Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 29
Filtrar
1.
Front Immunol ; 13: 1029818, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36439142

RESUMO

This review presents several aspects of the innovative concept of sebaceous immunobiology, which summarizes the numerous activities of the sebaceous gland including its classical physiological and pathophysiological tasks, namely sebum production and the development of seborrhea and acne. Sebaceous lipids, which represent 90% of the skin surface lipids in adolescents and adults, are markedly involved in the skin barrier function and perifollicular and dermal innate immune processes, leading to inflammatory skin diseases. Innovative experimental techniques using stem cell and sebocyte models have clarified the roles of distinct stem cells in sebaceous gland physiology and sebocyte function control mechanisms. The sebaceous gland represents an integral part of the pilosebaceous unit and its status is connected to hair follicle morphogenesis. Interestingly, professional inflammatory cells contribute to sebocyte differentiation and homeostasis, whereas the regulation of sebaceous gland function by immune cells is antigen-independent. Inflammation is involved in the very earliest differentiation changes of the pilosebaceous unit in acne. Sebocytes behave as potent immune regulators, integrating into the innate immune responses of the skin. Expressing inflammatory mediators, sebocytes also contribute to the polarization of cutaneous T cells towards the Th17 phenotype. In addition, the immune response of the perifollicular infiltrate depends on factors produced by the sebaceous glands, mostly sebaceous lipids. Human sebocytes in vitro express functional pattern recognition receptors, which are likely to interact with bacteria in acne pathogenesis. Sex steroids, peroxisome proliferator-activated receptor ligands, neuropeptides, endocannabinoids and a selective apoptotic process contribute to a complex regulation of sebocyte-induced immunological reaction in numerous acquired and congenital skin diseases, including hair diseases and atopic dermatitis.


Assuntos
Acne Vulgar , Dermatite Atópica , Adulto , Adolescente , Humanos , Imunidade Inata , Homeostase , Dermatite Atópica/complicações , Lipídeos
3.
EMBO Rep ; 22(5): e51573, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33780134

RESUMO

Fibroblasts are a major component of the microenvironment of most solid tumours. Recent research elucidated a large heterogeneity and plasticity of activated fibroblasts, indicating that their role in cancer initiation, growth and metastasis is complex and context-dependent. Here, we performed genome-wide expression analysis comparing fibroblasts in normal, inflammatory and tumour-associated skin. Cancer-associated fibroblasts (CAFs) exhibit a fibrotic gene signature in wound-induced tumours, demonstrating persistent extracellular matrix (ECM) remodelling within these tumours. A top upregulated gene in mouse CAFs encodes for PRSS35, a protease capable of collagen remodelling. In human skin, we observed PRSS35 expression uniquely in the stroma of high-grade squamous cell carcinomas. Ablation of PRSS35 in mouse models of wound- or chemically-induced tumorigenesis resulted in aberrant collagen composition in the ECM and increased tumour incidence. Our results indicate that fibrotic enzymes expressed by CAFs can regulate squamous tumour initiation by remodelling the ECM.


Assuntos
Matriz Extracelular , Fibroblastos , Animais , Carcinogênese/genética , Carcinogênese/patologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Fibrose , Camundongos , Pele , Microambiente Tumoral/genética
4.
Microbiome ; 7(1): 95, 2019 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-31234928

RESUMO

BACKGROUND: The skin is colonized by a large number of microorganisms, most of which are beneficial or harmless. However, disease states of skin have specific microbiome compositions that are different from those of healthy skin. Gut microbiome modulation through fecal transplant has been proven as a valid therapeutic strategy in diseases such as Clostridium difficile infections. Therefore, techniques to modulate the skin microbiome composition may become an interesting therapeutic option in diseases affecting the skin such as psoriasis or acne vulgaris. METHODS: Here, we have used mixtures of different skin microbiome components to alter the composition of recipient skin microbiomes. RESULTS: We show that after sequential applications of a donor microbiome, the recipient microbiome becomes more similar to the donor. After intervention, an initial week-long phase is characterized by the dominance of donor strains. The level of engraftment depends on the composition of the recipient and donor microbiomes, and the applied bacterial load. We observed higher engraftment using a multi-strain donor solution with recipient skin rich in Cutibacterium acnes subtype H1 and Leifsonia. CONCLUSIONS: We have demonstrated the use of living bacteria to modulate skin microbiome composition.


