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1.
Medicine (Baltimore) ; 99(38): e22091, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32957329

RESUMO

Inflammatory, angiogenic, and immune processes have been associated with uveal melanoma (UM). The aim of the present study was to evaluate the presence of some specific aqueous humor (AH) soluble biomarkers in eyes affected by UM. Thirty-five eyes affected by primary UM and 35 control eyes, scheduled for cataract surgery, underwent full ophthalmic examination and AH sampling at time of surgery (brachytherapy or cataract surgery, respectively). AH samples were analyzed by means of ELISA, to detect the concentration of selected cytokines, chemokines, and growth factors. Compared with the control group, higher levels of IL-6 (P = .049), IL-8 (P = .006), RANTES (P = .008), EGF (P = .032), bFGF (P = .016), MIF (P = .007), and MCP (P = .020) were detected in eyes with UM. VEGF concentration between the two groups was statistically borderline (P = .058). Comparison between clinical characteristics and cytokine concentrations showed a positive correlation between tumor thickness and IL-8 (P = .032), and degree of serous retinal detachment and IL-6 (P = .021). UM is characterized by the presence of retinal neuroinflammatory, angiogenic, and immune biomarkers in AH. The proteomic analysis of AH could characterize UM microenvironment, allowing to better understand its pathophysiology.


Assuntos
Humor Aquoso/metabolismo , Biomarcadores/metabolismo , Quimiocinas/metabolismo , Citocinas/metabolismo , Melanoma/metabolismo , Neoplasias Uveais/metabolismo , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Masculino , Melanoma/cirurgia , Pessoa de Meia-Idade , Proteômica , Neoplasias Uveais/cirurgia
2.
Nat Commun ; 11(1): 4830, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32973134

RESUMO

Non-invasively probing metabolites within single live cells is highly desired but challenging. Here we utilize Raman spectro-microscopy for spatial mapping of metabolites within single cells, with the specific goal of identifying druggable metabolic susceptibilities from a series of patient-derived melanoma cell lines. Each cell line represents a different characteristic level of cancer cell de-differentiation. First, with Raman spectroscopy, followed by stimulated Raman scattering (SRS) microscopy and transcriptomics analysis, we identify the fatty acid synthesis pathway as a druggable susceptibility for differentiated melanocytic cells. We then utilize hyperspectral-SRS imaging of intracellular lipid droplets to identify a previously unknown susceptibility of lipid mono-unsaturation within de-differentiated mesenchymal cells with innate resistance to BRAF inhibition. Drugging this target leads to cellular apoptosis accompanied by the formation of phase-separated intracellular membrane domains. The integration of subcellular Raman spectro-microscopy with lipidomics and transcriptomics suggests possible lipid regulatory mechanisms underlying this pharmacological treatment. Our method should provide a general approach in spatially-resolved single cell metabolomics studies.


Assuntos
Melanoma/metabolismo , Metabolômica/métodos , Microscopia/métodos , Análise Espectral Raman/métodos , Apoptose , Linhagem Celular Tumoral , Ácidos Graxos/metabolismo , Humanos , Gotículas Lipídicas , Metabolismo dos Lipídeos , Lipidômica , Lipídeos , Ácido Oleico , Estearoil-CoA Dessaturase/metabolismo , Transcriptoma
3.
Proc Natl Acad Sci U S A ; 117(33): 20159-20170, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32747553

RESUMO

Although immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment, many patients do not respond or develop resistance to ICB. N6 -methylation of adenosine (m6A) in RNA regulates many pathophysiological processes. Here, we show that deletion of the m6A demethylase Alkbh5 sensitized tumors to cancer immunotherapy. Alkbh5 has effects on m6A density and splicing events in tumors during ICB. Alkbh5 modulates Mct4/Slc16a3 expression and lactate content of the tumor microenvironment and the composition of tumor-infiltrating Treg and myeloid-derived suppressor cells. Importantly, a small-molecule Alkbh5 inhibitor enhanced the efficacy of cancer immunotherapy. Notably, the ALKBH5 gene mutation and expression status of melanoma patients correlate with their response to immunotherapy. Our results suggest that m6A demethylases in tumor cells contribute to the efficacy of immunotherapy and identify ALKBH5 as a potential therapeutic target to enhance immunotherapy outcome in melanoma, colorectal, and potentially other cancers.


