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1.
Genes Dev ; 34(1-2): 72-86, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31831627

RESUMO

Yes-associated protein (YAP) and its homolog transcriptional coactivator with PDZ-binding motif (TAZ) are key effectors of the Hippo pathway to control cell growth and organ size, of which dysregulation yields to tumorigenesis or hypertrophy. Upon activation, YAP/TAZ translocate into the nucleus and bind to TEAD transcription factors to promote transcriptional programs for proliferation or cell specification. Immediate early genes, represented by AP-1 complex, are rapidly induced and control later-phase transcriptional program to play key roles in tumorigenesis and organ maintenance. Here, we report that YAP/TAZ directly promote FOS transcription that in turn contributes to the biological function of YAP/TAZ. YAP/TAZ bind to the promoter region of FOS to stimulate its transcription. Deletion of YAP/TAZ blocks the induction of immediate early genes in response to mitogenic stimuli. FOS induction contributes to expression of YAP/TAZ downstream target genes. Genetic deletion or chemical inhibition of AP-1 suppresses growth of YAP-driven cancer cells, such as Lats1/2-deficient cancer cells as well as Gαq/11 mutated uveal melanoma. Furthermore, AP-1 inhibition almost completely abrogates the hepatomegaly induced by YAP overexpression. Our findings reveal a feed-forward interplay between immediate early transcription of AP-1 and Hippo pathway function.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Regulação Neoplásica da Expressão Gênica , Transativadores/metabolismo , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismo , Fatores de Transcrição/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Deleção de Genes , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes fos/genética , Células HEK293 , Humanos , Fígado/metabolismo , Melanoma/fisiopatologia , Camundongos , Mitógenos/farmacologia , Tamanho do Órgão/genética , Regiões Promotoras Genéticas/genética , Neoplasias Uveais/fisiopatologia
2.
Genes Dev ; 33(23-24): 1641-1656, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31727773

RESUMO

Angiopoietin-like protein 2 (ANGPTL2) is a secreted glycoprotein homologous to angiopoietins. Previous studies suggest that tumor cell-derived ANGPTL2 has tumor-promoting function. Here, we conducted mechanistic analysis comparing ANGPTL2 function in cancer progression in a murine syngeneic model of melanoma and a mouse model of translocation renal cell carcinoma (tRCC). ANGPTL2 deficiency in tumor cells slowed tRCC progression, supporting a tumor-promoting role. However, systemic ablation of ANGPTL2 accelerated tRCC progression, supporting a tumor-suppressing role. The syngeneic model also demonstrated a tumor-suppressing role of ANGPTL2 in host tumor microenvironmental cells. Furthermore, the syngeneic model showed that PDGFRα+ fibroblasts in the tumor microenvironment express abundant ANGPTL2 and contribute to tumor suppression. Moreover, host ANGPTL2 facilitates CD8+ T-cell cross-priming and enhances anti-tumor immune responses. Importantly, ANGPTL2 activates dendritic cells through PIR-B-NOTCH signaling and enhances tumor vaccine efficacy. Our study provides strong evidence that ANGPTL2 can function in either tumor promotion or suppression, depending on what cell type it is expressed in.


Assuntos
Proteínas Semelhantes a Angiopoietina/genética , Proteínas Semelhantes a Angiopoietina/metabolismo , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Renais/fisiopatologia , Progressão da Doença , Melanoma/fisiopatologia , Transdução de Sinais , Proteínas Semelhantes a Angiopoietina/deficiência , Proteínas Semelhantes a Angiopoietina/imunologia , Animais , Vacinas Anticâncer/imunologia , Carcinoma de Células Renais/imunologia , Células Dendríticas/imunologia , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Melanoma/imunologia , Camundongos , Transdução de Sinais/genética , Células Estromais/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
3.
Genes Dev ; 33(19-20): 1295-1318, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31575676

RESUMO

An incomplete view of the mechanisms that drive metastasis, the primary cause of cancer-related death, has been a major barrier to development of effective therapeutics and prognostic diagnostics. Increasing evidence indicates that the interplay between microenvironment, genetic lesions, and cellular plasticity drives the metastatic cascade and resistance to therapies. Here, using melanoma as a model, we outline the diversity and trajectories of cell states during metastatic dissemination and therapy exposure, and highlight how understanding the magnitude and dynamics of nongenetic reprogramming in space and time at single-cell resolution can be exploited to develop therapeutic strategies that capitalize on nongenetic tumor evolution.


