer metastasis and improve patient survival. In this review, we describe the principal vascular mimicry pathways in addition to emphasizing the roles of hypoxia, autophagy and select proangiogenic oncogenes in this process.


Assuntos
Neoplasias/irrigação sanguínea , Neoplasias/patologia , Animais , Autofagia/fisiologia , Hipóxia Celular/fisiologia , Modelos Animais de Doenças , Humanos , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia
13.
J Cancer Res Clin Oncol ; 146(10): 2547-2557, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32671503

RESUMO

INTRODUCTION: Colorectal cancer (CRC) constitutes one of the most prevalent malignancies in the world. Recent research suggests that cancer stem cells (CSCs) are responsible for tumor cell's malignant behavior in CRC. This study has been designed to determinate clinical implications of CSC markers: CD44, DCLK1, Lgr5, and ANXA2 in CRC. MATERIALS AND METHODS: The study was performed on tissue samples which were collected from 89 patients undergoing colectomy. Formalin-fixed paraffin-embedded tissue blocks with representative tumor areas were identified and corded. Immunohistochemical staining was performed using anti-CD44, anti-LGR5, anti-ANXA2, and anti-DCLK1 antibodies. The H-score system was utilized to determine the immunointensity of CRC cells. RESULTS: The lower expression of Lgr5 was significantly correlated with the presence of lymph-node metastases (p = 0.011), while high expression of Lgr5 was statistically significant in vascular invasion in examined cancer tissue samples (p = 0.027). Moreover, a high H-score value of Lgr5 expression was significantly related to a reduced overall survival rate (p = 0.043). CONCLUSION: Our results suggest a strong relationship between CSC marker Lgr5 and vascular invasion, presence of lymph-node metastasis, and overall poor survival. The presence of Lgr5 might be an unfavorable prognostic factor, and its high level in cancer tissue is related to an aggressive course. This marker could also be used to access the effectiveness of the treatment.


Assuntos
Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Receptores Acoplados a Proteínas-G/metabolismo , Idoso , Anexina A2/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/irrigação sanguínea , Progressão da Doença , Feminino , Humanos , Receptores de Hialuronatos/metabolismo , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Prognóstico , Proteínas Serina-Treonina Quinases/metabolismo , Receptores Acoplados a Proteínas-G/biossíntese , Análise Serial de Tecidos
14.
AJR Am J Roentgenol ; 215(3): 595-602, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32569515

RESUMO

OBJECTIVE. The purpose of this study was to investigate the correlation between iodine concentration (IC) derived from spectral CT and angiogenesis and the relationships between IC and clinical-pathologic features associated with lung cancer prognosis. SUBJECTS AND METHODS. Sixty patients with lung cancer were enrolled and underwent spectral CT. The IC, IC difference (ICD), and normalized IC (NIC) of tumors were measured in the arterial phase, venous phase (VP), and delayed phase. The microvessel densities (MVDs) of CD34-stained specimens were evaluated. Correlation analysis was performed for IC and MVD. The relationships between the IC index showing the best correlations with MVD and clinical-pathologic findings of pathologic types, histologic differentiation, tumor size, lymph node status, pathologic TNM stage, and intratumoral necrosis were investigated. RESULTS. The mean (± IQR) MVD of all tumors was 42.00 ± 27.50 vessels per field at ×400 magnification, with two MVD distribution types. The MVD of lung cancer correlated positively with the IC, ICD, and NIC on three-phase contrast-enhanced scanning (r range, 0.581-0.800; all p < 0.001), and the IC in the VP showed the strongest correlation with MVD (r = 0.800; p < 0.001). The correlations between IC and MVD, ICD and MVD, and NIC and MVD varied depending on whether the same scanning phase or same IC index was used. The IC in the VP showed statistically significant differences in the pathologic types of adenocarcinoma and squamous cell carcinoma, histologic differentiation, tumor size, and status of intratumoral necrosis of lung cancer (p < 0.05), but was not associated with nodal metastasis and pathologic TNM stages (p > 0.05). CONCLUSION. IC indexes derived from spectral CT, especially the IC in the VP, were useful indicators for evaluating tumor angiogenesis and prognosis.