Assuntos
Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Vacinas Anticâncer/imunologia , Lactatos/metabolismo , Melanoma/metabolismo , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T Reguladores/fisiologia , Homólogo AlkB 5 da RNA Desmetilase/genética , Anticorpos , Citocinas/genética , Citocinas/metabolismo , Deleção de Genes , Regulação Neoplásica da Expressão Gênica , Humanos , Melanoma/terapia , Metiltransferases/genética , Metiltransferases/metabolismo , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Células Supressoras Mieloides/fisiologia , Sítios de Splice de RNA , Processamento de RNA , Simportadores/genética , Simportadores/metabolismo , Transcriptoma , Microambiente Tumoral , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
4.
Nature ; 585(7823): 113-118, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32814895

RESUMO

Cancer cells, including melanoma cells, often metastasize regionally through the lymphatic system before metastasizing systemically through the blood1-4; however, the reason for this is unclear. Here we show that melanoma cells in lymph experience less oxidative stress and form more metastases than melanoma cells in blood. Immunocompromised mice with melanomas derived from patients, and immunocompetent mice with mouse melanomas, had more melanoma cells per microlitre in tumour-draining lymph than in tumour-draining blood. Cells that metastasized through blood, but not those that metastasized through lymph, became dependent on the ferroptosis inhibitor GPX4. Cells that were pretreated with chemical ferroptosis inhibitors formed more metastases than untreated cells after intravenous, but not intralymphatic, injection. We observed multiple differences between lymph fluid and blood plasma that may contribute to decreased oxidative stress and ferroptosis in lymph, including higher levels of glutathione and oleic acid and less free iron in lymph. Oleic acid protected melanoma cells from ferroptosis in an Acsl3-dependent manner and increased their capacity to form metastatic tumours. Melanoma cells from lymph nodes were more resistant to ferroptosis and formed more metastases after intravenous injection than did melanoma cells from subcutaneous tumours. Exposure to the lymphatic environment thus protects melanoma cells from ferroptosis and increases their ability to survive during subsequent metastasis through the blood.


Assuntos
Ferroptose , Linfa/metabolismo , Melanoma/patologia , Metástase Neoplásica/patologia , Animais , Sobrevivência Celular , Coenzima A Ligases/metabolismo , Feminino , Ferroptose/efeitos dos fármacos , Glutationa/metabolismo , Humanos , Ferro/metabolismo , Masculino , Melanoma/sangue , Melanoma/metabolismo , Camundongos , Metástase Neoplásica/tratamento farmacológico , Ácido Oleico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Análise de Componente Principal
5.
Yonsei Med J ; 61(7): 562-571, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32608199

RESUMO

Melanoma, originating from epidermal melanocytes, is a heterogeneous disease that has the highest mortality rate among all types of skin cancers. Numerous studies have revealed the cause of this cancer as related to various somatic driver mutations, including alterations in KIT-a proto-oncogene encoding for a transmembrane receptor tyrosine kinase. Although accounting for only 3% of all melanomas, mutations in c-KIT are mostly derived from acral, mucosal, and chronically sun-damaged melanomas. As an important factor for cell differentiation, proliferation, and survival, inhibition of c-KIT has been exploited for clinical trials in advanced melanoma. Here, apart from the molecular background of c-KIT and its cellular functions, we will review the wide distribution of alterations in KIT with a catalogue of more than 40 mutations reported in various articles and case studies. Additionally, we will summarize the association of KIT mutations with clinicopathologic features (age, sex, melanoma subtypes, anatomic location, etc.), and the differences of mutation rate among subgroups. Finally, several therapeutic trials of c-KIT inhibitors, including imatinib, dasatinib, nilotinib, and sunitinib, will be analyzed for their success rates and limitations in advanced melanoma treatment. These not only emphasize c-KIT as an attractive target for personalized melanoma therapy but also propose the requirement for additional investigational studies to develop novel therapeutic trials co-targeting c-KIT and other cytokines such as members of signaling pathways and immune systems.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Proteínas Proto-Oncogênicas c-kit/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/metabolismo , Feminino , Humanos , Masculino , Melanoma/genética , Membrana Mucosa/metabolismo , Mutação , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptores Proteína Tirosina Quinases/genética , Neoplasias Cutâneas/genética
6.
Nat Commun ; 11(1): 3588, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32680985