Assuntos
Plasticidade Celular , Melanoma/fisiopatologia , Metástase Neoplásica/fisiopatologia , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Humanos , Melanoma/terapia , Fator de Transcrição Associado à Microftalmia/genética , Fator de Transcrição Associado à Microftalmia/metabolismo , Células-Tronco Neoplásicas/citologia , Fenótipo , Microambiente Tumoral
4.
Arq. bras. med. vet. zootec. (Online) ; 71(5): 1477-1482, set.-out. 2019. ilus
Artigo em Inglês | LILACS, VETINDEX | ID: biblio-1038664

RESUMO

Recurrent laryngeal neuropathy (RLN) etiology can be acquired, iatrogenic or idiopathic. There are no previous reports of RLN caused by recurrent laryngeal nerve compression by melanomas. This report describes a horse presenting severe dyspnea and progressive weight loss. Physical exam demonstrated tachycardia, tachypnea, inspiratory dyspnea at rest, neck extension and mydriasis. Temporary tracheotomy was performed and videoendoscopic examination diagnosed grade IV laryngeal paralysis. The animal came suddenly to death by suppurative bacterial pneumonia. At necropsy, it was possible to observe multiple melanotic epithelioid melanoma nodules compressing the recurrent laryngeal nerve, alongside with lung and parotid metastasis. This finding emphasizes the importance of establishing a differential diagnosis for tumor mass compression in the etiology of RLN, especially melanomas in gray horses, with or without cutaneous manifestations of masses.(AU)


A neuropatia laríngea recorrente (NLR) pode apresentar etiologia adquirida, iatrogênica ou idiopática. Não há relatos prévios da ocorrência da NLR causada pela compressão do nervo laríngeo recorrente por melanomas. Este relato descreve um equino apresentando dispneia grave e perda de peso progressiva. O exame físico demonstrou taquicardia, taquipneia, dispneia inspiratória em repouso, extensão do pescoço e midríase. Foi realizada traqueotomia temporária e exame videoendoscópico, mediante o qual se diagnosticou paralisia laríngea grau IV. O animal veio a óbito por pneumonia bacteriana supurativa. Na necropsia, foi possível observar múltiplos nódulos de melanoma epitelioide amelanótico comprimindo o nervo laríngeo recorrente, juntamente com metástases pulmonares e parotídeas. Este achado enfatiza a importância de estabelecer um diagnóstico diferencial nos casos de NLR, pensando-se na compressão nervosa por massas tumorais, especialmente melanomas em cavalos tordilhos, com ou sem manifestações cutâneas de massas.(AU)


Assuntos
Animais , Masculino , Cavalos , Laringe/fisiopatologia , Melanócitos/patologia , Melanoma/fisiopatologia , Melanoma/veterinária
5.
Integr Cancer Ther ; 18: 1534735419864431, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31382768

