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1.
Cells ; 12(9)2023 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-37174717

RESUMO

Management of advanced melanoma remains challenging, with most BRAF (B-Raf proto-oncogene, serine/threonine kinase)-mutated metastatic patients relapsing within a few months upon MAPK inhibitors treatment. Modulation of tumor-derived extracellular vesicle (EVs) cargo with enrichment of antitumoral molecules is a promising strategy to impair tumor progression and increase treatment response. Herein, we report that restored expression of miR-195-5p, down-regulated in melanoma favoring drug resistance, increases the release of EVs enriched in the tumor suppressor miRNAs, miR-195-5p, miR-152-3p, and miR-202-3p. Incorporating these EVs by bystander tumor cells resulted in decreased proliferation and viability, accompanied by a reduction in CCND1 and YAP1 mRNA levels. Upon treatment with MAPK inhibitors, miR-195 EVs significantly decreased BCL2-L1 protein levels and increased cell death ratio and treatment efficacy. Additionally, EVs exogenously loaded with miR-195-5p by electroporation reduced tumor volume in vivo and impaired engraftment and growth of xenografts implanted with melanoma cells exposed to MAPK inhibitors. Our study shows that miR-195-5p antitumoral activity can be spread to bystander cells through EVs, improving melanoma response to targeted therapy and revealing a promising EV-based strategy to increase clinical response in patients harboring BRAF mutations.


Assuntos
Vesículas Extracelulares , Melanoma , MicroRNAs , Humanos , Proteínas Proto-Oncogênicas B-raf , Recidiva Local de Neoplasia/metabolismo , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , MicroRNAs/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/metabolismo , Vesículas Extracelulares/metabolismo
2.
J Control Release ; 364: 312-325, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37884210

RESUMO

Cell membrane-derived particles (Mp) are rounded membrane-enclosed particles that are shed from tumor cells. Mp are formed from tumor membranes and are capable of tumor targeting and immunotherapeutic agents because they share membrane homology with parental cells; thus, they are under consideration as a drug delivery vehicle. Prostate-specific membrane antigen (PSMA), a transmembrane glycoprotein with enzymatic functionality, is highly expressed in Mp and extracellular vesicles (EV) from prostate cancer (PCa) with poor clinical prognosis. Although PSMA expression was previously shown in EV and Mp isolated from cell lines and from the blood of patients with high-grade PCa, no pathophysiological effects have been linked to PCa-derived Mp. Here, we compared Mp from PSMA-expressing (PSMA-Mp) and PSMA-non-expressing (WT-Mp) cells side by side in vitro and in vivo. PSMA-Mp can transfer PSMA and new phenotypic characteristics to the tumor microenvironment. The consequence of PSMA transfer to cells and increased secretion of vascular endothelial growth factor-A (VEGF-A), pro-angiogenic and pro-lymphangiogenic mediators, with increased 4E binding protein 1 (4EBP-1) phosphorylation.


Assuntos
Neoplasias da Próstata , Fator A de Crescimento do Endotélio Vascular , Masculino , Humanos , Neoplasias da Próstata/patologia , Membrana Celular/metabolismo , Microambiente Tumoral
3.
BMC Cancer ; 10: 200, 2010 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-20465821