RESUMO

Tumors subvert immune cell function to evade immune responses, yet the complex mechanisms driving immune evasion remain poorly understood. Here we show that tumors induce de novo steroidogenesis in T lymphocytes to evade anti-tumor immunity. Using a transgenic steroidogenesis-reporter mouse line we identify and characterize de novo steroidogenic immune cells, defining the global gene expression identity of these steroid-producing immune cells and gene regulatory networks by using single-cell transcriptomics. Genetic ablation of T cell steroidogenesis restricts primary tumor growth and metastatic dissemination in mouse models. Steroidogenic T cells dysregulate anti-tumor immunity, and inhibition of the steroidogenesis pathway is sufficient to restore anti-tumor immunity. This study demonstrates T cell de novo steroidogenesis as a mechanism of anti-tumor immunosuppression and a potential druggable target.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Melanoma/imunologia , Esteroides/imunologia , Animais , Linfócitos T CD4-Positivos/metabolismo , Linhagem Celular Tumoral , Enzima de Clivagem da Cadeia Lateral do Colesterol/genética , Enzima de Clivagem da Cadeia Lateral do Colesterol/imunologia , Humanos , Evasão da Resposta Imune , Melanoma/genética , Melanoma/metabolismo , Camundongos , Camundongos Knockout , Esteroides/biossíntese
7.
Anticancer Res ; 40(7): 3723-3732, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620611

RESUMO

BACKGROUND/AIM: Skin melanoma belongs to the most invasive malignancies with no cure for a progressing disease. Personalized therapy would allow for the selection of patients that will benefit from treatment. For this purpose, proper predictive biomarkers must be defined. MATERIALS AND METHODS: Allogeneic whole-cell gene-modified therapeutic melanoma vaccine (AGI-101H) was applied in advanced melanoma patients. Humoral responses were analyzed using SEREX, and in silico gene expression analysis in TCGA melanoma patients was performed. RESULTS: A specific antibody response was raised against an antigen identified as BNIP3L, which correlated with a good prognosis. Moreover, AGI-101H directs an immune response against autophagy, as BNIP3L is a marker of this process. Medium and high expression of BNIP3L was also linked with longer overall survival. CONCLUSION: BNIP3L is a candidate prognostic marker of clinical outcome of melanoma patients treated with AGI-101H, and may be considered as a prediction marker for patient survival.


Assuntos
Autofagia/fisiologia , Biomarcadores Tumorais/metabolismo , Melanoma/metabolismo , Melanoma/patologia , Proteínas de Membrana/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Proteínas Supressoras de Tumor/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Vacinas Anticâncer/imunologia , Feminino , Humanos , Masculino , Melanoma/imunologia , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Neoplasias Cutâneas/imunologia
8.
BMC Bioinformatics ; 21(1): 329, 2020 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-32703153

RESUMO

BACKGROUND: Melanoma phenotype and the dynamics underlying its progression are determined by a complex interplay between different types of regulatory molecules. In particular, transcription factors (TFs), microRNAs (miRNAs), and long non-coding RNAs (lncRNAs) interact in layers that coalesce into large molecular interaction networks. Our goal here is to study molecules associated with the cross-talk between various network layers, and their impact on tumor progression. RESULTS: To elucidate their contribution to disease, we developed an integrative computational pipeline to construct and analyze a melanoma network focusing on lncRNAs, their miRNA and protein targets, miRNA target genes, and TFs regulating miRNAs. In the network, we identified three-node regulatory loops each composed of lncRNA, miRNA, and TF. To prioritize these motifs for their role in melanoma progression, we integrated patient-derived RNAseq dataset from TCGA (SKCM) melanoma cohort, using a weighted multi-objective function. We investigated the expression profile of the top-ranked motifs and used them to classify patients into metastatic and non-metastatic phenotypes. CONCLUSIONS: The results of this study showed that network motif UCA1/AKT1/hsa-miR-125b-1 has the highest prediction accuracy (ACC = 0.88) for discriminating metastatic and non-metastatic melanoma phenotypes. The observation is also confirmed by the progression-free survival analysis where the patient group characterized by the metastatic-type expression profile of the motif suffers a significant reduction in survival. The finding suggests a prognostic value of network motifs for the classification and treatment of melanoma.


