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Functional Screen of Paracrine Signals in Breast Carcinoma Fibroblasts 英文参考文献.docVIP

Functional Screen of Paracrine Signals in Breast Carcinoma Fibroblasts 英文参考文献.doc

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Functional Screen of Paracrine Signals in Breast Carcinoma Fibroblasts 英文参考文献

FunctionalScreenofParacrineSignalsinBreast CarcinomaFibroblasts GuiSu1,KyungE.Sung2,DavidJ.Beebe2,AndreasFriedl1,3* 1Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America, 2Department of Biomedical Engineering,UniversityofWisconsin-Madison,Madison,Wisconsin,UnitedStatesofAmerica,3PathologyandLaboratoryMedicineService,WilliamS.MiddletonMemorial VeteransHospital,DepartmentofVeteransAffairsMedicalCenter,Madison,Wisconsin,UnitedStatesofAmerica Abstract Stromal fibroblasts actively participate in normal mammary gland homeostasis and in breast carcinoma growth and progressionbysecretingparacrinefactors;however,littleisknownabouttheidentityofparacrinemediatorsinindividual patients.Thepurposeofthisstudywastocharacterizeparacrinesignalingpathwaysbetweenbreastcarcinomacellsand breastcarcinoma-associatedfibroblasts(CAF)ornormalmammaryfibroblasts(NF),respectively.CAFandNFwereisolated from breast carcinoma tissue samples and adjacent normal mammary gland tissue of 28 patients. The fibroblasts were grownin3Dcollagengelco-culturewithT47DhumanbreastcarcinomacellsandT47Dcellgrowthwasmeasured.CAF stimulated T47D cell growth to a significantly greater degree than NF. We detected a considerable inter-individual heterogeneity of paracrine interactions but identified FGF2, HB-EGF, heparanase-1 and SDF1 as factors that were consistently responsible for the activity of carcinoma-associated fibroblasts. CAF from low-grade but not high-grade carcinomas required insulin-like growth factor 1 and transforming growth factor beta 1 to stimulate carcinoma growth. Paradoxically,blockingofmembrane-type1matrixmetalloproteasestimulatedT47Dcellgrowthinco-culturewithNF.The results were largely mirrored by treating the fibroblasts with siRNA oligonucleotides prior to co-culture, implicating the fibroblastsasprincipalproductionsiteforthesecretedmediators.Insummary,weidentifyaparacrinesignalingnetwork withinter-individualcommonaliti

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