PTCH1+？ Dermal Fibroblasts Isolated from Healthy Skin of Gorlin Syndrome Patients Exhibit Features of Carcinoma Associated Fibroblasts 英文参考文献.docVIP

PTCH1+/2DermalFibroblastsIsolatedfromHealthySkin ofGorlinSyndromePatientsExhibitFeaturesof CarcinomaAssociatedFibroblasts AlexandreValin1.,Ste′phanieBarnay-Verdier2.,ThomasRobert3,HuguesRipoche1, FlorenceBrellier4,OdileChevallier-Lagente1,Marie-Franc?oiseAvril5,ThierryMagnaldo1* 1CNRSFRE2939,Universite′ ParisSud-InstitutGustaveRoussy,Villejuif,France,2INSERMUMRS872,Universite′ Paris5/6-CentrederecherchedesCordeliers,Paris,France, 3CNRS Unite′ de ge′nomique fonctionnelle, Universite′ Paris Sud-Institut Gustave Roussy, Villejuif, France, 4Biomedical Research, Friedrich Miescher Institute, Basel, Switzerland,5ServicedeDermatologie,Universite′ Paris5-APHP,Paris,France Abstract Gorlin’s or nevoid basal cell carcinoma syndrome (NBCCS) causes predisposition to basal cell carcinoma (BCC), the commonest cancer in adult human. Mutations in the tumor suppressor gene PTCH1 are responsible for this autosomal dominant syndrome. In NBCCS patients, as in the general population, ultraviolet exposure is a major risk factor for BCC development.HoweverthesepatientsalsodevelopBCCsinsun-protected areasoftheskin,suggestingtheexistenceof other mechanisms for BCC predisposition in NBCCS patients. As increasing evidence supports the idea that the stroma influencescarcinomadevelopment,wehypothesizedthatNBCCSfibroblastscouldfacilitateBCCoccurenceofthepatients. WT (n=3) and NBCCS fibroblasts bearing either nonsense (n=3) or missense (n=3) PTCH1 mutations were cultured in dermal equivalents made of a collagen matrix and their transcriptomes were compared by whole genome microarray analyses.Strikingly,NBCCSfibroblastsover-expressedmRNAsencodingpro-tumoralfactorssuchasMatrixMetalloprotei- nases 1 and 3 and tenascin C. They also over-expressed mRNA of pro-proliferative diffusible factors such as fibroblast growthfactor7andthestromalcell-derivedfactor1alpha,knownforitsexpressionincarcinomaassociatedfibroblasts. ThesedataindicatethatthePTCH1+/2genotypeofhealthyNBCCSfibroblastsresultsinph