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1.
Nat Commun ; 12(1): 4039, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193867

RESUMO

The controlled assembly of nanomaterials into desired architectures presents many opportunities; however, current preparations lack spatial precision and versatility in developing complex nano-architectures. Inspired by the amphiphilic nature of surfactants, we develop a facile approach to guide nanomaterial integration - spatial organization and distribution - in metal-organic frameworks (MOFs). Named surfactant tunable spatial architecture (STAR), the technology leverages the varied interactions of surfactants with nanoparticles and MOF constituents, respectively, to direct nanoparticle arrangement while molding the growing framework. By surfactant matching, the approach achieves not only tunable and precise integration of diverse nanomaterials in different MOF structures, but also fast and aqueous synthesis, in solution and on solid substrates. Employing the approach, we develop a dual-probe STAR that comprises peripheral working probes and central reference probes to achieve differential responsiveness to biomarkers. When applied for the direct profiling of clinical ascites, STAR reveals glycosylation signatures of extracellular vesicles and differentiates cancer patient prognosis.


Assuntos
Biomarcadores Tumorais/metabolismo , Técnicas Biossensoriais/métodos , Neoplasias Colorretais/diagnóstico , Vesículas Extracelulares/metabolismo , Estruturas Metalorgânicas/química , Nanoestruturas/química , Tensoativos/química , Ascite/metabolismo , Neoplasias Colorretais/metabolismo , Glicosilação , Humanos , Prognóstico
2.
Anticancer Res ; 41(6): 2895-2900, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34083280

RESUMO

BACKGROUND/AIM: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant tumor. Research using an innovative research approach is needed to identify effective biomarkers or therapeutic targets for PDAC. We aimed to identify proteins related to the peritoneal dissemination of PDAC. MATERIALS AND METHODS: We performed proteomic analysis using ascites samples from patients with advanced PDAC and peritoneal dissemination and patients with liver cirrhosis (LC). Proteins specific to PDAC were identified in comparison to the findings for ascites from patients with LC as a control group. RESULTS: In total, 336 proteins were identified in ascites from patients with PDAC. We identified 18 specific proteins in ascites from patients with advanced PDAC. Among these proteins, CD13, lymphatic vessel endothelial hyaluronan receptor 1, ficolin-3, and V-set and immunoglobulin domain containing 4 were the most frequently detected. In addition, these 18 proteins could be classified into four categories: extracellular matrix, immunity, metabolism, and others. CONCLUSION: The identified proteins could be informative for developing treatment strategies for patients with PDAC and peritoneal dissemination.


Assuntos
Ascite/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Neoplasias Pancreáticas/metabolismo , Proteômica/métodos , Ascite/patologia , Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pancreáticas/patologia
3.
J Immunol ; 206(10): 2478-2488, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33903172

RESUMO

Ovarian cancer is a highly fatal malignancy characterized by early chemotherapy responsiveness but the eventual development of resistance. Immune targeting therapies are changing treatment paradigms for numerous cancer types but have had minimal success in ovarian cancer. Through retrospective patient sample analysis, we have determined that high human epididymis protein 4 (HE4) production correlates with multiple markers of immune suppression in ovarian cancer, including lower CD8+ T cell infiltration, higher PD-L1 expression, and an increase in the peripheral monocyte to lymphocyte ratio. To further understand the impact that HE4 has on the immune microenvironment in ovarian cancer, we injected rats with syngeneic HE4 high- and low-expressing cancer cells and analyzed the differences in their tumor and ascites immune milieu. We found that high tumoral HE4 expression promotes an ascites cytokine profile that is rich in myeloid-recruiting and differentiation factors, with an influx of M2 macrophages and increased arginase 1 production. Additionally, CTL activation is significantly reduced in the ascites fluid, and there is a trend toward lower CTL infiltration of the tumor, whereas NK cell recruitment to the ascites and tumor is also reduced. PD-L1 expression by tumor cells and macrophages is increased by HE4 through a novel posttranscriptional mechanism. Our data have identified HE4 as a mediator of tumor-immune suppression in ovarian cancer, highlighting this molecule as a potential therapeutic target for the treatment of this devastating disease.


Assuntos
Antígeno B7-H1/metabolismo , Tolerância Imunológica/genética , Macrófagos/imunologia , Neoplasias Ovarianas/imunologia , Microambiente Tumoral/imunologia , Proteína 2 do Domínio Central WAP de Quatro Dissulfetos/metabolismo , Aloenxertos , Animais , Ascite/metabolismo , Biomarcadores Tumorais/sangue , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Macrófagos/metabolismo , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/patologia , Prognóstico , Ratos , Ratos Endogâmicos F344 , Estudos Retrospectivos , Linfócitos T Citotóxicos/imunologia , Transfecção , Carga Tumoral/genética , Proteína 2 do Domínio Central WAP de Quatro Dissulfetos/genética
4.
Int J Mol Sci ; 22(8)2021 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-33921783