Assuntos
Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Melanoma/genética , RNA Longo não Codificante/metabolismo , Biologia Computacional/métodos , Humanos , Melanoma/metabolismo , Melanoma/mortalidade , Melanoma/patologia , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Metástase Neoplásica , Fenótipo , RNA-Seq , Fatores de Transcrição/metabolismo
9.
Nat Commun ; 11(1): 2810, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32499572

RESUMO

The overexpression of the protein tyrosine kinase, Focal adhesion kinase (FAK), in endothelial cells has implicated its requirement in angiogenesis and tumour growth, but how pericyte FAK regulates tumour angiogenesis is unknown. We show that pericyte FAK regulates tumour growth and angiogenesis in multiple mouse models of melanoma, lung carcinoma and pancreatic B-cell insulinoma and provide evidence that loss of pericyte FAK enhances Gas6-stimulated phosphorylation of the receptor tyrosine kinase, Axl with an upregulation of Cyr61, driving enhanced tumour growth. We further show that pericyte derived Cyr61 instructs tumour cells to elevate expression of the proangiogenic/protumourigenic transmembrane receptor Tissue Factor. Finally, in human melanoma we show that when 50% or more tumour blood vessels are pericyte-FAK negative, melanoma patients are stratified into those with increased tumour size, enhanced blood vessel density and metastasis. Overall our data uncover a previously unknown mechanism of tumour growth by pericytes that is controlled by pericyte FAK.


Assuntos
Proteína Rica em Cisteína 61/metabolismo , Quinase 1 de Adesão Focal/metabolismo , Regulação Neoplásica da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neovascularização Patológica , Pericitos/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Animais , Aorta Torácica/patologia , Carcinoma Pulmonar de Lewis/metabolismo , Adesão Celular , Proliferação de Células , Feminino , Quinase 1 de Adesão Focal/genética , Humanos , Linfocinas/metabolismo , Masculino , Melanoma/irrigação sanguínea , Melanoma/metabolismo , Melanoma Experimental , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias/patologia , Fator de Crescimento Placentário/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Proteínas Proto-Oncogênicas c-sis/metabolismo , Transdução de Sinais , Microambiente Tumoral , Fator A de Crescimento do Endotélio Vascular/metabolismo
10.
Toxicol Appl Pharmacol ; 401: 115110, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32533954

RESUMO

Melanoma is characterized by high malignancy and early onset of metastasis. Epithelial-to-mesenchymal transition (EMT) is an early event during tumor metastasis. Tumor cells that develop EMT can escape apoptosis, but they are vulnerable to ferroptosis inducers. Gambogenic acid (GNA), a xanthone found in Gamboge, has cytotoxic effects in highly invasive melanoma cells. This study investigated the anti-melanoma effect and mechanism of action of GNA in TGF-ß1-induced EMT melanoma cells. We found that GNA significantly inhibited the invasion, migration and EMT in melanoma cells, and these cells exhibited small mitochondrial wrinkling (an important feature of ferroptosis). An iron chelator, but not an apoptosis inhibitor or a necrosis inhibitor, abolished the inhibitory effects of GNA on proliferation, invasion and migration of TGF-ß1-stimulated melanoma cells. GNA upregulated the expression of p53, solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) in the model cells, contributing to the mechanisms underlying GNA-induced ferroptosis. Collectively, our findings suggest that GNA induces ferroptosis in TGF-ß1-stimulated melanoma cells via the p53/SLC7A11/GPX4 signaling pathway.


Assuntos
Medicamentos de Ervas Chinesas/toxicidade , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Ferroptose/efeitos dos fármacos , Melanoma/metabolismo , Neoplasias Cutâneas/metabolismo , Xantenos/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Medicamentos de Ervas Chinesas/uso terapêutico , Transição Epitelial-Mesenquimal/fisiologia , Ferroptose/fisiologia , Humanos , Melanoma/tratamento farmacológico , Melanoma/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Xantenos/uso terapêutico
11.
Mol Cell ; 79(3): 472-487.e10, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32531202