Assuntos
Neoplasias Pulmonares/diagnóstico por imagem , Neovascularização Patológica/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Meios de Contraste , Feminino , Humanos , Iohexol , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/patologia , Prognóstico , Estudos Prospectivos , Carga Tumoral
15.
Nat Cell Biol ; 22(7): 828-841, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32541879

RESUMO

Mutations in chromatin-modifying complexes and metabolic enzymes commonly underlie complex human developmental syndromes affecting multiple organs. A major challenge is to determine how disease-causing genetic lesions cause deregulation of homeostasis in unique cell types. Here we show that neural-specific depletion of three members of the non-specific lethal (NSL) chromatin complex-Mof, Kansl2 or Kansl3-unexpectedly leads to severe vascular defects and brain haemorrhaging. Deregulation of the epigenetic landscape induced by the loss of the NSL complex in neural cells causes widespread metabolic defects, including an accumulation of free long-chain fatty acids (LCFAs). Free LCFAs induce a Toll-like receptor 4 (TLR4)-NFκB-dependent pro-inflammatory signalling cascade in neighbouring vascular pericytes that is rescued by TLR4 inhibition. Pericytes display functional changes in response to LCFA-induced activation that result in vascular breakdown. Our work establishes that neurovascular function is determined by the neural metabolic environment.


Assuntos
Núcleo Celular/patologia , Cromatina/metabolismo , Histona Acetiltransferases/fisiologia , Inflamação/patologia , Neovascularização Patológica/patologia , Neurônios/patologia , Pericitos/patologia , Animais , Encéfalo/citologia , Encéfalo/metabolismo , Núcleo Celular/metabolismo , Cromatina/genética , Ácidos Graxos/metabolismo , Feminino , Feto/citologia , Feto/metabolismo , Humanos , Inflamação/metabolismo , Masculino , Metaboloma , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neovascularização Patológica/metabolismo , Neurônios/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Pericitos/metabolismo
16.
Cancer Res ; 80(14): 2996-3008, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32536602

RESUMO

Tumor endothelial cells (TEC) lining tumor blood vessels actively contribute to tumor progression and metastasis. In addition to tumor cells, TEC may develop drug resistance during cancer treatment, allowing the tumor cells to survive chemotherapy and metastasize. We previously reported that TECs resist paclitaxel treatment via upregulation of ABCB1. However, whether TEC phenotypes are altered by anticancer drugs remains to be clarified. Here, we show that ABCB1 expression increases after chemotherapy in urothelial carcinoma cases. The ratio of ABCB1-positive TEC before and after first-line chemotherapy in urothelial carcinoma tissues (n = 66) was analyzed by ABCB1 and CD31 immunostaining. In 42 cases (64%), this ratio increased after first-line chemotherapy. Chemotherapy elevated ABCB1 expression in endothelial cells by increasing tumor IL8 secretion. In clinical cases, ABCB1 expression in TEC correlated with IL8 expression in tumor cells after first-line chemotherapy, leading to poor prognosis. In vivo, the ABCB1 inhibitor combined with paclitaxel reduced tumor growth and metastasis compared with paclitaxel alone. Chemotherapy is suggested to cause inflammatory changes in tumors, inducing ABCB1 expression in TEC and conferring drug resistance. Overall, these findings indicate that TEC can survive during chemotherapy and provide a gateway for cancer metastasis. Targeting ABCB1 in TEC represents a novel strategy to overcome cancer drug resistance. SIGNIFICANCE: These findings show that inhibition of ABCB1 in tumor endothelial cells may improve clinical outcome, where ABCB1 expression contributes to drug resistance and metastasis following first-line chemotherapy.