RESUMO

Although malignant ascites (MAs) are known to contribute to various aspects of ovarian cancer progression, knowledge regarding their role in the adhesion of cancer cells to normal peritoneal cells is incomplete. Here, we compared the effect of MAs and benign ascites (BAs) on the adhesion of A2780 and OVCAR-3 cancer cells to omentum-derived peritoneal mesothelial cells (PMCs) and peritoneal fibroblasts (PFBs). The results showed that MAs stimulated the adhesion of A2780 and OVCAR-3 cells to PMCs and PFBs more efficiently than did BAs, and the strongest binding occurred when both cancer and normal cells were exposed to the fluid. Intervention studies showed that MAs-driven adhesion of A2780 cells to PMCs/PFBs depends on the presence of TGF-ß1 and HGF, whereas binding of OVCAR-3 cells was mediated by TGF-ß1, GRO-1, and IGF-1. Moreover, MAs upregulated α5ß1 integrin expression on PFBs but not on PMCs or cancer cells, vimentin expression in all cells tested, and ICAM-1 only in cancer cells. When integrin-linked kinase was neutralized in PMCs or PFBs, cancer cell adhesion to PMCs and PFBs decreased. Collectively, our report shows that MAs may contribute to the early stages of ovarian cancer metastasis by modulating the proadhesive interplay between normal and cancer cells.


Assuntos
Ascite/metabolismo , Ascite/patologia , Adesão Celular/fisiologia , Neoplasias Ovarianas/metabolismo , Apoptose/fisiologia , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/patologia , Linhagem Celular Tumoral , Células Cultivadas , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Citometria de Fluxo , Imunofluorescência , Humanos , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/metabolismo , Neoplasias Peritoneais/patologia , Peritônio/metabolismo , Peritônio/patologia
5.
Mol Carcinog ; 60(5): 297-312, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33721368

RESUMO

Fluid accumulation in the abdominal cavity is commonly found in advanced-stage ovarian cancer patients, which creates a specialized tumor microenvironment for cancer progression. Using single-cell RNA sequencing (scRNA-seq) of ascites cells from five patients with ovarian cancer, we identified seven cell types, including heterogeneous macrophages and ovarian cancer cells. We resolved a distinct polarization state of macrophages by MacSpectrum analysis and observed subtype-specific enrichment of pathways associated with their functions. The communication between immune and cancer cells was predicted through a putative ligand-receptor pair analysis using NicheNet. We found that CCL5, a chemotactic ligand, is enriched in immune cells (T cells and NK cells) and mediates ovarian cancer cell survival in the ascites, possibly through SDC4. Moreover, SDC4 expression correlated with poor overall survival in ovarian cancer patients. Our study highlights the potential role of T cells and NK cells in long-term survival patients with ovarian cancer, indicating SDC4 as a potential prognostic marker in ovarian cancer patients.


Assuntos
Ascite/patologia , Quimiocina CCL5/genética , Quimiocina CCL5/metabolismo , Neoplasias Ovarianas/mortalidade , Sindecana-4/genética , Sindecana-4/metabolismo , Ascite/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Polaridade Celular , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Células Matadoras Naturais/metabolismo , Macrófagos/metabolismo , Pessoa de Meia-Idade , Modelos Teóricos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Prognóstico , Análise de Sequência de RNA , Análise de Célula Única/métodos , Análise de Sobrevida , Linfócitos T/metabolismo , Microambiente Tumoral
6.
Toxicol Appl Pharmacol ; 418: 115491, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33737021

RESUMO

Pyrazole or 1,2-Diazole is a five-membered heteroaromatic ring with two nitrogen atoms which is widely used in pharmacological research and organic synthesis. Several natural and synthetic pyrazole derivatives possess anti-cancer potential and some of them have underwent clinical trials. In this aspect, an investigation into the efficiency of the pyrazole nucleus to inhibit the growth and progression of various cancer cell lines/ experimental tumours would help in giving a better clarity to the anti-cancer behaviour of pyrazole containing drugs. This paper investigates the efficiency of pyrazole against Dalton's Lymphoma Ascites (DLA) cell line. Pyrazole inhibited the growth of DLA cells in vitro by committing them towards apoptosis. In vitro results were consistent in DLA induced murine solid tumour in vivo systems. Drug-treatment improved survival, reduced tumour loads, stabilized body weights and improved the haematological and serum biochemical parameters of DLA solid tumour bearing mice, thereby improving their overall survivability. Drug administration contained the aggravation of solid tumour by targeted downregulation of Cyclin-D1 and Ki-67. In addition, the mRNA expression levels of anti-apoptotic genes, BCL-2 and BCL-XL were downregulated in solid tumours, corroborating the in vitro results that pyrazole encourage apoptotic cell death in DLA cells. The new findings establish pyrazole as a potential anti-cancer drug candidate. The results must encourage future investigations into the efficacy of the drug against various cancer types.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ascite/tratamento farmacológico , Ciclina D1/metabolismo , Antígeno Ki-67/metabolismo , Linfoma/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Pirazóis/farmacologia , Proteína bcl-X/metabolismo , Animais , Ascite/genética , Ascite/metabolismo , Ascite/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Linfoma/genética , Linfoma/metabolismo , Linfoma/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Proto-Oncogênicas c-bcl-2/genética , Transdução de Sinais , Proteína bcl-X/genética
7.
Cell Death Dis ; 12(2): 210, 2021 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-33627627