Assuntos
Microbiota , Probióticos/administração & dosagem , Pele/microbiologia , Adulto , Bactérias/classificação , Bactérias/isolamento & purificação , Carga Bacteriana , Feminino , Voluntários Saudáveis , Humanos , Masculino , Probióticos/uso terapêutico , Propionibacteriaceae , Dermatopatias/terapia , Adulto Jovem
5.
Stem Cells Int ; 2019: 9320701, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31065284

RESUMO

Stem cells are multipotent cells that maintain the skin epidermis including skin appendages such as hair follicle, sebaceous glands, and sweat glands. There is evidence that reciprocal signalling between the epidermis and the dermis plays an important role in skin development, homeostasis, wound repair, and skin cancer. The origin of skin cancer that derive from skin appendages is still controversial, including basal cell carcinoma and even more of rare tumours such as sebaceous carcinomas and whether those tumours originate from resident tissue stem cells. To investigate whether markers reported to label dermal progenitor cells are preserved in the tumour including the tumour stroma of skin adnexal tumours, we tested 45 human basal cell carcinomas, including superficial, nodular, adenoid, infiltrating, and sclerosing types, and further 38 human tumours of skin appendages including 13 sebaceous adenomas and carcinomas, 20 eccrine sweat gland tumours, and 5 pilomatricomas, syringomas, and hair follicle tumours for the expression of the potential dermal and epidermal cell markers CRABP1, Nestin, and Ephrin B2 and compared these findings with healthy, age-related human epidermis. We detected that CRABP1, Nestin, and Ephrin B2 are expressed in the intratumoural stroma as well as the tumour invasive front of skin tumours of appendages and BCCs.

6.
Materials (Basel) ; 11(5)2018 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-29702553

RESUMO

Cytokines and chemokines play important roles in cell signalling, and microdialysis is a promising tool for monitoring these inflammation markers ex vivo. Therefore, the collecting of these mediators at the highest concentrations possible is crucial. Depending on the size of the mediator of interest, the collection of these high molecular mass molecules has thus far been difficult due to their low recovery, even when using high cut-off (100 kDa) microdialysis membranes. This study aimed to optimize the recovery of various cytokines and chemokines by validating the use of different perfusates in cutaneous microdialysis, and comparing intravenous (i.v.) colloids, crystalloids, and a lipid emulsion formulations that are approved for i.v. METHODS: In vitro and in vivo recovery experiments using six recombinant cytokines varying in molecular size (interleukin-2 (15 kDa), interleukin-6 (20.5 kDa), interleukin-8 (8 kDa), interleukin-12p70 (70 kDa), TNF-α (17.5 kDa), and vascular endothelial growth factor (VEGF) (38 kDa)) were performed in the presence of different perfusates for i.v. APPLICATIONS: Ringer’s lactate, dextran 60 kDa, hydroxyethyl starch 70 kDa, and hydroxyethyl starch 200 kDa solutions as well as a lipid emulsion formulation. Recovery was determined through (i) microdialysis of cytokines and chemokines in Ringer’s lactate solution or human serum in vitro, and (ii) retrodialysis of excised porcine and human skin cadavers in vitro and porcine skin in vivo. Furthermore, we used skin trauma (catheter insertion) and Ultraviolet B irradiation of 3 × 3 cm² skin areas to sample cytokines and chemokines in vivo and compared the amounts that were obtained using crystalloid and colloid perfusates. All the cytokines and chemokines within the dialysates were quantified through a flow cytometry-based bead array assay. RESULTS: Overall, recovery was strongly increased by the colloids, particularly hydroxyethyl starch 70 kDa, in vitro, ex vivo, and in vivo. When compared with the recovery achieved using Ringer’s lactate, this increase was most effective for proteins ranging from 8 to 20.5 kDa. Hydroxyethyl starch 70 kDa significantly increased the recovery of interleukin (IL)-8 in human serum in vitro when compared with Ringer’s lactate. More cytokines and chemokines were recovered using colloids compared with crystalloids. However, the increase in recovery values was lower for IL-12p70 and VEGF. CONCLUSIONS: Regarding the dialysate volumes and final dialysate concentrations, colloid perfusates are overall superior to crystalloid perfusates, such as Ringer’s lactate, when sampling cytokines and chemokines, resulting in higher recoveries. However, the sampling of high-molecular-mass cytokines during microdialysis remains challenging, and experimental in vitro data are not completely comparable with data obtained ex vivo or in vivo.