Assuntos
Biomarcadores Tumorais/metabolismo , Resistencia a Medicamentos Antineoplásicos , Interleucina-8/metabolismo , Neovascularização Patológica/patologia , Paclitaxel/farmacologia , Neoplasias da Bexiga Urinária/mortalidade , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antineoplásicos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Resistência a Múltiplos Medicamentos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Quimioterapia de Indução , Interleucina-8/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Neovascularização Patológica/induzido quimicamente , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas , Neoplasias da Bexiga Urinária/irrigação sanguínea , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Clín. investig. ginecol. obstet. (Ed. impr.) ; 47(2): 51-57, abr.-jun. 2020. graf, ilus, tab
Artigo em Espanhol | IBECS | ID: ibc-191314

RESUMO

Los miomas uterinos son una de las patologías ginecológicas más comunes encontrándose hasta en el 70% de las mujeres de raza caucásica y en el 80% de las mujeres de raza negra1,2. En los últimos años, la angiogénesis y la vascularización se han convertido en pieza fundamental de estudio del crecimiento de los tumores. En el caso de los miomas uterinos se ha descubierto que existen diferencias en la vascularización cuando se compara con el tejido uterino adyacente. La patogenia de los miomas es multifactorial existiendo varias vías que intervienen en el crecimiento de los mismos como la vía estrogénica, la progestagénica y la de los factores de crecimiento3. Otra de las vías qué influyen en su desarrollo es la vía de la vitamina D. Niveles inadecuados de dicha vitamina pueden favorecer el crecimiento de los mismos. En nuestro trabajo hemos analizado cómo influye la terapia con vitamina D en el volumen de los miomas y en su vascularización mediante el análisis sérico de VEGF y ecografía 3 DPW


Uterine fibroids are one of the most common gynaecological disorders, being found in 70% of Caucasian women and 80% of Afro-Caribbean women 1,2. In recent years, angiogenesis and vascularisation have become a key part of study of tumour growth. Differences in vascularisation have been discovered in uterine fibroids when compared to adjacent uterine tissue. The pathogenesis of uterine fibroids is multifactorial. Several pathways are involved in their growth have been described, such as the oestrogen pathway, the gestagen pathway, and the pathway of the growth factors. Another of the pathways that influences their development is the vitamin D pathway, as inadequate levels of this vitamin may favour the growth of uterine fibroids3. In this work, an analysis is made on how vitamin D therapy influences the volume and vascularity of uterine fibroids, using serum VEGF levels and 3DPW Ultrasound


Assuntos
Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Leiomioma/diagnóstico por imagem , Leiomioma/terapia , Projetos Piloto , Vitamina D/administração & dosagem , Neovascularização Patológica/diagnóstico por imagem , Fatores de Crescimento Endotelial/sangue , Leiomioma/patologia , Neovascularização Patológica/sangue , Neovascularização Patológica/patologia , Ultrassonografia Pré-Natal/métodos , Leiomioma/classificação
18.
Gene ; 754: 144851, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32525044

RESUMO

Tumor angiogenesis is a common feature of rapidly growing solid tumors, accelerated by tumor hypoxia. It is associated with subsequent metastasis, progression, poor prognosis, and aggressive phenotype in many types of cancer. The hypoxia-inducible factors/vascular endothelial growth factor 1(HIF1/VEGF) signal pathway plays an important role in tumor angiogenesis. Proteasome-mediated ubiquitin degradation pathway is one of the most important processes involved in regulating the level of cellular HIF-1α. Our study revealed that Histone Deacetylase 1 (HDAC1) directly inhibits the ubiquitination of HIF1α. Additionally, HDAC1 activates HIF1α/VEGFA signaling pathway, promoting s tumor angiogenesis. These findings have enhanced our understanding of the molecular mechanisms of colorectal (CRC) tumor angiogenesis. HDAC1/HIF1α/VEGFA signaling pathway may provide a novel therapeutic window for CRC.


Assuntos
Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Histona Desacetilase 1/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neovascularização Patológica/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Apoptose , Biomarcadores Tumorais , Ciclo Celular , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Progressão da Doença , Histona Desacetilase 1/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Camundongos , Camundongos Nus , Invasividade Neoplásica , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Prognóstico , Transdução de Sinais , Células Tumorais Cultivadas , Fator A de Crescimento do Endotélio Vascular/genética , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Life Sci ; 256: 118011, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32592723