RESUMO

The poor prognosis of ovarian cancer is mainly due to metastasis, and the specific mechanism underlying ovarian cancer metastasis is not clear. Ascites-derived exosomes (ADEs) play an important role in the progression of ovarian cancer, but the mechanism is unknown. Here, we found that ADEs promoted ovarian cancer metastasis not only in vitro but also in vivo. This promotive function was based on epithelial-mesenchymal transition (EMT) of ovarian cancer cells. Bioinformatics analysis of RNA sequencing microarray data indicated that miR-6780b-5p may be the key microRNA (miRNA) in ADEs that facilitates cancer metastasis. Moreover, the expression of exosomal miR-6780b-5p correlated with tumor metastasis in ovarian cancer patients. miR-6780b-5p overexpression promoted and miR-6780b-5p downregulation suppressed EMT of ovarian cancer cells. These results suggest that ADEs transfer miR-6780b-5p to ovarian cancer cells, promoting EMT and finally facilitating ovarian cancer metastasis.


Assuntos
Ascite/metabolismo , Carcinoma/metabolismo , Transição Epitelial-Mesenquimal , Exossomos/metabolismo , MicroRNAs/metabolismo , Neoplasias Ovarianas/metabolismo , Adulto , Idoso , Animais , Ascite/genética , Ascite/patologia , Carcinoma/genética , Carcinoma/secundário , Linhagem Celular Tumoral , Movimento Celular , Criança , Exossomos/genética , Exossomos/patologia , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Transcriptoma , Células Tumorais Cultivadas , Adulto Jovem
8.
Molecules ; 26(4)2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33578967

RESUMO

This study evaluated the anti-ascites effect of total diterpenoids extracted from Euphorbiae Ebracteolatae Radix (TDEE) on malignant ascitic mice and elucidated its underlying mechanism. TDEE was extracted by dichloromethane and subjected to column chromatography. The purity of six diterpenoids isolated from TDEE was determined to be 77.18% by HPLC. TDEE (3 and 0.6 g raw herbs/kg, p.o.) reduced ascites and increased urine output. Meanwhile, analysis of tumor cell viability, cycle and apoptosis indicated that TDEE had no antitumor activity. In addition, the expression levels of aquaporins (AQPs) and the membrane translocation levels of protein kinase C (PKC) α and PKCß in kidney and cells were measured. TDEE reduced the levels of AQP1-4, and inhibited PKCß expression in membrane fraction. Four main diterpenoids, except compound 2, reduced AQP1 level in human kidney-2 cells. Compounds 4 and 5 inhibited AQP2-4 expression in murine inner medullary collecting duct cells. The diterpenoid-induced inhibition of AQP1-4 expression was blocked by phorbol-12-myristate-13-acetate (PMA; agonist of PKC). The diterpenoids from TDEE are the main anti-ascites components. The anti-ascites effect of diterpenoids may be associated with alterations in AQPs in the kidneys to promote diuresis. The inhibition of AQP1-4 expression by TDEE is related to the inhibition of PKCß activation.


Assuntos
Aquaporinas/metabolismo , Ascite/tratamento farmacológico , Diterpenos/farmacologia , Euphorbia/química , Rim/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Proteína Quinase C/antagonistas & inibidores , Animais , Apoptose , Aquaporinas/genética , Ascite/metabolismo , Ascite/patologia , Carcinoma Hepatocelular , Proliferação de Células , Regulação da Expressão Gênica , Humanos , Rim/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Int J Mol Sci ; 22(2)2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33466775