7.
Acta Derm Venereol ; 98(1): 50-58, 2018 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-28853491

RESUMO

Differential diagnosis of palmoplantar non-pustular psoriasis and chronic allergic contact dermatitis (ACD) and the combination of these conditions, termed "eczema in psoriatico" (EIP), is difficult, especially in cases of isolated involvement. A blind re-evaluation of 63 archived formalin-fixed palmoplantar samples, previously diagnosed clinically as either psoriasis or chronic ACD, was performed. Samples were allocated to histopathological diagnoses of psoriasis, contact dermatitis or EIP. Immunohistological stainings were performed for better characterization. Immunochemistry of EIP revealed features that overlapped contemporarily with psoriasis (cytokeratin 17 (CK17), Ki67, interleukin (IL)-8, IL-17, IL-23) and with ACD (CD1a, major histocompatibility complex (MHC) class I, MHC class II, epidermal T-cell subsets). Surprisingly, a significantly much higher number of dermal CD8+ T cells was found in EIP than in ACD and psoriasis. In conclusion, this study provides insight into the immunohistological differentiation of palmoplantar psoriasis, chronic ACD and EIP.


Assuntos
Dermatite Alérgica de Contato/diagnóstico , Dermatite Alérgica de Contato/metabolismo , Interleucinas/metabolismo , Psoríase/diagnóstico , Psoríase/metabolismo , Antígenos CD1/metabolismo , Linfócitos T CD8-Positivos/patologia , Doença Crônica , Dermatite Alérgica de Contato/complicações , Dermatite Alérgica de Contato/patologia , Diagnóstico Diferencial , Proteínas Filagrinas , Antígenos de Histocompatibilidade Classe I/metabolismo , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Imunoglobulina E/sangue , Imuno-Histoquímica , Proteínas de Filamentos Intermediários/metabolismo , Queratina-17/metabolismo , Antígeno Ki-67/metabolismo , Contagem de Linfócitos , Psoríase/complicações , Psoríase/patologia , Subpopulações de Linfócitos T/patologia
8.
Nat Commun ; 8: 14744, 2017 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-28332498

RESUMO

Individual human epidermal cells differ in their self-renewal ability. To uncover the molecular basis for this heterogeneity, we performed genome-wide pooled RNA interference screens and identified genes conferring a clonal growth advantage on normal and neoplastic (cutaneous squamous cell carcinoma, cSCC) human epidermal cells. The Hippo effector YAP was amongst the top positive growth regulators in both screens. By integrating the Hippo network interactome with our data sets, we identify WW-binding protein 2 (WBP2) as an important co-factor of YAP that enhances YAP/TEAD-mediated gene transcription. YAP and WPB2 are upregulated in actively proliferating cells of mouse and human epidermis and cSCC, and downregulated during terminal differentiation. WBP2 deletion in mouse skin results in reduced proliferation in neonatal and wounded adult epidermis. In reconstituted epidermis YAP/WBP2 activity is controlled by intercellular adhesion rather than canonical Hippo signalling. We propose that defective intercellular adhesion contributes to uncontrolled cSCC growth by preventing inhibition of YAP/WBP2.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proliferação de Células/genética , Proteínas Nucleares/genética , Células-Tronco/metabolismo , Fatores de Transcrição/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Células Cultivadas , Células Epidérmicas , Feminino , Regulação da Expressão Gênica , Humanos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Knockout , Proteínas Nucleares/metabolismo , Células-Tronco/citologia , Transativadores , Fatores de Transcrição/metabolismo
9.
J Dtsch Dermatol Ges ; 15(1): 34-41, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28140542