RESUMO

BACKGROUND: Phagocytosis of apoptotic cells by macrophages induces a suppressor phenotype. Previous data from our group suggested that this occurs via Platelet-activating factor receptor (PAF-R)-mediated pathways. In the present study, we investigated the impact of apoptotic cell inoculation or induction by a chemotherapeutic agent (dacarbazine, DTIC) on tumour growth, microenvironmental parameters and survival, and the effect of treatment with a PAF-R antagonist (WEB2170). These studies were performed in murine tumours: Ehrlich Ascitis Tumour (EAT) and B16F10 melanoma. METHODS: Tumour growth was assessed by direct counting of EAT cells in the ascitis or by measuring the volume of the solid tumour. Parameters of the tumour microenvironment, such as the frequency of cells expressing cyclo-oxygenase-2 (COX-2), caspase-3 and galectin-3, and microvascular density, were determined by immunohistochemistry. Levels of vascular endothelium growth factor (VEGF) and prostaglandin E2 (PGE2) were determined by ELISA, and levels of nitric oxide (NO) by Griess reaction. PAF-R expression was analysed by immunohistochemistry and flow cytometry. RESULTS: Inoculation of apoptotic cells before EAT implantation stimulated tumour growth. This effect was reversed by in vivo pre-treatment with WEB2170. This treatment also reduced tumour growth and modified the microenvironment by reducing PGE2, VEGF and NO production. In B16F10 melanoma, WEB2170 alone or in association with DTIC significantly reduced tumour volume. Survival of the tumour-bearing mice was not affected by WEB2170 treatment but was significantly improved by the combination of DTIC with WEB2170. Tumour microenvironment elements were among the targets of the combination therapy since the relative frequency of COX-2 and galectin-3 positive cells and the microvascular density within the tumour mass were significantly reduced by treatment with WEB2170 or DTIC alone or in combination. Antibodies to PAF-R stained the cells from inside the tumour, but not the tumour cells grown in vitro. At the tissue level, a few cells (probably macrophages) stained positively with antibodies to PAF-R. CONCLUSIONS: We suggest that PAF-R-dependent pathways are activated during experimental tumour growth, modifying the microenvironment and the phenotype of the tumour macrophages in such a way as to favour tumour growth. Combination therapy with a PAF-R antagonist and a chemotherapeutic drug may represent a new and promising strategy for the treatment of some tumours.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma de Ehrlich/tratamento farmacológico , Melanoma Experimental/tratamento farmacológico , Glicoproteínas da Membrana de Plaquetas/antagonistas & inibidores , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos Alquilantes/administração & dosagem , Apoptose/efeitos dos fármacos , Azepinas/administração & dosagem , Carcinoma de Ehrlich/irrigação sanguínea , Carcinoma de Ehrlich/metabolismo , Carcinoma de Ehrlich/patologia , Caspase 3/metabolismo , Proliferação de Células/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Dacarbazina/administração & dosagem , Dinoprostona/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Galectina 3/metabolismo , Imuno-Histoquímica , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Melanoma Experimental/irrigação sanguínea , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neovascularização Patológica/metabolismo , Neovascularização Patológica/prevenção & controle , Óxido Nítrico/metabolismo , Fenótipo , Glicoproteínas da Membrana de Plaquetas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Fatores de Tempo , Triazóis/administração & dosagem , Carga Tumoral , Fator A de Crescimento do Endotélio Vascular/metabolismo
4.
NPJ Breast Cancer ; 5: 11, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30963110

RESUMO

The risk of developing metastatic disease in breast cancer patients is traditionally predictable based on the number of positive axillary lymph nodes, complemented with additional clinicopathological factors. However, since lymph node-negative patients have a 20-30% probability of developing metastatic disease, lymph node information alone is insufficient to accurately assess individual risk. Molecular approaches, such as multigene expression panels, analyze a set of cancer-related genes that more accurately predict the early risk of metastasis and the treatment response. Here, we present N-Myc downstream-regulated gene 4 (NDRG4) epigenetic silencing as a mechanistic biomarker of metastasis in ductal invasive breast tumors. While aberrant NDRG4 DNA hypermethylation is significantly associated with the development of metastatic disease, downregulation of NDRG4 transcription and protein expression is functionally associated with enhanced lymph node adhesion and cell mobility. Here, we show that epigenetic silencing of NDRG4 modulates integrin signaling by assembling ß1-integrins into large punctate clusters at the leading edge of tumor cells to promote an "adhesive switch," decreasing cell adhesion to fibronectin and increasing cell adhesion and migration towards vitronectin, an important component of human lymph nodes. Taken together, our functional and clinical observations suggest that NDRG4 is a potential mechanistic biomarker in breast cancer that is functionally associated with metastatic disease.

