Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Cell Rep ; 31(9): 107702, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32492418

RESUMO

To better understand the influence of ultraviolet (UV) irradiation on the initial steps of skin carcinogenesis, we examine patches of labeled keratinocytes as a proxy for clones in the interfollicular epidermis (IFE) and measure their size variation upon UVB irradiation. Multicolor lineage tracing reveals that in chronically irradiated skin, patches near hair follicles (HFs) increase in size, whereas those far from follicles do not change. This is explained by proliferation of basal epidermal cells within 60 µm of HF openings. Upon interruption of UVB, patch size near HFs regresses significantly. These anatomical differences in proliferative behavior have significant consequences for the cell of origin of basal cell carcinomas (BCCs). Indeed, a UV-inducible murine BCC model shows that BCC patches are more frequent, larger, and more invasive near HFs. These findings have major implications for the prevention of field cancerization in the epidermis.


Assuntos
Epiderme/metabolismo , Neoplasias Induzidas por Radiação/patologia , Raios Ultravioleta , Animais , Carcinoma Basocelular/metabolismo , Carcinoma Basocelular/patologia , Proliferação de Células , Ciclina D1/metabolismo , Modelos Animais de Doenças , Epiderme/efeitos da radiação , Folículo Piloso/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neoplasias Induzidas por Radiação/metabolismo , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Células-Tronco/citologia , Células-Tronco/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
2.
J Invest Dermatol ; 139(9): 2004-2015.e13, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31059696

RESUMO

The management of large congenital melanocytic nevi (lCMN) is based exclusively on iterative surgical procedures in the absence of validated medical therapy. The aim of our study was to develop an intra-lesional medical treatment for lCMN. Seventeen patients harboring NRAS-mutated lCMN were included. Nevocytes obtained from lCMN displayed an overactivation of mitogen-activated protein kinase and phosphoinositide 3-kinase (Akt) pathways. Mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) and Akt inhibitors reduced the nevosphere diameter in sphere-forming assays, as well as cell viability and proliferation in in vitro assays. Standardized lCMN explants were then cultured ex vivo with the same inhibitors, which induced a decrease in MelanA+ and Sox10+ cells in both epidermis and dermis. Finally, intradermal injections of these inhibitors were administered within standardized lCMN xenografts in Rag2-/- mice. They induced a dramatic decrease in nevocytes in treated xenografts, which persisted 30 days after the end of treatment. Using original nevus explant and xenograft preclinical models, we demonstrated that intradermal MEK/Akt inhibition might serve as neoadjuvant therapy for the treatment of NRAS-mutated congenital melanocytic nevi to avoid iterative surgeries.


Assuntos
Antineoplásicos/administração & dosagem , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Nevo Pigmentado/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Animais , Proliferação de Células/efeitos dos fármacos , Criança , Pré-Escolar , Feminino , GTP Fosfo-Hidrolases/genética , Humanos , Lactente , Injeções Intradérmicas , Injeções Intralesionais , Antígeno MART-1/metabolismo , Masculino , Melanócitos/efeitos dos fármacos , Melanócitos/patologia , Proteínas de Membrana/genética , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Nevo Pigmentado/congênito , Nevo Pigmentado/genética , Nevo Pigmentado/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Transcrição SOXE/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Pele/citologia , Pele/patologia , Neoplasias Cutâneas/congênito , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Exp Dermatol ; 25(10): 789-96, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27193390

RESUMO

Congenital melanocytic nevi (CMN) are benign proliferations that may be associated with various consequences depending on their size. They are characterized by a specific molecular signature, namely a postzygotic somatic NRAS or BRAF mutation. We have recently reported that large CMN (lCMN), which are classically associated with an increased melanoma risk, harbour cell subpopulations with specific clonogenic and tumorigenic potential. We wished to ascertain whether cells displaying similar properties persisted postnatally in medium CMN (mCMN). Eighteen medium M1, nine large and one giant NRAS-mutated CMN were prospectively included in the study. Subpopulations of mCMN cells expressed stem cell/progenitor lineage markers such as Sox10, nestin and Oct4, as was the case in lCMN. Nevertheless, conversely to lCMN, mCMN cells with clonogenic properties were rarer. In vitro, approximatively one in 1500 cells isolated from fresh mCMN formed colonies that could be passaged. In vivo, mCMN seemed to harbour cells with less proliferative potential than the larger lesions as lCMN biopsies displayed a threefold expansion compared to mCMN when xenografted in Rag2(-/-) mice. Thus, our data revealed variations in clonogenicity and tumorigenic properties in NRAS-mutated CMN according to size.


Assuntos
Carcinogênese , Melanoma/etiologia , Nevo Pigmentado/patologia , Pele/patologia , Adolescente , Biomarcadores/metabolismo , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Nevo Pigmentado/congênito , Nevo Pigmentado/genética , Nevo Pigmentado/metabolismo , Células-Tronco/metabolismo
4.
J Invest Dermatol ; 135(3): 824-833, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25310409

RESUMO

Large congenital melanocytic nevi (lCMN) are benign melanocytic tumors associated with an increased risk of melanoma transformation. They result predominantly from a post-zygotic somatic NRAS mutation. These lesions persist and even increase after birth proportionally to the child's growth. Therefore, we asked here whether cells with clonogenic and tumorigenic properties persisted postnatally in lCMN. Subpopulations of lCMN cells expressed stem cell/progenitor lineage markers such as Sox10, Nestin, Oct4, and ABCB5. In vitro, 1 in 250 cells from fresh lCMN formed colonies that could be passaged and harbored the same NRAS mutation as the original nevus. In vivo, lCMN specimens xenografted in immunocompromised mice expanded 4-fold. BrdU(+)-proliferating and label-retaining melanocytes were found within the outgrowth skin tissue of these xenografts, which displayed the same benign nested architecture as the original nevus. lCMN cell suspensions were not able to expand when xenografted alone in Rag 2-/- mice. Conversely, when mixed with keratinocytes, these cells reconstituted the architecture of the human nevus with its characteristic melanocyte layout, lentiginous hyperplasia, and nested architecture. Overall, our data demonstrate that, after birth, certain lCMN cell subtypes still display features such as clonogenic potential and expand into nevus-like structures when cooperating with adjacent keratinocytes.


Assuntos
Nevo Pigmentado/congênito , Nevo Pigmentado/patologia , Neoplasias Cutâneas/congênito , Neoplasias Cutâneas/patologia , Ensaio Tumoral de Célula-Tronco , Animais , Proliferação de Células , Transformação Celular Neoplásica , Pré-Escolar , GTP Fosfo-Hidrolases/genética , Xenoenxertos , Proteínas de Homeodomínio/genética , Humanos , Técnicas In Vitro , Lactente , Queratinócitos/patologia , Melanócitos/patologia , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Mutação/genética , Nevo Pigmentado/genética , Neoplasias Cutâneas/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...