RESUMO

It is widely assumed that decreasing transcription factor DNA-binding affinity reduces transcription initiation by diminishing occupancy of sequence-specific regulatory elements. However, in vivo transcription factors find their binding sites while confronted with a large excess of low-affinity degenerate motifs. Here, using the melanoma lineage survival oncogene MITF as a model, we show that low-affinity binding sites act as a competitive reservoir in vivo from which transcription factors are released by mitogen-activated protein kinase (MAPK)-stimulated acetylation to promote increased occupancy of their regulatory elements. Consequently, a low-DNA-binding-affinity acetylation-mimetic MITF mutation supports melanocyte development and drives tumorigenesis, whereas a high-affinity non-acetylatable mutant does not. The results reveal a paradoxical acetylation-mediated molecular clutch that tunes transcription factor availability via genome-wide redistribution and couples BRAF to tumorigenesis. Our results further suggest that p300/CREB-binding protein-mediated transcription factor acetylation may represent a common mechanism to control transcription factor availability.


Assuntos
Regulação Neoplásica da Expressão Gênica , Genoma , Melanoma/genética , Fator de Transcrição Associado à Microftalmia/genética , Processamento de Proteína Pós-Traducional , Neoplasias Cutâneas/genética , Acetilação , Sequência de Aminoácidos , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Sequência Conservada , Elementos Facilitadores Genéticos , Feminino , Xenoenxertos , Humanos , Masculino , Melanócitos/metabolismo , Melanócitos/patologia , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Camundongos Nus , Fator de Transcrição Associado à Microftalmia/química , Fator de Transcrição Associado à Microftalmia/metabolismo , Motivos de Nucleotídeos , Regiões Promotoras Genéticas , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Peixe-Zebra
12.
Nat Commun ; 11(1): 2935, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32523045

RESUMO

Personalized cancer treatments using combinations of drugs with a synergistic effect is attractive but proves to be highly challenging. Here we present an approach to uncover the efficacy of drug combinations based on the analysis of mono-drug effects. For this we used dose-response data from pharmacogenomic encyclopedias and represent these as a drug atlas. The drug atlas represents the relations between drug effects and allows to identify independent processes for which the tumor might be particularly vulnerable when attacked by two drugs. Our approach enables the prediction of combination-therapy which can be linked to tumor-driving mutations. By using this strategy, we can uncover potential effective drug combinations on a pan-cancer scale. Predicted synergies are provided and have been validated in glioblastoma, breast cancer, melanoma and leukemia mouse-models, resulting in therapeutic synergy in 75% of the tested models. This indicates that we can accurately predict effective drug combinations with translational value.


Assuntos
Sinergismo Farmacológico , Animais , Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Biologia Computacional , Combinação de Medicamentos , Glioblastoma/metabolismo , Humanos , Modelos Logísticos , Melanoma/metabolismo
13.
Nat Commun ; 11(1): 2749, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32488012

RESUMO

The tumour microenvironment (TME) forms a major obstacle in effective cancer treatment and for clinical success of immunotherapy. Conventional co-cultures have shed light onto multiple aspects of cancer immunobiology, but they are limited by the lack of physiological complexity. We develop a human organotypic skin melanoma culture (OMC) that allows real-time study of host-malignant cell interactions within a multicellular tissue architecture. By co-culturing decellularized dermis with keratinocytes, fibroblasts and immune cells in the presence of melanoma cells, we generate a reconstructed TME that closely resembles tumour growth as observed in human lesions and supports cell survival and function. We demonstrate that the OMC is suitable and outperforms conventional 2D co-cultures for the study of TME-imprinting mechanisms. Within the OMC, we observe the tumour-driven conversion of cDC2s into CD14+ DCs, characterized by an immunosuppressive phenotype. The OMC provides a valuable approach to study how a TME affects the immune system.


Assuntos
Plasticidade Celular/fisiologia , Células Dendríticas/metabolismo , Melanoma/metabolismo , Microambiente Tumoral/fisiologia , Comunicação Celular , Sobrevivência Celular , Técnicas de Cocultura , Fibroblastos/patologia , Humanos , Queratinócitos/patologia , Melanoma/imunologia , Melanoma/patologia , Pele/patologia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Microambiente Tumoral/imunologia
14.
Am J Med Sci ; 359(6): 339-346, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32498941