RESUMO

Objective: Treatment with immunotherapy has positively changed the long-term outlook of many patients with advanced melanoma; however, fatigue is a common and debilitating side effect. Evidence indicates exercise can improve treatment-related fatigue for patients receiving chemotherapy and radiotherapy. However, currently little is known about exercise behaviors and preferences of patients receiving immunotherapy. This project aimed to describe self-reported levels of fatigue related to immunotherapy; patient perspectives of exercise behaviors; and barriers and facilitators to engagement in exercise for patients receiving, or recently completed immunotherapy for unresectable stage III and stage IV melanoma. Method: A cross-sectional purpose-built survey was distributed to members of the Melanoma Patients Australia closed Facebook group via an online survey platform. The survey remained active for 1 month, with 3 posts during this time inviting members to participate. Results: A total of 55 responses were collected. Just over half the participants (n = 31; 56%) described exercising while receiving immunotherapy, with walking as the most common activity (n = 24; 77%). Participants described a range of physical and emotional benefits of exercise, the most predominant being fatigue reduction. Barriers to exercise also included fatigue and competing physical demands at home or work. Patient understanding of what constitutes exercise appeared to differ from clinical classifications. Conclusions: Results from this study indicate that patients are engaging in exercise while receiving immunotherapy, with the intent of mediating treatment-related fatigue. Identification of preferred exercise activities and barriers will assist in developing tailored exercise interventions for this cohort.


Assuntos
Exercício/fisiologia , Fadiga/fisiopatologia , Melanoma/fisiopatologia , Adulto , Idoso , Austrália , Estudos Transversais , Terapia por Exercício/métodos , Feminino , Humanos , Imunoterapia/métodos , Masculino , Melanoma/imunologia , Melanoma/terapia , Pessoa de Meia-Idade , Mídias Sociais , Inquéritos e Questionários , Caminhada/fisiologia
6.
Int J Mol Sci ; 20(16)2019 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-31426515

RESUMO

Modulated electrohyperthermia (mEHT), an innovative complementary technique of radio-, chemo-, and targeted oncotherapy modalities, can induce tumor apoptosis and contribute to a secondary immune-mediated cancer death. Here, we tested the efficiency of high-fever range (~42 °C) mEHT on B16F10 melanoma both in cell culture and allograft models. In vivo, mEHT treatment resulted in significant tumor size reduction when repeated three times, and induced major stress response as indicated by upregulated cytoplasmic and cell membrane hsp70 levels. Despite the increased PUMA and apoptosis-inducing factor 1, and moderate rise in activated-caspase-3, apoptosis was not significant. However, phospho-H2AX indicated DNA double-strand breaks, which upregulated p53 protein and its downstream cyclin-dependent kinase inhibitors p21waf1 and p27kip. Combined in vitro treatment with mEHT and the p53 activator nutlin-3a additively reduced cell viability compared to monotherapies. Though mEHT promoted the release of damage-associated molecular pattern (DAMP) damage signaling molecules hsp70, HMGB1 and ATP to potentiate the tumor immunogenicity of melanoma allografts, it reduced MHC-I and melan-A levels in tumor cells. This might explain why the number of cytotoxic T cells was moderately reduced, while the amount of natural killer (NK) cells was mainly unchanged and only macrophages increased significantly. Our results suggest that mEHT-treatment-related tumor growth control was primarily mediated by cell-stress-induced p53, which upregulated cyclin-dependent kinase inhibitors. The downregulated tumor antigen-presenting machinery may explain the reduced cytotoxic T-cell response despite increased DAMP signaling. Decreased tumor antigen and MHC-I levels suggest that natural killer (NK) cells and macrophages were the major contributors to tumor eradication.


Assuntos
Hipertermia Induzida , Melanoma/fisiopatologia , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Proteína HMGB1 , Proteínas de Choque Térmico HSP70 , Macrófagos/imunologia , Melanoma/imunologia , Melanoma/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células T Matadoras Naturais/imunologia , Transplante de Neoplasias , Estresse Fisiológico , Proteína Supressora de Tumor p53/fisiologia
7.
Molecules ; 24(13)2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31277366