RESUMO

The development of malignant effusions such as ascites reflects a massive progression of a malignant disease. In patients with ovarian carcinoma, a high amount of ascites (>500 mL) is an independent negative prognostic marker. The composition and constituents of ascites reflect the inflammatory environment of the underlying tumor. Increased cellular resistance of ascites-derived tumor cells and the development of venous thromboembolic events (VTE) are major risks for these patients, especially in patients with advanced ovarian carcinoma. In this study, we discuss the release of tissue factor-bearing extracellular vesicles (TF+ EVs) from tumor cells into the environment (ascites fluid) and their systemic spreading as a possible causal explanation of the pathologic coagulation status in these patients. We obtained ascites from patients with advanced ovarian carcinoma, collected during surgery or therapeutic paracentesis (n = 20). Larger ectosome-like EVs were isolated using sequential centrifugation, quantified by high-resolution flow cytometry and analyzed using nanoparticle tracking analysis. Furthermore, the pro-coagulant properties (TF activity) of EVs were determined. Compared to published TF activities of EVs from healthy persons, TF activities of EVs derived from ascites of patients with ovarian cancer were very high, with a median of 80 pg/mL. The rate of VTE, as reported in the patient files, was high as well (35%, 7 out of 20). Furthermore, all but one patient with VTE had EV concentrations above the median within their ascetic fluid (p < 0.02). Since VTE continues to be a frequent cause of death in cancer patients, prophylactic antithrombotic treatment might be worth considering in these patients. However, given the risk of bleeding, more clinical data are warranted. Although the study is too small to enable reaching a conclusion on direct clinical implementation, it can well serve as a proof of principle and a rationale to initiate a prospective clinical study with different patient subgroups. We also show ex vivo that these larger ectosome-like EVs induce intracellular ERK phosphorylation and tumor cell migration, which is not directly related to their pro-coagulative potency, but might help to understand why cancer patients with thromboembolic events have a poorer prognosis.


Assuntos
Líquido Ascítico/metabolismo , Micropartículas Derivadas de Células/metabolismo , Vesículas Extracelulares/metabolismo , Neoplasias Ovarianas/metabolismo , Tromboplastina/metabolismo , Idoso , Idoso de 80 Anos ou mais , Ascite/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Feminino , Humanos , Incidência , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Trombose/metabolismo
10.
J Ethnopharmacol ; 267: 113507, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33098970

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Malignant ascites (MA) effusion is mainly caused by hepatocellular, ovarian, and breast cancer etc. It has been reported that Euphorbia kansui (EK), the root of Euphorbia kansui S.L.Liou ex S.B.Ho, possessing a therapeutic effect on MA. However, the clinical applications of EK are seriously restricted for its severe toxicity. Although studies demonstrated that vinegar-processing can reduce the toxicity and retain the water expelling effect of EK, its specific mechanism remains unknown. AIM OF THE STUDY: This study aims to explore the underlying mechanisms of toxicity reduction without compromising the pharmacological effects of EK stir-fried with vinegar (VEK). MATERIALS AND METHODS: 3-O-(2'E,4'Z-decadienoyl)-20-O-acetylingenol (3-O-EZ), a major diterpenoid of EK, could convert into ingenol after processing EK with vinegar. The H22 mouse hepatoma ascites model was replicated, and were given 3-O-EZ and ingenol seven days (110.14, 50.07 and 27.54 mg/kg). The histopathological observation, serum liver enzymes, serum Renin-Angiotensin-Aldosterone System (RAAS) levels, ascites volumes, pro-inflammatory cytokines levels and H22 cells apoptosis in ascites were examined. Then the intestine (Aquaporin 8, AQP8) and kidney (Aquaporin 2, AQP2; Vasopressin type 2 receptor, V2R) protein expression were detected, as well as the metabolomics of serum were analyzed. Finally, the content of 3-O-EZ and ingenol in EK and VEK were investigated. RESULTS: 3-O-EZ and ingenol can relieve hepatic and gastrointestinal injuries, reduce ascites volumes, enhance the H22 cells apoptosis, ameliorate abnormal pro-inflammatory cytokines and RAAS levels, and down-regulate the expression of AQP8, AQP2, V2R. The involved metabolic pathways mainly included glycerophospholipid metabolism and arachidonic acid metabolism. And the decreasing rate of 3-O-EZ in VEK was 19.14%, the increasing rate of ingenol in VEK was 92.31%. CONCLUSION: 3-O-EZ and ingenol possess significant effect in treating MA effusion, while ingenol has lower toxicity compared with 3-O-EZ. And provide evidence for the mechanism of attenuation in toxicity without compromising the pharmacological effects of VEK.


Assuntos
Ácido Acético/química , Antineoplásicos Fitogênicos/farmacologia , Ascite/prevenção & controle , Carcinoma Hepatocelular/tratamento farmacológico , Cromatografia Líquida de Alta Pressão , Culinária , Diterpenos/farmacologia , Euphorbia , Neoplasias Hepáticas/tratamento farmacológico , Extratos Vegetais/farmacologia , Animais , Antineoplásicos Fitogênicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Aquaporina 2/metabolismo , Aquaporinas/metabolismo , Ascite/metabolismo , Ascite/patologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Citocinas/metabolismo , Diterpenos/isolamento & purificação , Euphorbia/química , Feminino , Temperatura Alta , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Extratos Vegetais/isolamento & purificação , Receptores de Vasopressinas/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Transdução de Sinais
11.
Cancer Sci ; 112(2): 668-678, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33053268

