74 research outputs found
CO033 - Expression de BerEP4 dans les carcinomes de Merkel : un piĂšge diagnostique potentiel
National audienc
CO035 - LâAdcitmerÂź, un nouvel anticorps ciblant le CD56, bioconjuguĂ© Ă la MMAE, comme option thĂ©rapeutique dans le carcinome de Merkel
National audienc
CO032 - Carcinomes de Merkel associĂ©s aux carcinomes Ă©pidermoĂŻdes cutanĂ©s : une tumeur dâorigine kĂ©ratinocytaire avec diffĂ©renciation neuroendocrine secondaire
National audienc
Histogenese des Merkelzellkarzinoms
Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer. In approximately 80% of cases, genomic integration of the Merkel cell polyomavirus (MCPyV) is observed and overexpression of the two MCPyV T antigens (TAgs) is regarded as the main oncogenic determinant of MCPyV-positive MCC cases. However, the nature of the cells from which MCC arises is unknown. Therefore, the goal of the present work was to determine the cell of origin of MCC.
First, we characterized MCC patientsâ tumors and demonstrated a high similarity of MCPyV- negative MCC with extracutaneous neuroendocrine carcinoma while MCPyV-positive MCC differs from these two groups with respect to morphology, immunohistochemical profile, genetics, origin and behavior. Based on the analysis of a trichoblastoma/MCC combined tumor, we demonstrated that a MCPyV-positive MCC can arise following MCPyV integration in an epithelial cell. In addition, the high similarity between trichoblastoma cells and Merkel cell (MC) progenitors of the hair follicle suggests that these hair follicle cells may represent a general start point for the development of MCPyV-positive MCC. A contribution of the viral TAgs to the development of the characteristic Merkel cell-like MCC phenotype is suggested by experiments demonstrating induction of Merkel cell markers upon TAg expression in human primary keratinocytes or hair follicle cells. As potential mechanisms mediating these phenotypic changes, we identified the capability of MCPyV LT to repress degradation of master regulator of MC development, i.e. the transcription factor ATOH1.
To conclude, our work suggests that MCPyV integration in epithelial cells of the hair follicle may represent an important path for MCC development.Das Merkelzellkarzinom (MCC) ist ein seltener und aggressiver Hautkrebs. In etwa 80% der FĂ€lle wird die genomische Integration des Merkelzell-Polyomavirus (MCPyV) beobachtet und die Ăberexpression der beiden MCPyV-T-Antigene (TAgs) gilt als die wichtigste onkogene Determinante der MCPyV-positiven MCC-FĂ€lle. Die Ursprungszelle des MCC ist jedoch bisher unbekannt. Daher war das Ziel der vorliegenden Arbeit, die Hinweise auf die Herkunftszelle zu generieren. ..