RESUMO

Uveal melanoma (UM) represents the most frequent primary intraocular tumor, however, limited therapeutic options are still available. We have previously shown that cluster of differentiation 47 (CD47) is significantly upregulated in UM cells following inflammatory stimuli and that it represents a predictor of disease progression. Here, we aimed to better characterize the pathophysiological role of CD47 in UM. We show that CD47 is not modulated at different cancer stages, although patients with the lowest expression of CD47 show significant better progression-free survival, after correcting for the presence of BAP1, GNAQ, and GNA11 mutations. By stratifying patients based on the expression of CD47 in the tumor, we observed that patients with high levels of CD47 have a significant increase in immune score as compared to patients with low levels of CD47. In particular, deconvolution analysis of infiltrating immune cell populations revealed that a significantly higher number of CD4+ and CD8+ T cells can be found in patients with high CD47 levels, with the most enriched populations being the Th2, Treg, and CD8+ Tcm cells. We also show that a large number of transcripts are significantly modulated between the groups of patients with high and low levels of CD47, with a significant enrichment of interferon IFN-alpha regulated genes. The results from this study may propel the development of anti-CD47 therapies for UM patients.


Assuntos
Complexo CD3/metabolismo , Melanoma/metabolismo , Melanoma/fisiopatologia , Neoplasias Uveais/metabolismo , Neoplasias Uveais/fisiopatologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Ligantes , Melanoma/genética , Melanoma/imunologia , Transcriptoma/genética , Microambiente Tumoral , Regulação para Cima/genética , Neoplasias Uveais/genética , Neoplasias Uveais/imunologia
8.
Am J Chin Med ; 47(5): 1171-1191, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31315419

RESUMO

Melanoma, which has a high metastatic capacity and death rate, is a common skin cancer in Western countries. The purpose of this study was to address whether Juniperus communis (JCo) extract is effective in the suppression of melanoma and to elucidate the anticancer mechanisms involved in vitro and in vivo. The antitumor capacities of JCo extract on tumor suppression and toxicity were evaluated and the results demonstrated that the tumor burden was reduced via mediation of cell cycle, reduction of autocrine signaling, and induction of apoptosis. Moreover, JCo extract significantly prolonged the survival rate of the test subjects with only low pathological and physiological toxicity. Additionally, JCo extract also reduced cancer stem cell-related angiogenic and metastatic proteins in the process of tumor elimination. Based on these results, this study suggests that JCo extract suppresses tumor growth and induces apoptosis, and JCo extract may be useful for the prevention of melanoma tumorigenesis.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Juniperus/química , Melanoma/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Animais , Carcinogênese/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Humanos , Melanoma/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Endogâmicos F344
9.
J Agric Food Chem ; 67(32): 9060-9069, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31339696

RESUMO

Glutathione S-transferases (GSTs) play an active role in the development of drug resistance by numerous cancer cells, including melanoma cells, which is a major cause of chemotherapy failure. As part of our continuous effort to explore why dietary polyphenols bearing the catechol moiety (dietary catechols) show usually anticancer activity, catechol-type diphenylbutadiene (3,4-DHB) was selected as a model of dietary catechols to probe whether they work as pro-oxidative chemosensitizers via GST inhibition in melanoma cells. It was found that, in human melanoma A375 cells, 3,4-DHB is easily converted to its ortho-quinone via copper-containing tyrosinase-mediated two-electron oxidation along with generation of reactive oxygen species (ROS) derived from the oxidation; the resulting ortho-quinone and ROS are responsible for its ability to sensitize the cisplatin-resistant cells by inhibiting GST, followed by induction of apoptosis in an ASK1-JNK/p38 signaling cascade and mitochondria-dependent pathway. This work provides further evidence to support that dietary catechols exhibit antimelanoma activity by virtue of their tyrosinase-dependent pro-oxidative role and gives useful information for designing polyphenol-inspired GST inhibitors and sensitizers in chemotherapy against melanoma.