RESUMO

Das Pyoderma gangraenosum (PG) gehört zu den orphan diseases, deren Erforschung sich lediglich auf einzelne, randomisierte, multizentrische sowie retrospektive Studien stützen kann und überwiegend auf Fallserien an kleinen Patientenkollektiven beruht. Die Therapie basiert neben topischen und lokal intraläsionalen Therapieoptionen, bei initialem und leichtem Krankheitsverlauf, insbesondere auf der Gabe von Systemtherapeutika. Diese beinhaltet neben den systemischen Glukokortikosteroiden und Ciclosporin A (CsA) auch Biologika wie intravenöses Immunglobulin G (IVIG), die TNFα-Inhibitoren Infliximab, Adalimumab und Etanercept, den IL-12/23-Antikörper Ustekinumab, den Interleukin-1-Rezeptorantagonist Anakinra und den Interleukin-1ß-Antikörper Canakinumab. Die besten evidenzbasierten Studienergebnisse liegen zu CsA, Prednisolon und Infliximab vor, letzteres insbesondere bei gleichzeitigem Vorliegen einer Colitis ulcerosa oder eines Morbus Crohn. Kleinere Fallserien liegen für ein Ansprechen auf IVIG und Canakinumab vor. Obwohl die Erstbeschreibung durch Brocq fast 100 Jahren zurückliegt und die Behandlungsnotwendigkeit des PG früh erkannt wurde, bleibt die Therapie des PG bis heute eine klinische Herausforderung. Weitere klinische Studien, insbesondere an dringend erforderlichen größeren Patientenkollektiven, ein besseres Verständnis der Ätiopathogenese, der Einsatz moderner zielgerichteter Therapien mit höherer Effektivität und geringerer Nebenwirkungsrate als die konventionellen Immunsuppressiva Prednisolon und CsA lassen trotz des seltenen aber schwerwiegenden Krankheitsbildes eine Verbesserung der Therapieoptionen in Zukunft erwarten.


Assuntos
Fármacos Dermatológicos/uso terapêutico , Pioderma Gangrenoso/tratamento farmacológico , Administração Oral , Administração Tópica , Produtos Biológicos/efeitos adversos , Produtos Biológicos/uso terapêutico , Fármacos Dermatológicos/efeitos adversos , Esquema de Medicação , Quimioterapia Combinada , Medicina Baseada em Evidências , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Infusões Intravenosas , Injeções Subcutâneas , Pioderma Gangrenoso/diagnóstico
10.
J Dtsch Dermatol Ges ; 15(1): 34-40, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28140549

RESUMO

Pyoderma gangrenosum (PG) is an orphan disease. While research on such disorders is based on only few randomized multicenter as well as retrospective studies, most of the data comes from case series of small patient groups. Apart from topical and intralesional therapeutic options for early stages and mild disease courses, treatment predominantly involves systemic therapeutic agents. Besides systemic corticosteroids and cyclosporine A (CsA), options also include intravenous immunoglobulins (IVIG) and biologics such as the TNFα inhibitors infliximab, adalimumab, and etanercept; the interleukin (IL) 12/23 antibody ustekinumab; the IL-1 receptor antagonist anakinra; and the IL-1ß antibody canakinumab. The best evidence-based study data is available for CsA, prednisolone, and infliximab; the latter especially in patients with concomitant ulcerative colitis or Crohn's disease. A response to IVIG and canakinumab has been reported in smaller case series. First described by Brocq almost 100 years ago, it was soon recognized that PG did in fact require treatment. To this day, however, such treatment remains a clinical challenge. Despite the severe - albeit rare -clinical picture, improvement in therapeutic options may be expected in the future, primarily due to further clinical studies - especially with a greater number of patients, a better understanding of the etiopathogenesis, as well as the use of modern targeted therapies with higher efficacy and a lower rate of side effects than conventional immunosuppressants such as prednisolone and CsA.


Assuntos
Imunossupressores/uso terapêutico , Pioderma Gangrenoso/tratamento farmacológico , Doenças Raras , Administração Oral , Administração Tópica , Corticosteroides/efeitos adversos , Corticosteroides/uso terapêutico , Produtos Biológicos/efeitos adversos , Produtos Biológicos/uso terapêutico , Comorbidade , Ciclosporina/efeitos adversos , Ciclosporina/uso terapêutico , Diagnóstico Diferencial , Humanos , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/imunologia , Imunização Passiva , Imunossupressores/efeitos adversos , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Injeções Intralesionais , Estudos Multicêntricos como Assunto , Pioderma Gangrenoso/diagnóstico , Pioderma Gangrenoso/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos
11.
Acta Derm Venereol ; 96(7): 910-916, 2016 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-26984454