From genetic characterization to new potential therapeutic options: targeting Bcl-xL in Merkel carcinoma
EditorialInternational audienc
HistogenĂšse du carcinome Ă cellules de Merkel
Le carcinome Ă cellules de Merkel (CCM) est un cancer neuroendocrine de la peau rare et agressif. Dans environ 80 % des cas, l'intĂ©gration gĂ©nomique du polyomavirus Ă cellules de Merkel (MCPyV) est retrouvĂ©e au sein de ces tumeurs et la surexpression des deux oncoprotĂ©ines virales est considĂ©rĂ©e comme le principal dĂ©terminant oncogĂ©nique des tumeurs viro-positives. Cependant, la nature de la cellule au sein de laquelle cette intĂ©gration virale se produit est Ă ce jour inconnue. L'objectif de ce travail Ă©tait de dĂ©terminer la cellule d'origine du CCM.Dans une premiĂšre partie, une cohorte multicentrique de tumeurs de patients CCM a Ă©tĂ© caractĂ©risĂ©e. Alors que les tumeurs viro-nĂ©gatives prĂ©sentaient de fortes similaritĂ©s phĂ©notypiques avec les carcinomes neuroendocrines extra-cutanĂ©s, les tumeurs viro-positives diffĂ©raient de ces derniers, dâun point de vue morphologique, immunohistochimique, gĂ©nĂ©tique, et pronostique. Sur la base de l'observation de tumeurs composites Trichoblastome/CCM-viro-positifs, nous avons dĂ©montrĂ© que l'intĂ©gration du MCPyV dans une cellule Ă©pithĂ©liale pouvait donner lieu au dĂ©veloppement dâun carcinome Ă cellules de Merkel viro-induit. De plus, la caractĂ©risation de ces cas et la comparaison avec la peau saine suggĂ©raient fortement que les progĂ©niteurs Ă©pithĂ©liaux du follicule pileux, comportant des capacitĂ©s intrinsĂšques de diffĂ©renciation en cellules de Merkel, Ă©taient Ă lâorigine des tumeurs viro-positives. Ces rĂ©sultats ont pu ĂȘtre confortĂ©s par des donnĂ©es gĂ©nĂ©rĂ©es in vitro. En effet, l'expression ectopique des antigĂšnes viraux au sein de cultures de kĂ©ratinocytes primaires humains et de cellules du follicule pileux conduisait Ă lâacquisition dâun phĂ©notype Merkel-like. Bien que de multiples facteurs molĂ©culaires soient probablement impliquĂ©s dans ce mĂ©canisme, des expĂ©riences de cotransfection de lâantigĂšne grand T avec le facteur ATOH1, principal facteur de transcription de la diffĂ©renciation des cellules de Merkel, ont permis de dĂ©montrer que lâantigĂšne grand T stabilisait ATOH1 en bloquant sa dĂ©gradation, contribuant ainsi aux changements phĂ©notypiques observĂ©s. En conclusion, nos travaux suggĂšrent que l'intĂ©gration du MCPyV dans une cellule Ă©pithĂ©liale du follicule pileux est Ă lâorigine du dĂ©veloppement des CCM viro-induits. Ces rĂ©sultats constituent une Ă©tape prĂ©liminaire essentielle Ă la reproduction de l'oncogenĂšse du MCPyV-MCC dans un modĂšle de souris transgĂ©niques.Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer. In approximately 80% of cases, genomic integration of the Merkel cell polyomavirus (MCPyV) is observed and overexpression of the two MCPyV T antigens (TAgs) is regarded as the main oncogenic determinant of MCPyV-positive MCC cases. However, the nature of the cells from which MCC arises is unknown. Therefore, the goal of the present work was to determine the cell of origin of MCC.First, we characterized MCC patientsâ tumors and demonstrated a high similarity of MCPyV-negative MCC with extracutaneous neuroendocrine carcinoma while MCPyV-positive MCC differs from these two groups with respect to morphology, immunohistochemical profile, genetics, origin and behavior. Based on the analysis of a trichoblastoma/MCC combined tumor, we demonstrated that a MCPyV-positive MCC can arise following MCPyV integration in an epithelial cell. In addition, the high similarity between trichoblastoma cells and Merkel cell (MC) progenitors of the hair follicle suggests that these hair follicle cells may represent a general start point for the development of MCPyV-positive MCC. A contribution of the viral TAgs to the development of the characteristic Merkel cell-like MCC phenotype is suggested by experiments demonstrating induction of Merkel cell markers upon TAg expression in human primary keratinocytes or hair follicle cells. As potential mechanisms mediating these phenotypic changes, we identified the capability of MCPyV LT to repress degradation of master regulator of MC development, i.e. the transcription factor ATOH1.To conclude, our work suggests that MCPyV integration in epithelial cells of the hair follicle may represent an important path for MCC development
Acral BRAFâmutated tubular adenoma should be distinguished from HPV42ârelated digital papillary adenocarcinoma
Notes and CommentsInternational audienc
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