RESUMO

BACKGROUND: There is a growing interest in using programmed death ligand-1 (PD-L1) as a prognostic marker for melanoma. We conducted this meta-analysis to explore the prognostic and clinicopathological value of PD-L1 in melanoma. MATERIALS AND METHODS: The electronic databases PubMed, Web of Science and the Cochrane Library were searched for relevant studies. The major investigated parameters were PD-L1 expression levels in relation to patient gender, tumor-infiltrating lymphocytes (TILs), tumor stage, lymph node (LN) metastasis, histological type, progression-free survival (PFS) and overall survival (OS). Odds ratios (ORs) and hazard ratios (HRs) were computed using the fixed-effect or random-effects model according to data heterogeneity. RESULTS: Positive PD-L1 expression was significantly associated with high levels of TILs (OR = 7.56, 95% CI 2.04-28.02), metastatic melanoma (OR = 0.45, 95% CI 0.30-0.67) and LN-positive melanoma (OR = 2.56, 95% CI 1.31-4.99) but not gender or histological type. In addition, the pooled HRs showed no relation between PD-L1 expression and PFS (HR = 1.18, 95% CI 0.83-1.69) or OS (HR = 0.77, 95% CI 0.47-1.25). When restricted to metastatic melanoma, positive PD-L1 expression was significantly related to prolonged OS (HR = 0.57, 95% CI 0.46-0.70). CONCLUSIONS: Positive PD-L1 expression may be an important prognostic factor for longer OS in patients with metastatic melanoma.


Assuntos
Antígeno B7-H1/metabolismo , Melanoma/diagnóstico , Melanoma/metabolismo , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/metabolismo , Biomarcadores Tumorais/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Linfócitos do Interstício Tumoral/citologia , Masculino , Metástase Neoplásica , Razão de Chances , Prognóstico , Modelos de Riscos Proporcionais , Resultado do Tratamento
15.
Proc Natl Acad Sci U S A ; 117(26): 15066-15074, 2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32554492

RESUMO

Cancer incidence increases exponentially with age when human telomeres are shorter. Similarly, telomerase reverse transcriptase (tert) mutant zebrafish have premature short telomeres and anticipate cancer incidence to younger ages. However, because short telomeres constitute a road block to cell proliferation, telomere shortening is currently viewed as a tumor suppressor mechanism and should protect from cancer. This conundrum is not fully understood. In our current study, we report that telomere shortening promotes cancer in a noncell autonomous manner. Using zebrafish chimeras, we show increased incidence of invasive melanoma when wild-type (WT) tumors are generated in tert mutant zebrafish. Tissues adjacent to melanoma lesions (skin) and distant organs (intestine) in tert mutants exhibited higher levels of senescence and inflammation. In addition, we transferred second generation (G2) tert blastula cells into WT to produce embryo chimeras. Cells with very short telomeres induced increased tumor necrosis factor1-α (TNF1-α) expression and senescence in larval tissues in a noncell autonomous manner, creating an inflammatory environment. Considering that inflammation is protumorigenic, we transplanted melanoma-derived cells into G2 tert zebrafish embryos and observed that tissue environment with short telomeres leads to increased tumor development. To test if inflammation was necessary for this effect, we treated melanoma transplants with nonsteroid anti-inflammatory drugs and show that higher melanoma dissemination can be averted. Thus, apart from the cell autonomous role of short telomeres in contributing to genome instability, we propose that telomere shortening with age causes systemic chronic inflammation leading to increased tumor incidence.


Assuntos
Melanoma/metabolismo , Telômero/metabolismo , Peixe-Zebra/metabolismo , Animais , Modelos Animais de Doenças , Humanos , Melanoma/genética , Melanoma/imunologia , Telomerase/genética , Telomerase/metabolismo , Telômero/genética , Encurtamento do Telômero , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Peixe-Zebra/genética , Peixe-Zebra/imunologia , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
16.
Nat Cell Biol ; 22(7): 803-814, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32572169

RESUMO

Cell shape is controlled by the submembranous cortex, an actomyosin network mainly generated by two actin nucleators: the Arp2/3 complex and the formin mDia1. Changes in relative nucleator activity may alter cortical organization, mechanics and cell shape. Here we investigate how nucleation-promoting factors mediate interactions between nucleators. In vitro, the nucleation-promoting factor SPIN90 promotes formation of unbranched filaments by Arp2/3, a process thought to provide the initial filament for generation of dendritic networks. Paradoxically, in cells, SPIN90 appears to favour a formin-dominated cortex. Our in vitro experiments reveal that this feature stems mainly from two mechanisms: efficient recruitment of mDia1 to SPIN90-Arp2/3 nucleated filaments and formation of a ternary SPIN90-Arp2/3-mDia1 complex that greatly enhances filament nucleation. Both mechanisms yield rapidly elongating filaments with mDia1 at their barbed ends and SPIN90-Arp2/3 at their pointed ends. Thus, in networks, SPIN90 lowers branching densities and increases the proportion of long filaments elongated by mDia1.