Assuntos
Antineoplásicos/farmacologia , Butadienos/farmacologia , Catecóis/farmacologia , Inibidores Enzimáticos/farmacologia , Glutationa Transferase/antagonistas & inibidores , Melanoma/enzimologia , Monofenol Mono-Oxigenase/química , Antineoplásicos/química , Antineoplásicos/metabolismo , Apoptose , Butadienos/química , Butadienos/metabolismo , Catecóis/química , Catecóis/metabolismo , Linhagem Celular Tumoral , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Glutationa Transferase/metabolismo , Humanos , Melanoma/metabolismo , Melanoma/fisiopatologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Modelos Químicos , Monofenol Mono-Oxigenase/metabolismo , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
10.
Vet J ; 249: 1-9, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31239158

RESUMO

Haematological parameters, plasma iron concentration, and bodyweight were monitored in Melanoma-bearing Libechov Minipigs (MeLiM) from 5 to 18 weeks old. Animals with melanoma progression (P group) and spontaneous regression (SR group) were compared. The P group showed the lowest median values of red blood cell counts (RBC), haematocrit (HCT), haemoglobin concentration (HGB), and bodyweight, whereas the control white (tumour-free) pigs (C group) revealed the highest mean values of these parameters. The mean values of pigs with SR fell between the P and C groups. In addition, a stable concentration of plasma iron was found in the C group, while iron deficiency that increases with age was observed in the MeLiM groups. These results indicate that MeLiM are affected by cancer-related microcytic hypochromic anaemia. The lowest values of HGB, RBC, and HCT, together with the highest number of platelets (PLT) in the P group correspond to melanoma progression. Higher values of these parameters and lower PLT in the MeLiM pigs with SR reflected health improvement due to the destruction of melanoma cells during spontaneous regression. Monitoring of these haematological parameters can help distinguish MeLiM piglets with progression and spontaneous regression of melanoma in the early stages of postnatal development. The findings of this study correspond to findings in human patients in which cancer-related anaemia, thrombocytosis, and iron deficiency are often diagnosed.


Assuntos
Testes Hematológicos/veterinária , Melanoma/veterinária , Neoplasias Cutâneas/veterinária , Doenças dos Suínos/sangue , Animais , Peso Corporal , Progressão da Doença , Ferro/administração & dosagem , Ferro/sangue , Melanoma/sangue , Melanoma/fisiopatologia , Regressão Neoplásica Espontânea , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/fisiopatologia , Suínos , Doenças dos Suínos/fisiopatologia , Porco Miniatura
11.
PLoS Comput Biol ; 15(6): e1007034, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31166947

RESUMO

Phenotypic plasticity is associated with non-genetic drug tolerance in several cancers. Such plasticity can arise from chromatin remodeling, transcriptomic reprogramming, and/or protein signaling rewiring, and is characterized as a cell state transition in response to molecular or physical perturbations. This, in turn, can confound interpretations of drug responses and resistance development. Using BRAF-mutant melanoma cell lines as the prototype, we report on a joint theoretical and experimental investigation of the cell-state transition dynamics associated with BRAF inhibitor drug tolerance. Thermodynamically motivated surprisal analysis of transcriptome data was used to treat the cell population as an entropy maximizing system under the influence of time-dependent constraints. This permits the extraction of an epigenetic potential landscape for drug-induced phenotypic evolution. Single-cell flow cytometry data of the same system were modeled with a modified Fokker-Planck-type kinetic model. The two approaches yield a consistent picture that accounts for the phenotypic heterogeneity observed over the course of drug tolerance development. The results reveal that, in certain plastic cancers, the population heterogeneity and evolution of cell phenotypes may be understood by accounting for the competing interactions of the epigenetic potential landscape and state-dependent cell proliferation. Accounting for such competition permits accurate, experimentally verifiable predictions that can potentially guide the design of effective treatment strategies.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Evolução Molecular , Melanoma , Fenótipo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Melanoma/genética , Melanoma/fisiopatologia , Modelos Biológicos , Transcriptoma/efeitos dos fármacos , Transcriptoma/genética
12.
Medicina (Kaunas) ; 55(5)2019 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-31100919