RESUMO

Peritoneal dissemination and malignant ascites in pancreatic ductal adenocarcinoma (PDAC) patients represent a major clinical issue. Lysophosphatidic acid (LPA) is a lipid mediator that modulates the progression of various cancers. Based on the increasing evidence showing that LPA is abundant in malignant ascites, we focused on autotaxin (ATX), which is a secreted enzyme that is important for the production of LPA. This study aimed to elucidate the importance of the ATX-LPA axis in malignant ascites in PDAC and to determine whether ATX works as a molecular target for treating peritoneal dissemination. In a PDAC peritoneal dissemination mouse model, the amount of ATX was significantly higher in ascites than in serum. An in vitro study using two PDAC cell lines, AsPC-1 and PANC-1, showed that ATX-LPA signaling promoted cancer cell migration via the activation of the downstream signaling, and this increased cell migration was suppressed by an ATX inhibitor, PF-8380. An in vivo study showed that PF-8380 suppressed peritoneal dissemination and decreased malignant ascites, and these results were validated by the biological analysis as well as the in vitro study. Moreover, there was a positive correlation between the amount of ATX in ascites and the degree of disseminated cancer progression. These findings demonstrated that ATX in ascites works as a promotor of peritoneal dissemination, and the targeting of ATX must represent a useful and novel therapy for peritoneal dissemination of PDAC.


Assuntos
Carcinoma Ductal Pancreático/secundário , Neoplasias Pancreáticas/patologia , Neoplasias Peritoneais/secundário , Diester Fosfórico Hidrolases/metabolismo , Animais , Ascite/metabolismo , Ascite/patologia , Carcinoma Ductal Pancreático/metabolismo , Feminino , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Peritoneais/metabolismo
12.
PLoS One ; 15(12): e0241500, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33270665

RESUMO

The presence of ascites in the peritoneal cavity leads to morphological and functional changes of the peritoneal mesothelial cell layer. Cells loose cell-cell interactions, rearrange their cytoskeleton, activate the production of fibronectin, and change their cell surface morphology in a proinflammatory environment. Moreover, ovarian cancer cell adhesion has been shown to be facilitated by these changes due to increased integrin- and CD44-mediated binding sites. In this study, the biological responsiveness of the human pleural mesothelial cell line MeT-5A to patient-derived and artificial ascites was studied in vitro and adhesion of ovarian cancer cells, i.e. SKOV-3 cells, investigated. Changes were mainly observed in cells exposed to artificial ascites containing higher cytokine concentrations than patient-derived ascites. Interestingly, reduced cell-cell interactions were already observed in untreated MeT-5A cells and effects on tight junction protein expression and permeability upon exposure to ascites were minor. Ascites induced upregulation of CDC42 effector protein 2 expression, which affects stress fiber formation, however significant F-actin reorganization was not observed. Moreover, fibronectin production remained unchanged. Analysis of mesothelial cell surface characteristics showed upregulated expression of intercellular adhesion molecule 1, slightly increased hyaluronic acid secretion and decreased microvillus expression upon exposure to ascites. Nevertheless, the observed changes were not sufficient to facilitate adhesion of SKOV-3 cells on MeT-5A cell layer. This study revealed that MeT-5A cells show a reduced biological responsiveness to the presence of ascites, in contrast to published studies on primary human peritoneal mesothelial cells.


Assuntos
Adesão Celular/efeitos dos fármacos , Citocinas/farmacologia , Neoplasias Mesoteliais/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Ascite/metabolismo , Ascite/patologia , Linhagem Celular Tumoral , Citocinas/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Receptores de Hialuronatos/genética , Integrina beta1/genética , Molécula 1 de Adesão Intercelular/genética , Neoplasias Mesoteliais/genética , Neoplasias Mesoteliais/metabolismo , Neoplasias Mesoteliais/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Pacientes , Peritônio/química , Peritônio/metabolismo , Transdução de Sinais/genética , Proteína cdc42 de Ligação ao GTP/genética
13.
Am J Gastroenterol ; 115(11): 1775-1785, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33156095

RESUMO

Hyponatremia is frequently seen in patients with ascites secondary to advanced cirrhosis and portal hypertension. Although not apparent in the early stages of cirrhosis, the progression of cirrhosis and portal hypertension leads to splanchnic vasodilation, and this leads to the activation of compensatory mechanisms such as renin-angiotensin-aldosterone system (RAAS), sympathetic nervous system, and antidiuretic hormone (ADH) to ameliorate low circulatory volume. The net effect is the avid retention of sodium and water to compensate for the low effective circulatory volume, resulting in the development of ascites. These compensatory mechanisms lead to impairment of the kidneys to eliminate solute-free water in decompensated cirrhosis. Nonosmotic secretion of antidiuretic hormone (ADH), also known as arginine vasopressin, further worsens excess water retention and thereby hyponatremia. The management of hyponatremia in this setting is a challenge as conventional therapies for hyponatremia including fluid restriction and correction of hypokalemia are frequently inefficacious. In this review, we discuss the pathophysiology, complications, and various treatment modalities, including albumin infusion, selective vasopressin receptor antagonists, or hypertonic saline for patients with severe hyponatremia and those awaiting liver transplantation.