Assuntos
Citoesqueleto de Actina/fisiologia , Complexo 2-3 de Proteínas Relacionadas à Actina/metabolismo , Actinas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Forminas/metabolismo , Melanoma/patologia , Proteínas Musculares/metabolismo , Complexo 2-3 de Proteínas Relacionadas à Actina/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Blástula/citologia , Blástula/metabolismo , Forma Celular , Embrião não Mamífero/citologia , Embrião não Mamífero/metabolismo , Forminas/genética , Humanos , Melanoma/genética , Melanoma/metabolismo , Proteínas Musculares/genética , Xenopus laevis/crescimento & desenvolvimento , Xenopus laevis/metabolismo
17.
Invest Ophthalmol Vis Sci ; 61(5): 12, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32396633

RESUMO

Purpose: Adiponectin is an insulin-sensitizing and anticarcinogenic hormone that is encoded by a gene on chromosome 3. Here, we analyzed the expression of adiponectin and its receptor Adipor1 in primary uveal melanoma (UM) with regard to the monosomy-3 status and clinical factors, as well as the physiological response of UM cells to adiponectin. Methods: Immunohistochemistry was performed on the primary UM of 34 patients. Circulating melanoma cells (CMC) were isolated by immunomagnetic enrichment. Monosomy-3 was evaluated by Immuno-FISH. Gene expression was analyzed using the RNAseq data of The Cancer Genome Atlas study. Cultures of choroidal melanocytes and UM were established from the samples of two patients. The proliferative potential of the UM cell lines Mel-270 and OMM-2.5 was determined by immunocytochemistry, immunoblotting, cell cycle analysis, nucleolar staining, and adenosine triphosphate (ATP) levels. Results: UM with monosomy-3 exhibited a lower immunoreactivity for adiponectin and Adipor1, which was associated with monosomy-3-positive CMC and the development of extraocular growth or metastases. Both proteins were more abundant in the irradiated tumors and present in the cultured cells. Gene expression profile indicated the impairment of adiponectin-mediated signaling in the monosomy-3 tumors. Adiponectin induced a significant decline in the ATP levels, Ki-67 expression, cells in the G2/M phase, and nucleolar integrity in UM cultures. Conclusions: Adiponectin deficiency appears to enhance the metastatic potential of the UM cells with monosomy-3 and the termination of tumor dormancy. Counteracting insulin resistance and improving the serum adiponectin levels might therefore be a valuable approach to prevent or delay the UM metastases.


Assuntos
Adiponectina/metabolismo , Cromossomos Humanos Par 3 , Melanoma/metabolismo , Monossomia , Receptores de Adiponectina/metabolismo , Neoplasias Uveais/metabolismo , Trifosfato de Adenosina/metabolismo , Idoso , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular , Humanos , Imuno-Histoquímica , Antígeno Ki-67/metabolismo , Masculino , Melanoma/genética , Metástase Neoplásica , Células Neoplásicas Circulantes/patologia , Neoplasias Uveais/genética
18.
Life Sci ; 253: 117600, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32234492

RESUMO

BACKGROUND: Skin cutaneous melanoma (SKCM) is the most common subtype of skin malignancy, with ever-increasing incidence, mortality, and disease burden. Dysregulation of JAK-STATs signaling pathway is involved in the pathogenesis and progression of cancers, thus affecting the prognosis of cancer patients. The function of JAKs in SKCM is still not clarified. METHODS: A total of five online portal (GEPIA, TIMER, GeneMANIA, LinkedOmics, and GSCALite) is used to mine the expression and gene regulation network JAK2 in SKCM. RESULTS: JAK2 expression was downregulated in SKCM and significantly associated with pathological stage and the prognosis of patients. The functions of JAK2 and associated genes were primarily involved in the DNA recombination, cell cycle checkpoint, metabolic process, NOD-like receptor signaling pathways, p53 signaling pathway and apoptosis. JAK2 level was significantly correlated with the abundance of immune cells and the level of immune biomarkers. Low expression of JAK2 were resistant to QL-VIII-58, TL-1-85, Ruxolitinib, TG101348 and Sunitinib. CONCLUSIONS: Our results reveal the expression and gene regulation network of JAK2 in skin cutaneous melanoma, providing more evidences about the role of JAK2 in carcinogenesis.