RESUMO

Background and objectives: Melanin, which has a confirmed role in melanoma cell behaviour, is formed in the process of melanogenesis and is synthesized from tryptophan, L-tyrosine and their metabolites. All these metabolites are easily detectable by chromatography in urine. Materials and Methods: Urine samples of 133 individuals (82 malignant melanoma patients and 51 healthy controls) were analysed by reversed-phase high-performance liquid chromatography (RP-HPLC). The diagnosis of malignant melanoma was confirmed histologically. Results: Chromatograms of melanoma patients showed increased levels of 5,6-dihydroxyindole-2-carboxylic acid, vanilmandelic acid, homovanilic acid, tryptophan, 5-hydroxyindole-3-acetic acid, and indoxyl sulphate compared to healthy controls. Concentration of indoxyl sulphate, homovanilic acid and tryptophan were significantly increased even in the low clinical stage 0 of the disease (indoxyl sulphate, homovanilic acid and tryptophan in patients with clinical stage 0 vs. controls expressed as medium/ interquartile range in µmol/mmol creatinine: 28.37/15.30 vs. 5.00/6.91; 47.97/33.08 vs. 7.33/21.25; and 16.38/15.98 vs. 3.46/6.22, respectively). Conclusions: HPLC detection of metabolites of L-tyrosine and tryptophan in the urine of melanoma patients may play a significant role in diagnostics as well as a therapeutic strategy of melanoma cancer.


Assuntos
Biomarcadores Tumorais/urina , Melanoma/fisiopatologia , Adulto , Idoso , Biomarcadores Tumorais/análise , Feminino , Ácido Homovanílico/análise , Ácido Homovanílico/urina , Humanos , Ácido Hidroxi-Indolacético/análise , Ácido Hidroxi-Indolacético/urina , Indicã/análise , Indicã/urina , Indóis/análise , Indóis/urina , Masculino , Melanoma/urina , Pessoa de Meia-Idade , Triptofano/análise , Triptofano/urina , Ácido Vanilmandélico/análise , Ácido Vanilmandélico/urina
13.
Genes Dev ; 33(15-16): 983-1007, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31123060

RESUMO

All transcription factors are equal, but some are more equal than others. In the 25 yr since the gene encoding the microphthalmia-associated transcription factor (MITF) was first isolated, MITF has emerged as a key coordinator of many aspects of melanocyte and melanoma biology. Like all transcription factors, MITF binds to specific DNA sequences and up-regulates or down-regulates its target genes. What marks MITF as being remarkable among its peers is the sheer range of biological processes that it appears to coordinate. These include cell survival, differentiation, proliferation, invasion, senescence, metabolism, and DNA damage repair. In this article we present our current understanding of MITF's role and regulation in development and disease, as well as those of the MITF-related factors TFEB and TFE3, and highlight key areas where our knowledge of MITF regulation and function is limited.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Regulação Neoplásica da Expressão Gênica , Melanócitos/fisiologia , Melanoma/fisiopatologia , Fator de Transcrição Associado à Microftalmia/metabolismo , Animais , Genoma , Humanos , Fator de Transcrição Associado à Microftalmia/genética , Ligação Proteica , Isoformas de Proteínas
15.
Anticancer Res ; 39(5): 2633-2640, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31092462

RESUMO

BACKGROUND/AIM: There is a growing need for information regarding the Health-Related Quality of Life (HRQoL) of cancer survivors. This study aimed to assess the HRQoL of patients treated for cutaneous malignant melanoma between 1980 and 2004 in the Helsinki and Uusimaa Hospital district and compare the results to the general population. MATERIALS AND METHODS: HRQoL of 981 cutaneous melanoma patients (aged 13 to 97 years, 56.1% female) was assessed using the generic 15D instrument and compared to the general population. The association between demographic and clinical factors and HRQoL was analyzed using oneway ANOVA, student's t-test and multivariate regression. RESULTS: The mean 15D score of melanoma patients was slightly lower (0.904) than that of the general population (0.911, p=0.027), but the difference was not statistically significant. HRQoL deteriorates with age and metastatic disease and improves with time. CONCLUSION: No evidence was found that long-term HRQoL of melanoma survivors was worse than the general population.