RESUMO

Melatonin is recognized as an anti-angiogenic agent, but its function in the tumor microenvironment especially in osteosarcoma remains uncertain. Among the selected miRNAs, miR-205, miR-424, miR-140, miR-106, and miR-519 were upregulated by melatonin in osteosarcoma cells. The functional role of miR-424-5p in osteosarcoma was further analyzed using miR-424-5p mimic/inhibitor. VEGFA mRNA and protein expression were altered by miR-424-5p mimic/inhibitor transfection with and without melatonin treatment and it was further identified that the VEGFA 3'UTR is directly targeted by miR-424-5p using the luciferase reporter gene system. The conditioned medium from SaOS2 and MG63 cells treated with melatonin and/or transfected with miR-424-5p mimic/inhibitor was exposed to endothelial cells, and cell proliferation and migration was analyzed. MG-63 and SaOS2 cells are also transfected with miR-424-5p inhibitors and positioned on CAM vascular bed to study the angiogenic activity at both morphological and molecular level under melatonin treatment. Our observations demonstrate for the first time that, melatonin upregulated the expression of miR-424-5p in osteosarcoma inhibiting VEGFA. Furthermore, it suppresses tumor angiogenesis, modulating surrounding endothelial cell proliferation and migration as well as the morphology of blood vessels, and angiogenic growth factors. These findings suggest that melatonin could play a pivotal role in tumor suppression via miR-424-5p/VEGFA axis.


Assuntos
Inibidores da Angiogênese/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Melatonina/farmacologia , Osteossarcoma/tratamento farmacológico , Animais , Neoplasias Ósseas/irrigação sanguínea , Linhagem Celular Tumoral , Galinhas , Gema de Ovo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Humanos , MicroRNAs/genética , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Osteossarcoma/irrigação sanguínea , RNA Mensageiro/genética , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
20.
Oncogene ; 39(24): 4695-4710, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32404985

RESUMO

The overexpression of SOX4 in various kinds of cancer cells was associated with poor prognosis for patients. The role of SOX4 in angiogenesis and tumor microenvironment modulation was recently documented in breast cancer but remains unclear in hepatocellular carcinoma (HCC). In our study, the clinical relevance of SOX4 overexpression in HCC and its role in the tumor microenvironment were investigated. The overexpression of SOX4 (SOX4high) in tumor lesions was associated with higher microvessel density (P = 0.012), tumor thrombosis formation (P = 0.012), distant metastasis (P < 0.001), and an independent prognostic factor for disease-free survival in HCC patients (P = 0.048). Endogenous SOX4 knockout in Hep3B cells by the CRISPR/cas9 system reduced the expression of CXCL12, which, in turn, attenuated chemotaxis in human umbilical vein endothelial cells, tube formation in vitro, reduced tumor growth, reticular fiber production, and angiogenesis in vivo in a xenograft mouse model. Treatment with an antagonist targeting CXCR4 (AMD3100), a receptor of CXCL12, inhibited chemotaxis and tube formation in endothelial cells in vitro. The CXCL12 promoter was activated by ectopic expression of a Flag-tagged SOX4 plasmid, endogenous SOX4 knockdown abolished promoter activity of CXCL12 as shown by luciferase assays, and an association with the CXCL12 promoter was identified via chromatin immunoprecipitation in HCC cells. In conclusion, SOX4 modulates the CXCL12 promoter in HCC cells. The secretory CXCL12, in turn, modulates CXCR4 in endothelial cells, reticular fibers to regulate the tumor microenvironment and modulate neovascularization, which might contribute to the distant metastasis of tumors.


Assuntos
Carcinoma Hepatocelular , Movimento Celular , Quimiocina CXCL12/metabolismo , Células Endoteliais da Veia Umbilical Humana , Neoplasias Hepáticas Experimentais , Proteínas de Neoplasias , Neovascularização Patológica , Fatores de Transcrição SOXC/metabolismo , Trombose , Animais , Sistemas CRISPR-Cas , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Quimiocina CXCL12/genética , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Neoplasias Hepáticas Experimentais/irrigação sanguínea , Neoplasias Hepáticas Experimentais/genética , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Fatores de Transcrição SOXC/genética , Trombose/genética , Trombose/metabolismo , Trombose/patologia , Microambiente Tumoral/genética
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