5.
PLoS One ; 10(5): e0126298, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25970341

RESUMO

The aim of this preclinical study was to evaluate the characteristics of the monoclonal antibody Rebmab200, which is a humanized version of the ovarian-specific murine antibody MX35. This investigation contributes to the foundation for future clinical α-radioimmunotherapy of minimal residual ovarian cancer with 211At-Rebmab200. Here, the biodistribution of 211At-Rebmab200 was evaluated, as was the utility of 99mTc-Rebmab200 for bioimaging. Rebmab200 was directly compared with its murine counterpart MX35 in terms of its in-vitro capacity for binding the immobilized NaPi2B epitope and live cells; we also assessed its biodistribution in nude mice carrying subcutaneous OVCAR-3 tumors. Tumor antigen and cell binding were similar between Rebmab200 and murine MX35, as was biodistribution, including normal tissue uptake and in-vivo tumor binding. We also demonstrated that 99mTc-Rebmab200 can be used for single-photon emission computed tomography of subcutaneous ovarian carcinomas in tumor-bearing mice. Taken together, our data support the further development of Rebmab200 for radioimmunotherapy and diagnostics.


Assuntos
Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais/farmacocinética , Antígenos de Neoplasias/metabolismo , Antineoplásicos/farmacocinética , Carcinoma/diagnóstico por imagem , Neoplasias Ovarianas/diagnóstico por imagem , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados/farmacologia , Afinidade de Anticorpos , Especificidade de Anticorpos , Antígenos de Neoplasias/genética , Antineoplásicos/farmacologia , Astato/química , Carcinoma/genética , Carcinoma/imunologia , Carcinoma/terapia , Linhagem Celular Tumoral , Feminino , Expressão Gênica , Humanos , Camundongos , Camundongos Nus , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/terapia , Radioimunoterapia , Compostos Radiofarmacêuticos/química , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIb/genética , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIb/metabolismo , Tecnécio/química , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único , Ensaios Antitumorais Modelo de Xenoenxerto
6.
J Pineal Res ; 36(3): 204-11, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15009512

RESUMO

Melatonin, a derivative of tryptophan that is present in all vertebrates, was first described in bovine pineal gland. It is known that melatonin is a highly conserved molecule, present also in unicellular organisms and plants. Several effects of melatonin have been described, including receptor- and non-receptor-mediated actions. Herein, we studied the effects of melatonin on in vitro and in vivo cell proliferation of Cloudman S-91 murine melanoma cells. We demonstrated that melatonin treatment significantly inhibits S-91 melanoma cell proliferation in vitro (EC50 = 10-7 m) as well as reduces tumor growth in vivo. We also demonstrated that melatonin directly increases the activity of the antioxidant enzymes catalase and glutathione peroxidase. These effects are most likely triggered through the direct intracellular action of melatonin, since the presence of receptors could not be demonstrated in this cell line. Expression of MT-1 melatonin receptor by stable transfection, mediated a dramatic antiproliferative melatonin effect (EC50 = 10-10 m) in S-91 cells. The expressed receptor is negatively coupled to the adenylyl cyclase/cyclic AMP signaling pathway via Gi protein. These results suggest that expression of the MT-1 melatonin receptor in melanoma cells is a potential alternative approach to specifically target cells in cancer therapeutic treatment.


Assuntos
Melanoma/tratamento farmacológico , Melatonina/farmacologia , Receptor MT1 de Melatonina/metabolismo , Animais , Antineoplásicos/farmacologia , Sítios de Ligação , Catalase/efeitos dos fármacos , Catalase/metabolismo , Divisão Celular/efeitos dos fármacos , Colforsina/farmacologia , AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/efeitos dos fármacos , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Glutationa Peroxidase/efeitos dos fármacos , Glutationa Peroxidase/metabolismo , Masculino , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Camundongos Endogâmicos DBA , Receptor MT1 de Melatonina/efeitos dos fármacos , Receptor MT1 de Melatonina/genética , Transdução de Sinais , Transfecção , Células Tumorais Cultivadas
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