Assuntos
Sobreviventes de Câncer , Melanoma/epidemiologia , Qualidade de Vida , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Melanoma/fisiopatologia , Pessoa de Meia-Idade , Inquéritos e Questionários , Adulto Jovem
16.
J Eur Acad Dermatol Venereol ; 33(5): 816-827, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30963614

RESUMO

The European Academy of Dermatology and Venereology (EADV) Task Forces (TFs) on Quality of Life (QoL) and Patient Oriented Outcomes, Melanoma and Non-Melanoma Skin Cancer (NMSC) present a review of the literature and position statement on health-related (HR) QoL assessment in skin cancer patients. A literature search was carried out to identify publications since 1980 that included information about the impact of SC on QoL. Generic, dermatology-specific, cancer-specific, SC-specific, facial SC-specific, NMSC-specific, basal cell carcinoma-specific and melanoma-specific QoL questionnaires have been used to assess HRQoL in SC patients. HRQoL was assessed in the context of creation and validation of the HRQoL instruments, clinical trials, comparison of QoL in SC and other cancers, other diseases or controls, HRQoL assessment after treatment, comorbidities, behaviour modification, predictors of QoL and survival, supportive care needs, coping strategies and fear of cancer recurrence. The most widely used instruments for HRQoL assessment in SC patients are the European Organisation for Research and Treatment of Cancer Core Questionnaire (EORTC QLQ-C30), the Functional Assessment of Cancer Therapy-Melanoma (FACT-M), Skin Cancer Index (SCI), Short Form 36 Item Health Survey (SF-36) and the Dermatology Life Quality Index (DLQI). The TFs recommend the use of the cancer-specific EORTC QLQ-C30, especially in late stages of disease, and the melanoma-specific FACT-M and SC-specific SCI questionnaires. These instruments have been well validated and used in several studies. Other HRQoL instruments, also with good basic validation, are not currently recommended because the experience of their use is too limited. Dermatology-specific HRQoL instruments can be used to assess the impact of skin-related problems in SC. The TFs encourage further studies to validate HRQoL instruments for use in different stages of SC, in order to allow more detailed practical recommendations on HRQoL assessment in SC.


Assuntos
Melanoma/fisiopatologia , Qualidade de Vida , Neoplasias Cutâneas/fisiopatologia , Estudos de Casos e Controles , Europa (Continente) , Humanos , Resultado do Tratamento
17.
CMAJ ; 191(6): E166-E167, 2019 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-31009377
18.
Nat Commun ; 10(1): 1492, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940817

RESUMO

Accumulating evidence points to an important role for the gut microbiome in anti-tumor immunity. Here, we show that altered intestinal microbiota contributes to anti-tumor immunity, limiting tumor expansion. Mice lacking the ubiquitin ligase RNF5 exhibit attenuated activation of the unfolded protein response (UPR) components, which coincides with increased expression of inflammasome components, recruitment and activation of dendritic cells and reduced expression of antimicrobial peptides in intestinal epithelial cells. Reduced UPR expression is also seen in murine and human melanoma tumor specimens that responded to immune checkpoint therapy. Co-housing of Rnf5-/- and WT mice abolishes the anti-tumor immunity and tumor inhibition phenotype, whereas transfer of 11 bacterial strains, including B. rodentium, enriched in Rnf5-/- mice, establishes anti-tumor immunity and restricts melanoma growth in germ-free WT mice. Altered UPR signaling, exemplified in Rnf5-/- mice, coincides with altered gut microbiota composition and anti-tumor immunity to control melanoma growth.