Assuntos
Ascite/metabolismo , Hipertensão Portal/metabolismo , Hiponatremia/metabolismo , Cirrose Hepática/metabolismo , Sistema Renina-Angiotensina/fisiologia , Vasopressinas/metabolismo , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/fisiopatologia , Insuficiência Hepática Crônica Agudizada/metabolismo , Insuficiência Hepática Crônica Agudizada/fisiopatologia , Albuminas/uso terapêutico , Antagonistas dos Receptores de Hormônios Antidiuréticos/uso terapêutico , Ascite/fisiopatologia , Hidratação , Encefalopatia Hepática/metabolismo , Encefalopatia Hepática/fisiopatologia , Síndrome Hepatorrenal/metabolismo , Síndrome Hepatorrenal/fisiopatologia , Humanos , Hipertensão Portal/fisiopatologia , Hiponatremia/fisiopatologia , Hiponatremia/terapia , Cirrose Hepática/fisiopatologia , Transplante de Fígado , Solução Salina Hipertônica/uso terapêutico , Circulação Esplâncnica/fisiologia , Tolvaptan/uso terapêutico , Vasodilatação/fisiologia
14.
J Environ Pathol Toxicol Oncol ; 39(3): 247-260, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32865916

RESUMO

The anticancer activity of malvidin was studied in Dalton's lymphoma ascites (DLA)-induced solid and ascitic tumor mice models. Malvidin is a natural compound belonging to the family of O-methylated anthocyanidin and plays a predominant role in regulating both short- and long-term cellular activities. Animals were injected with DLA cells (1.5 × 106 cells/animal) to induce solid and ascitic tumors. The administration of malvidin (5 mg/kg bw and 10 mg/kg bw) was carried out for 10 consecutive days from the day of tumor induction for both solid and ascitic tumors. Cyclophosphamide, CTX (25 mg/kg bw), used as the standard drug, was also administered for 10 consecutive days. Treatment with malvidin showed a significant reduction in tumor volume and elevated white blood cell (WBC) count when compared to the DLA-bearing control animals. The treatment also maintained the body weight and hemoglobin level, and decreases in aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT) were also noted. This investigation also reported the decreased levels of cellular glutathione (GSH) in ascitic tumor groups. Malvidin reduced inflammatory mediator and cytokine levels, such as tumor necrosis factor level alpha (TNF-α) and interleukin-6 (IL-6), which serve as molecular targets for cancer prevention. A decrease in the level of reactive oxygen species (ROS), like nitric oxide (NO), was observed. Histopathological examination revealed altered morphological changes in tumor tissue and the alleviation of hepatic architecture due to DLA. Immunohistochemical analysis revealed the inhibition of iNOS. This study demonstrated that malvidin exhibited significant in vivo antitumor activity and that it was reasonably imputable to its increasing endogenous mechanism. We accent the pertinence of malvidin as a potential naturally derived drug target for tumor control.


Assuntos
Antocianinas/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Ascite/tratamento farmacológico , Citocinas/sangue , Linfoma/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Animais , Antocianinas/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Ascite/metabolismo , Ascite/patologia , Biomarcadores/sangue , Biomarcadores/metabolismo , Linhagem Celular Tumoral , Citocinas/metabolismo , Linfoma/metabolismo , Linfoma/patologia , Masculino , Camundongos , Transplante de Neoplasias , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Estresse Oxidativo/imunologia
15.
Cancer Res ; 80(16): 3200-3214, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32606006

RESUMO

N 6-Methyladenosine (m6A) is the most abundant modification of mammalian mRNAs. RNA methylation fine tunes RNA stability and translation, altering cell fate. The fat mass- and obesity-associated protein (FTO) is an m6A demethylase with oncogenic properties in leukemia. Here, we show that FTO expression is suppressed in ovarian tumors and cancer stem cells (CSC). FTO inhibited the self-renewal of ovarian CSC and suppressed tumorigenesis in vivo, both of which required FTO demethylase activity. Integrative RNA sequencing and m6A mapping analysis revealed significant transcriptomic changes associated with FTO overexpression and m6A loss involving stem cell signaling, RNA transcription, and mRNA splicing pathways. By reducing m6A levels at the 3'UTR and the mRNA stability of two phosphodiesterase genes (PDE1C and PDE4B), FTO augmented second messenger 3', 5'-cyclic adenosine monophosphate (cAMP) signaling and suppressed stemness features of ovarian cancer cells. Our results reveal a previously unappreciated tumor suppressor function of FTO in ovarian CSC mediated through inhibition of cAMP signaling. SIGNIFICANCE: A new tumor suppressor function of the RNA demethylase FTO implicates m6A RNA modifications in the regulation of cyclic AMP signaling involved in stemness and tumor initiation.


