Arousal of Cancer-Associated Stroma Overexpression of Palladin Activates Fibroblasts to Promote Tumor Invasion 英文参考文献.docVIP

ArousalofCancer-AssociatedStroma:Overexpressionof PalladinActivatesFibroblaststoPromoteTumor Invasion TeresaA.Brentnall1*.,LisaA.Lai1.,JoshuaColeman2,MaryP.Bronner2,3,ShengPan1,RuChen1 1GIDivision,DepartmentofMedicine,UniversityofWashington,Seattle,Washington,UnitedStatesofAmerica,2DepartmentofAnatomicPathology,ClevelandClinic Foundation,Cleveland,Ohio,UnitedStatesofAmerica,3DivisionofAnatomicPathology,UniversityofUtah,SaltLakeCity,Utah,UnitedStatesofAmerica Abstract Background:Cancer-associatedfibroblasts,comprisedofactivatedfibroblastsormyofibroblasts,arefoundinthestroma surroundingsolidtumors.Thesemyofibroblastspromoteinvasionandmetastasisofcancercells.Mechanismsregulating the activation of the fibroblasts and the initiation of invasive tumorigenesis are of great interest. Upregulation of the cytoskeletal protein, palladin, has been detected in the stromal myofibroblasts surrounding many solid cancers and in expression screens for genes involved in invasion. Using a pancreatic cancer model, we investigated the functional consequence of overexpression of exogenous palladin in normal fibroblasts in vitro and its effect on the early stages of tumorinvasion. Principal Findings: Palladin expression in stromal fibroblasts occurs very early in tumorigenesis. In vivo , concordant expression of palladin and the myofibroblast marker, alpha smooth muscle actin (a-SMA), occurs early at the dysplastic stagesinperi-tumoralstromaandprogressivelyincreasesinpancreatictumorigenesis.Invitrointroductionofexogenous 90kDpalladinintonormalhumandermalfibroblasts(HDFs)inducesactivationofstromalfibroblastsintomyofibroblastsas marked by induction of a-SMA and vimentin, and through the physical change of cell morphology. Moreover, palladin expressioninthefibroblastsenhancescellularmigration,invasionthroughtheextracellularmatrix,andcreationoftunnels through which cancer cells can follow. The fibroblast invasion and creation of tunnels results from the development of invadopodia-likecellula