Chemokine axes in breast cancer: factors of the tumor microenvironment reshape the CCR7‐driven metastatic spread of luminal‐A breast tumors

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

关键词: bone metastasis;    CCL21;    CXCR4‐;    CXCL12 axis;    lymph node metastasis;    migration;   

DOI  :  10.1189/jlb.3MA0815-373R

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Chemokineaxeshavebeenshowntomediatesite‐specificmetastasisinbreastcancer,buttheirrelevancetodifferentsubtypeshasbeenhardlyaddressed.Here,withthefocusontheCCR7‐CCL21axis,patientdatasetsdemonstratedthatluminal‐AtumorsexpressrelativelylowCCR7levelscomparedwithmoreaggressivediseasesubtypes.Furthermore,lymphnodemetastasiswasnotassociatedwithhighCCR7levelsinluminal‐Apatients.Themetastaticpatternofluminal‐Abreasttumorsmaybeinfluencedbythewayluminal‐Atumorcellsinterpretsignalsprovidedbyfactorsoftheprimarytumormicroenvironment.Thus,CCR7‐expressinghumanluminal‐Acellswerestimulatedsimultaneouslybyfactorsrepresenting3tumormicroenvironmentarmstypicalofluminal‐Atumors,hormonal,inflammatory,andgrowthstimulating:estrogen+TNF‐α+epidermalgrowthfactor.Suchtumormicroenvironmentstimulationdown‐regulatedthemigrationofCCR7‐expressingtumorcellstowardCCL21andinhibitedtheformationofdirectionalprotrusionstowardCCL21inanovel3‐dimensionalhydrogelsystem.CCL21‐inducedmigrationofCCR7‐expressingtumorcellsdependedonPI3KandMAPKactivation;however,whenCCR7‐expressingcancercellswereprestimulatedbytumormicroenvironmentfactors,CCL21couldnoteffectivelyactivatethesesignalingpathways.Invivo,pre‐exposureofthetumorcellstotumormicroenvironmentfactorshasputrestraintsonCCL21‐mediatedlymphnode‐homingcuesandshiftedthemetastaticpatternofCCR7‐expressingcellstotheaggressivephenotypeofdisseminationtobones.SeveraloftheaspectswerealsostudiedintheCXCR4‐CXCL12system,demonstratingsimilarpatientandinvitrofindings.Thus,weprovidenovelevidencetosubtype‐specificregulationoftheCCR7‐CCL21axis,withmoregeneralimplicationstochemokine‐dependentpatternsofmetastaticspread,revealingdifferentialregulationintheluminal‐Asubtype...

【 授权许可】

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