Assuntos
Adenosina/análogos & derivados , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Células-Tronco Neoplásicas/metabolismo , Neoplasias Ovarianas/metabolismo , Sistemas do Segundo Mensageiro , Proteínas Supressoras de Tumor/metabolismo , Regiões 3' não Traduzidas/genética , Adenosina/genética , Adenosina/metabolismo , Homólogo AlkB 5 da RNA Desmetilase/genética , Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Processamento Alternativo , Animais , Ascite/metabolismo , Carcinogênese/metabolismo , Linhagem Celular Tumoral , AMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Regulação para Baixo , Tubas Uterinas/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Xenoenxertos , Humanos , Metilação , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Ovarianas/patologia , Ovário/metabolismo , Estabilidade de RNA , RNA Mensageiro/genética , RNA Mensageiro/isolamento & purificação , Análise de Sequência de RNA , Esferoides Celulares , Análise Serial de Tecidos , Transcriptoma , Proteínas Supressoras de Tumor/genética
17.
J Cancer Res Ther ; 16(1): 78-87, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32362613

RESUMO

Aims: In the present study, the flavonoid fraction of Tabernaemontana divaricata flavonoid fraction(TdFf) leaves was investigated for its in vitro and in vivo antioxidative and antitumor activity. Subjects and Methods: The flavonoid fraction of ethyl acetate extract was assessed for their in vitro antioxidant activity by 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) (ABTS), superoxide radicals, ferric reducing antioxidant power (FRAP), hydrogen peroxide, hydroxyl radicals and nitric oxide and in vivo antioxidative activity by enzymic and nonenzymic antioxidants in the liver of intraperitoneally implanted Ehrlich's lymphoma (EAC) and Dalton's lymphoma ascites (DLAs) model. The in vitro cytotoxicity was assessed using trypan blue exclusion assay and in vivo antitumor activity was assessed by screening the ILS, serum liver marker enzymes and histopathology of the liver. Statistical Analysis Used: The data were expressed as the mean ± standard deviation of the means, and statistical analysis was carried out employing one-way and two-way analysis of variance using Web Agri Stat Package 2.0. Results: The dose-dependent percentage scavenging of ABTS, DPPH, FRAP, OH, superoxide radical, and nonradical NO and H2O2 by TdFf indicated their antioxidative potential. Incubation of EAC/DLA tumor cells with TdFf showed a concentration-dependent cytotoxic effect, and the extract killed 50% of EAC/DLA tumor cells at a concentration of 80 µg of TdFf. Coadministration of TdFf with EAC/DLA-induced mice showed a significant increase in the liver enzymic and nonenzymic antioxidants and significant decrease in the serum liver marker enzymes to prove the in vivo antioxidative and antitumor activity of TdFf. It was also confirmed by the histopathology of the liver. Conclusions: It may be concluded that the flavonoid fractions of Td possess considerable antioxidative and antitumorigenic activity against the tested DLA/EAC in both in vitro and in vivo system.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/farmacologia , Ascite/tratamento farmacológico , Carcinoma de Ehrlich/tratamento farmacológico , Flavonoides/farmacologia , Linfoma/tratamento farmacológico , Tabernaemontana/química , Animais , Ascite/metabolismo , Ascite/patologia , Carcinoma de Ehrlich/metabolismo , Carcinoma de Ehrlich/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Técnicas In Vitro , Linfoma/metabolismo , Linfoma/patologia , Camundongos , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Extratos Vegetais/farmacologia , Folhas de Planta/química
18.
Biomarkers ; 25(4): 360-366, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32364003

RESUMO

Objective: To assess the role of ascitic endocan levels in the diagnosis of spontaneous bacterial peritonitis (SBP) in decompensated cirrhosis.Methods: Ascites samples, as well as demographic and laboratory data, were collected at admission from patients with decompensated cirrhosis. Ascitic endocan, tumour necrosis factor-α (TNF-α), and interleukin-6 (IL-6) levels were measured by ELISA. The influencing factors of SBP, the correlation of ascitic endocan with other inflammatory indicators, and the diagnostic value of ascitic endocan for SBP were analyzed.Results: A total of 167 patients were enrolled, 39 with the SBP group and 128 in the non-SBP group. Ascitic endocan, TNF-α, and IL-6 levels were significantly higher in the SBP group than in the non-SBP group (p < 0.001). Multivariate analysis demonstrated that ascitic endocan was an independent risk factor for SBP [OR = 1.006 (95% CI: 1.002-1.011); p < 0.001]. Endocan was positively correlated with ascites polymorphonuclear leukocytes, TNF-α, and IL-6. ROC curve analysis showed that ascitic endocan had an AUC of 0.805 for the diagnosis of SBP (p < 0.001) and had a sensitivity of 82.1% and specificity of 73.4% when the cut-off value was 295.011 pg/ml.Conclusions: Ascitic endocan level is an independent risk factor and a valuable diagnostic indicator for SBP in decompensated cirrhosis.