RESUMO

Ultraviolet B (UVB) irradiation affects epidermal cells, which respond via a cascade of inflammation markers. After initial in vitro and ex vivo experiments, this study used cutaneous microdialysis to generate a kinetic profile for 16 cytokines and 4 prostanoids in human skin in vivo. Skin areas 9 cm2 were irradiated with UVB (2× minimal erythematous dose) 16 h after catheter placement in the dermis of the volar forearms of healthy volunteers. Dialysates were collected at 4-h intervals up to 64 h and analysed for 5- and 8-iso-PGF2α, 9α,11α-PGF2α and PGE2 by gas chromatography-mass spectrometry (GC/MS). Dialysates were also analysed for interleukin (IL)-1ß, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, tumour necrosis factor (TNF)-α, Fas ligand (FasL), interferon-γ-inducible protein-10 (IP-10), monocyte chemoattractant protein 1 (MCP-1), RANTES, eotaxin, and granulocyte-macrophage colony-stimulating factor (GM-CSF) using a multiplex-based cytometric-bead-array. In conclusion, 3 peaks with synchronic release of T helper (TH) 1-directed inflammatory cytokines and prostanoids could be detected post-UVB: an early phase (4-12 h), an intermediate phase (16-24 h) and a late phase (32-40 h). A TH2-directed cytokine response was detectable at intermediate and late phases.


Assuntos
Citocinas/metabolismo , Prostaglandinas/metabolismo , Pele/metabolismo , Pele/efeitos da radiação , Raios Ultravioleta , Adulto , Células Cultivadas , Feminino , Antebraço , Cromatografia Gasosa-Espectrometria de Massas , Voluntários Saudáveis , Humanos , Masculino , Microdiálise , Pessoa de Meia-Idade , Pele/citologia
12.
Acta Derm Venereol ; 96(7): 905-909, 2016 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-26911315

RESUMO

Atopic dermatitis (AD) is a multifactorial inflammatory skin disease with release of distinct inflammatory signals. This study investigated the presence of eicosanoids in AD skin and the effect of topical agents with potential to suppress inflammation. Twelve patients with moderate AD received topical treatment on either arm with tacrolimus 0.1% ointment or a lotion containing 12% ω-6 fatty acids (polyunsaturated fatty acids; PUFA) twice daily for 5 consecutive days. Interstitial fluid was collected in vivo via dermal microdialysis from 4 defined skin areas: lesional, non-lesional and topically treated skin (tacrolimus or PUFA). Markers of oxidative stress (F2-isoprostanes; 5- and 8-prostaglandin F2α) and inflammation (9α,11α-prostaglandin F2α; and prostaglandin E2) were determined by gas chromatography-mass spectrometry. All eicosanoid levels were reduced in non-lesional and tacrolimus-treated skin. A significant reduction was observed in total F2-isoprostanes; 9α,11α-prostaglandin F2α; and prostaglandin E2 in non-lesional skin and in 9α,11α-prostaglandin F2α in tacrolimus-treated compared with untreated AD skin. In conclusion, treatment with tacrolimus compared with PUFA appears to suppress eicosanoids more efficiently in AD skin.


Assuntos
Dermatite Atópica/tratamento farmacológico , Eicosanoides/metabolismo , Ácidos Graxos Insaturados/uso terapêutico , Imunossupressores/farmacologia , Microdiálise , Tacrolimo/farmacologia , Administração Tópica , Animais , Biomarcadores/metabolismo , Ácidos Graxos Insaturados/administração & dosagem , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Imunossupressores/administração & dosagem , Masculino , Estresse Oxidativo , Suínos , Tacrolimo/administração & dosagem , Adulto Jovem
13.
Stem Cell Reports ; 3(4): 620-33, 2014 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-25358790