Assuntos
Antineoplásicos/farmacologia , Janus Quinases/metabolismo , Melanoma/metabolismo , Pirazóis/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Sunitinibe/farmacologia , Antineoplásicos/metabolismo , Bases de Dados de Ácidos Nucleicos , Bases de Dados de Proteínas , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Janus Quinases/genética , MicroRNAs/metabolismo , Modelos Biológicos , Prognóstico , Pirazóis/metabolismo , Transdução de Sinais , Neoplasias Cutâneas/metabolismo , Sunitinibe/metabolismo
19.
Mol Carcinog ; 59(6): 640-650, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32232919

RESUMO

A few single-nucleotide polymorphisms (SNPs) have been identified to be associated with cutaneous melanoma (CM) survival through genome-wide association studies, but stringent multiple testing corrections required for the hypothesis-free testing may have masked some true associations. Using a hypothesis-driven analysis approach, we sought to evaluate associations between SNPs in ketone body metabolic pathway genes and CM survival. We comprehensively assessed associations between 4196 (538 genotyped and 3658 imputed) common SNPs in 44 ketone body metabolic pathway genes and CM survival, using a dataset of 858 patients of a case-control study from The University of Texas M.D. Anderson Cancer Center as the discovery set and another dataset of 409 patients from the Nurses' Health Study and the Health Professionals Follow-up Study as the replication set. There were 95/858 (11.1%) and 48/409 (11.7%) patients who died of CM, respectively. We identified two independent SNPs (ie, PDSS1 rs12254548 G>C and SLC16A6 rs71387392 G>A) that were associated with CM survival, with allelic hazards ratios of 0.58 (95% confidence interval [CI] = 0.44-0.76, P = 9.00 × 10-5 ) and 1.98 (95% CI = 1.34-2.94, P = 6.30 × 10-4 ), respectively. Additionally, associations between genotypes of the SNPs and messenger RNA expression levels of their corresponding genes support the biologic plausibility of a role for these two variants in CM tumor progression and survival. Once validated by other larger studies, PDSS1 rs12254548 and SLC16A6 rs71387392 may be valuable biomarkers for CM survival.


Assuntos
Alquil e Aril Transferases/genética , Biomarcadores Tumorais/genética , Cetonas/metabolismo , Melanoma/mortalidade , Transportadores de Ácidos Monocarboxílicos/genética , Polimorfismo de Nucleotídeo Único , Neoplasias Cutâneas/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Melanoma/genética , Melanoma/metabolismo , Melanoma/patologia , Redes e Vias Metabólicas , Pessoa de Meia-Idade , Prognóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Taxa de Sobrevida , Adulto Jovem
20.
Anticancer Res ; 40(4): 2157-2163, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32234909

RESUMO

BACKGROUND/AIM: There is a lack of quality biomarkers of survival for patients with metastatic melanoma treated with immunotherapy. Although the baseline level of S100 has prognostic value, its role during/after therapy in survival is unclear. PATIENTS AND METHODS: We evaluated patients with metastatic melanoma treated with pembrolizumab with the goal of analysing the relationship between a relative change in S100 level at 12 weeks of immunotherapy and survival. RESULTS: Patients with a relative change in S100 level >145% at 12 weeks of immunotherapy had significantly shorter progression-free (5.1 vs. 18.5 months, p≤0.0001) and overall survival (5.7 vs. 26.3 months, p<0.0001), further confirmed on multivariate analysis with hazard ratio of 32.25 (95% confidence interval=4.78-217.6, p=0.0004) for overall survival. CONCLUSION: A relative change in S100 level might be useful as a more precise biomarker of survival for patients with metastatic melanoma treated with pembrolizumab.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Biomarcadores Tumorais/análise , Melanoma/tratamento farmacológico , Proteínas S100/análise , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Antineoplásicos Imunológicos/uso terapêutico , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/secundário , Metástase Linfática , Masculino , Melanoma/metabolismo , Melanoma/patologia , Pessoa de Meia-Idade , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia
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