Assuntos
Biomarcadores/metabolismo , Fibrose/genética , Proteínas de Neoplasias/genética , Peritonite/genética , Proteoglicanas/genética , Adulto , Ascite/metabolismo , Ascite/patologia , Líquido Ascítico/metabolismo , Infecções Bacterianas/genética , Infecções Bacterianas/microbiologia , Infecções Bacterianas/patologia , Calcitonina/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Fibrose/complicações , Fibrose/microbiologia , Fibrose/patologia , Humanos , Interleucina-6/genética , Cirrose Hepática/complicações , Cirrose Hepática/genética , Cirrose Hepática/microbiologia , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Peritonite/complicações , Peritonite/microbiologia , Peritonite/patologia , Curva ROC , Fator de Necrose Tumoral alfa/genética
19.
Br J Cancer ; 123(2): 275-287, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32390009

RESUMO

BACKGROUND: Ovarian cancer is characterised by frequent recurrence due to persistent presence of residual cancer stem cells (CSCs). Here, we identify and characterise tumour subsets from ascites-derived tumour cells with stemness, metastasis and metabolic switch properties and to delineate the involvement of pyruvate dehydrogenase kinase 4 (PDK4) in such process. METHODS: Ovarian cancer cells/cell lines derived from ascites were used for tumourspheres/ALDH+CD44+ subset isolation. The functional roles and downstream signalling of PDK4 were explored. Its association with clinical outcome of ovarian cancer was analysed. RESULTS: We demonstrated enhanced CSC characteristics of tumour cells derived from ovarian cancer ascites, concomitant with ALDH and CD44 subset enrichment and high PDK4 expression, compared to primary tumours. We further showed tumourspheres/ALDH+CD44+ subsets from ascites-derived tumour cells/cell lines with CSC properties and enhanced glycolysis. Clinically, PDK4 expression was correlated with aggressive features. Notably, blockade of PDK4 in tumourspheres/ALDH+CD44+ subsets led to inhibition of CSC characteristics, glycolysis and activation of STAT3/AKT/NF-κB/IL-8 (signal transducer and activator of transcription 3/protein kinases B/nuclear factor-κB/interleukin-8) signalling. Conversely, overexpression of PDK4 in ALDH-CD44- subsets exerted the opposite effects. CONCLUSION: Ascites-derived ALDH+CD44+ tumour cell subsets endow stemness, metastatic and metabolic switch properties via PDK4-mediated STAT3/AKT/NF-κB/IL-8 signalling, suggesting PDK4 as a viable therapeutic molecular target for ovarian cancer management.


Assuntos
Interleucina-8/genética , Recidiva Local de Neoplasia/genética , Neoplasias Ovarianas/genética , Piruvato Desidrogenase Quinase de Transferência de Acetil/genética , Fator de Transcrição STAT3/genética , Aldeído Desidrogenase/genética , Ascite/metabolismo , Ascite/patologia , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Receptores de Hialuronatos/genética , NF-kappa B/genética , Metástase Neoplásica , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Proteína Oncogênica v-akt/genética , Neoplasias Ovarianas/patologia , Receptores de Interleucina-8A/genética , Transdução de Sinais/genética
20.
Oncogene ; 39(21): 4227-4240, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32284541

RESUMO

Malignant ascites of epithelial ovarian cancer is a metastatic tumor microenvironment in which large amounts of disseminated single cells (DSCs) and disseminated tumor cell clusters (DTCCs) are commonly observed. The tumor cell clusters are known to be more aggressive than individual tumor cells in cancer metastasis; however, little is known about the mechanism. Applying single-cell epithelial-to-mesenchymal transition (EMT)-related transcriptional analysis in 120 DSCs and 195 intra-cluster cells from 27 DTCCs, we demonstrated that DTCCs were heterogeneous cellular units comprised of epithelial tumor cells, leukocytes, and cancer-associated fibroblasts (CAFs). Through the analysis of intra-DTCC heterogeneity, we identified that CAFs induced EMT of tumor cells via TGFß signaling within the DTCC microenvironment. The activation of EMT program, in particular the upregulation of ZEB2, enabled the acquisition of additional chemoresistance and metastasis abilities of the intra-DTCC tumor cells, which resulted in the aggressiveness of DTCCs.


Assuntos
Ascite/metabolismo , Carcinogênese/metabolismo , Carcinoma Epitelial do Ovário/metabolismo , Transição Epitelial-Mesenquimal , Neoplasias Ovarianas/metabolismo , Análise de Célula Única , Ascite/patologia , Carcinogênese/patologia , Carcinoma Epitelial do Ovário/patologia , Feminino , Humanos , Neoplasias Ovarianas/patologia
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