Assuntos
Proliferação de Células , Microbioma Gastrointestinal , Melanoma/imunologia , Melanoma/microbiologia , Proteínas de Membrana/deficiência , Ubiquitina-Proteína Ligases/deficiência , Animais , Peptídeos Catiônicos Antimicrobianos/imunologia , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Humanos , Intestinos/imunologia , Intestinos/microbiologia , Melanoma/enzimologia , Melanoma/fisiopatologia , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/imunologia , Resposta a Proteínas não Dobradas
19.
Artigo em Inglês | MEDLINE | ID: mdl-30871230

RESUMO

In order to explore melanoma risk factors through gender-, age-, race-, and site-specific incidence rates, malignant melanoma cases from the Caucasian whites and non-whites were retrieved from the US SEER database. Age-standardized, age-, and site-specific tumor rates were calculated. All races and both genders showed positive annual average percentage changes (AAPCs) over the years, but AAPCs varied at different body sites, with men's trunk exhibiting the fastest increase. Non-whites were diagnosed at a significantly younger age than whites and showed a trend towards fewer gender differences in the age of diagnosis. However, non-whites and whites showed a similar pattern of age-specific gender differences in the incidence rate ratios. A consistent spiked difference (female vs. male, incidence rate ratio (IRR) >2) was observed at or near the age of 20⁻24 in all race groups and at all body sites. The highest female vs. male IRR was found in the hip and lower extremities, and the lowest IRR was found in the head and neck region in all races. These race-, gender-, and site-dependent differences suggest that age-associated cumulative sun exposure weighs significantly more in late-onset melanomas, while genetics and/or pathophysiological factors make important contributions to early-onset melanomas.


Assuntos
Idade de Início , Grupos de Populações Continentais , Melanoma/fisiopatologia , Neoplasias Cutâneas/fisiopatologia , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
20.
J Exp Clin Cancer Res ; 38(1): 56, 2019 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-30728057

RESUMO

BACKGROUND: Melanoma is the most aggressive and deadly form of skin cancer with increasing case numbers worldwide. The development of inhibitors targeting mutated BRAF (found in around 60% of melanoma patients) has markedly improved overall survival of patients with late-stage tumors, even more so when combined with MEK inhibitors targeting the same signaling pathway. However, invariably patients become resistant to this targeted therapy resulting in rapid progression with treatment-refractory disease. The purpose of this study was the identification of new kinase inhibitors that do not lead to the development of resistance in combination with BRAF inhibitors (BRAFi), or that could be of clinical benefit as a 2nd line treatment for late-stage melanoma patients that have already developed resistance. METHODS: We have screened a 274-compound kinase inhibitor library in 3 BRAF mutant melanoma cell lines (each one sensitive or made resistant to 2 distinct BRAFi). The screening results were validated by dose-response studies and confirmed the killing efficacies of many kinase inhibitors. Two different tools were applied to investigate and quantify potential synergistic effects of drug combinations: the Chou-Talalay method and the Synergyfinder application. In order to exclude that resistance to the new treatments might occur at later time points, synergistic combinations were administered to fluorescently labelled parental and resistant cells over a period of > 10 weeks. RESULTS: Eight inhibitors targeting Wee1, Checkpoint kinase 1/2, Aurora kinase, MEK, Polo-like kinase, PI3K and Focal adhesion kinase killed melanoma cells synergistically when combined with a BRAFi. Additionally, combination of a Wee1 and Chk inhibitor showed synergistic killing effects not only on sensitive cell lines, but also on intrinsically BRAFi- and treatment induced-resistant melanoma cells. First in vivo studies confirmed these observations. Interestingly, continuous treatment with several of these drugs, alone or in combination, did not lead to emergence of resistance. CONCLUSIONS: Here, we have identified new, previously unexplored (in the framework of BRAFi resistance) inhibitors that have an effect not only on sensitive but also on BRAFi-resistant cells. These promising combinations together with the new immunotherapies could be an important step towards improved 1st and 2nd line treatments for late-stage melanoma patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Inibidores de Proteínas Quinases/isolamento & purificação , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Humanos , Melanoma/fisiopatologia , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Bibliotecas de Moléculas Pequenas
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