RESUMO

B-lymphocyte-induced nuclear maturation protein 1 (BLIMP1) was previously reported to define a sebaceous gland (SG) progenitor population in the epidermis. However, the recent identification of multiple stem cell populations in the hair follicle junctional zone has led us to re-evaluate its function. We show, in agreement with previous studies, that BLIMP1 is expressed by postmitotic, terminally differentiated epidermal cells within the SG, interfollicular epidermis, and hair follicle. Epidermal overexpression of c-Myc results in loss of BLIMP1(+) cells, an effect modulated by androgen signaling. Epidermal-specific deletion of Blimp1 causes multiple differentiation defects in the epidermis in addition to SG enlargement. In culture, BLIMP1(+) sebocytes have no greater clonogenic potential than BLIMP1(-) sebocytes. Finally, lineage-tracing experiments reveal that, under steady-state conditions, BLIMP1-expressing cells do not divide. Thus, rather than defining a sebocyte progenitor population, BLIMP1 functions in terminally differentiated cells to maintain homeostasis in multiple epidermal compartments.


Assuntos
Células-Tronco Adultas/citologia , Células Epidérmicas , Homeostase , Queratinócitos/citologia , Glândulas Sebáceas/citologia , Fatores de Transcrição/metabolismo , Células-Tronco Adultas/metabolismo , Células-Tronco Adultas/fisiologia , Animais , Diferenciação Celular , Linhagem da Célula , Proliferação de Células , Células Cultivadas , Humanos , Queratinócitos/metabolismo , Queratinócitos/fisiologia , Camundongos , Fator 1 de Ligação ao Domínio I Regulador Positivo , Fatores de Transcrição/genética
14.
Cell Rep ; 9(1): 104-117, 2014 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-25284788

RESUMO

Metastatic colonization of distant organs underpins the majority of human-cancer-related deaths, including deaths from head and neck squamous cell carcinoma (HNSCC). We report that miR-203, a miRNA that triggers differentiation in multilayered epithelia, inhibits multiple postextravasation events during HNSCC lung metastasis. Inducible reactivation of miR-203 in already established lung metastases reduces the overall metastatic burden. Using an integrated approach, we reveal that miR-203 inhibits metastasis independently of its effects on differentiation. In vivo genetic reconstitution experiments show that miR-203 inhibits lung metastasis by suppressing the prometastatic activities of three factors involved in cytoskeletal dynamics (LASP1), extracellular matrix remodeling (SPARC), and cell metabolism (NUAK1). Expression of miR-203 and its downstream effectors correlates with HNSCC overall survival outcomes, indicating the therapeutic potential of targeting this signaling axis.


Assuntos
Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias Pulmonares/prevenção & controle , Neoplasias Pulmonares/secundário , MicroRNAs/genética , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Animais , Carcinoma de Células Escamosas/metabolismo , Diferenciação Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proteínas do Citoesqueleto/antagonistas & inibidores , Neoplasias de Cabeça e Pescoço/metabolismo , Xenoenxertos , Humanos , Proteínas com Domínio LIM/antagonistas & inibidores , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos , Metástase Neoplásica , Osteonectina/antagonistas & inibidores , Prognóstico , Proteínas Quinases , Proteínas Repressoras/antagonistas & inibidores , Transdução de Sinais , Carcinoma de Células Escamosas de Cabeça e Pescoço
16.
Elife ; 3: e01888, 2014 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-24843010

RESUMO

Atopic dermatitis can result from loss of structural proteins in the outermost epidermal layers, leading to a defective epidermal barrier. To test whether this influences tumour formation, we chemically induced tumours in EPI-/- mice, which lack three barrier proteins-Envoplakin, Periplakin, and Involucrin. EPI-/- mice were highly resistant to developing benign tumours when treated with 7,12-dimethylbenz(a)anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA). The DMBA response was normal, but EPI-/- skin exhibited an exaggerated atopic response to TPA, characterised by abnormal epidermal differentiation, a complex immune infiltrate and elevated serum thymic stromal lymphopoietin (TSLP). The exacerbated TPA response could be normalised by blocking TSLP or the immunoreceptor NKG2D but not CD4+ T cells. We conclude that atopy is protective against skin cancer in our experimental model and that the mechanism involves keratinocytes communicating with cells of the immune system via signalling elements that normally protect against environmental assaults.DOI: http://dx.doi.org/10.7554/eLife.01888.001.


Assuntos
Carcinoma de Células Escamosas/prevenção & controle , Transformação Celular Neoplásica/metabolismo , Dermatite Atópica/metabolismo , Epiderme/metabolismo , Proteínas de Membrana/deficiência , Papiloma/prevenção & controle , Plaquinas/deficiência , Precursores de Proteínas/deficiência , Neoplasias Cutâneas/prevenção & controle , 9,10-Dimetil-1,2-benzantraceno , Animais , Carcinoma de Células Escamosas/induzido quimicamente , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Comunicação Celular , Diferenciação Celular , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/patologia , Citocinas/sangue , Dermatite Atópica/genética , Dermatite Atópica/imunologia , Dermatite Atópica/patologia , Modelos Animais de Doenças , Epiderme/imunologia , Epiderme/patologia , Queratinócitos/imunologia , Queratinócitos/metabolismo , Proteínas de Membrana/genética , Camundongos da Linhagem 129 , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Nus , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Papiloma/induzido quimicamente , Papiloma/genética , Papiloma/imunologia , Papiloma/metabolismo , Papiloma/patologia , Permeabilidade , Plaquinas/genética , Precursores de Proteínas/genética , Transdução de Sinais , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Acetato de Tetradecanoilforbol , Fatores de Tempo , Linfopoietina do Estroma do Timo
17.
Acta Derm Venereol ; 94(5): 517-20, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24531394

RESUMO

There is growing evidence that not only malign keratinocytic but also melanocytic tumours can arise during treatment with vemurafenib. During an on-going early access trial, 13 patients harbouring a BRAF-V600E mutation received vemurafenib (Zelboraf®) 960 mg twice daily to test the safety, tolerability, efficacy and response rate for advanced melanoma. Clinically or dermatoscopically suspicious cutaneous tumours under treatment with vemurafenib were excised. The BRAF-V600E status of confirmed new primary melanoma and dysplastic naevi was tested using a genetic mutation assay and immunohistochemistry. Four of the 13 patients (31%) developed 4 new naevi-associated malignant melanomas and 5 dysplastic naevi between 6 weeks and 6 months after the start of treatment. With the exception of one in situ melanoma, all tumours were BRAF wild-type. Immunohistochemistry revealed increased expression of ERK, pERK and active Rac1-GTP in the naevi-associated melanoma and dysplastic naevi. Careful and continuous skin examination, including dermoscopy, appears to be required during treatment with vemurafenib.


Assuntos
Antineoplásicos/efeitos adversos , Síndrome do Nevo Displásico/patologia , Indóis/efeitos adversos , Melanoma/patologia , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/patologia , Sulfonamidas/efeitos adversos , Adulto , Idoso , Neoplasias Encefálicas/secundário , Síndrome do Nevo Displásico/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Genótipo , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/secundário , Melanoma/tratamento farmacológico , Melanoma/genética , Pessoa de Meia-Idade , Fragmentos de Peptídeos/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Vemurafenib , Proteínas rac1 de Ligação ao GTP/metabolismo
19.
Cell Rep ; 3(2): 427-41, 2013 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-23403291

RESUMO

Although the sebaceous gland (SG) plays an important role in skin function, the mechanisms regulating SG differentiation and carcinoma formation are poorly understood. We previously reported that c-MYC overexpression stimulates SG differentiation. We now demonstrate roles for the androgen receptor (AR) and p53. MYC-induced SG differentiation was reduced in mice lacking a functional AR. High levels of MYC triggered a p53-dependent DNA damage response, leading to accumulation of proliferative SG progenitors and inhibition of AR signaling. Conversely, testosterone treatment or p53 deletion activated AR signaling and restored MYC-induced differentiation. Poorly differentiated human sebaceous carcinomas exhibited high p53 and low AR expression. Thus, the consequences of overactivating MYC in the SG depend on whether AR or p53 is activated, as they form a regulatory axis controlling proliferation and differentiation.


Assuntos
Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptores Androgênicos/metabolismo , Glândulas Sebáceas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Antineoplásicos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-myc/genética , RNA Mensageiro/metabolismo , Receptores Androgênicos/genética , Neoplasias das Glândulas Sebáceas/metabolismo , Neoplasias das Glândulas Sebáceas/patologia , Glândulas Sebáceas/citologia , Transdução de Sinais/efeitos dos fármacos , Tamoxifeno/análogos & derivados , Tamoxifeno/farmacologia , Testosterona/farmacologia , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...