Chronic Stress Promotes Cancer Development - Frontiers

Stress hormones promote the occurrence and development of cancers through various mechanisms such as by inducing DNA damage, increasing p53 ... Articles SridharMuthusami KarpagamAcademyofHigherEducation,India RaviManoharan UniversityofMadras,India AruljothiMuralidharan SchoolofMedicine,UniversityofCalifornia,Riverside,UnitedStates Theeditorandreviewers'affiliationsarethelatestprovidedontheirLoopresearchprofilesandmaynotreflecttheirsituationatthetimeofreview. Abstract Introduction StressHormonesPromoteTumorigenesisandCancerDevelopment ChronicStressEnhancesInflammationtoPromoteTumorDevelopment ChronicStressPromotesTumorigenesisandCancerDevelopmentbySuppressingImmunity ConclusionsandFuturePerspectives AuthorContributions Funding ConflictofInterest Abbreviations References SuggestaResearchTopic> DownloadArticle DownloadPDF ReadCube EPUB XML(NLM) Supplementary Material Exportcitation EndNote ReferenceManager SimpleTEXTfile BibTex totalviews ViewArticleImpact SuggestaResearchTopic> SHAREON OpenSupplementalData REVIEWarticle Front.Oncol.,19August2020 |https://doi.org/10.3389/fonc.2020.01492 ChronicStressPromotesCancerDevelopment ShiruiDai1,2,3,YongzhenMo2,YuminWang2,BoXiang1,2,3,QianjinLiao1,2,MingZhou1,2,3,XiaolingLi1,2,3,YongLi4,WeiXiong1,2,3,GuiyuanLi1,2,3,CanGuo1,2,3andZhaoyangZeng1,2,3* 1NHCKeyLaboratoryofCarcinogenesisandHunanKeyLaboratoryofTranslationalRadiationOncology,HunanCancerHospitalandtheAffiliatedCancerHospitalofXiangyaSchoolofMedicine,CentralSouthUniversity,Changsha,China 2KeyLaboratoryofCarcinogenesisandCancerInvasionoftheChineseMinistryofEducation,CancerResearchInstitute,CentralSouthUniversity,Changsha,China 3HunanKeyLaboratoryofNonresolvingInflammationandCancer,DiseaseGenomeResearchCenter,TheThirdXiangyaHospital,CentralSouthUniversity,Changsha,China 4DepartmentofMedicine,DanLDuncanComprehensiveCancerCenter,BaylorCollegeofMedicine,Houston,TX,UnitedStates Stressisaninevitablepartoflife.Chronicstressonaccountofreasonslikeadversity,depression,anxiety,orloneliness/socialisolationcanendangerhumanhealth.Recentstudieshaveshownthatchronicstresscaninducetumorigenesisandpromotecancerdevelopment.Thisreviewdescribesthelatestprogressofresearchonthemolecularmechanismsbywhichchronicstresspromotescancerdevelopment.Primarily,chronicstressactivatestheclassicneuroendocrinesystem[thehypothalamic-pituitary-adrenal(HPA)axis]andthesympatheticnervoussystem(SNS)andleadstoadeclineanddysfunctionoftheprefrontalcortexandthehippocampusunderstress.StresshormonesproducedduringtheactivationofboththeHPAaxisandtheSNScanpromotetumorigenesisandcancerdevelopmentthroughavarietyofmechanisms.Chronicstresscanalsocausecorrespondingchangesinthebody'simmunefunctionandinflammatoryresponse,whichissignificantbecausealong-terminflammatoryresponseandthedeclineofthebody'simmunesurveillancecapabilitiesareimplicatedintumorigenesis.Stressmanagementisessentialforbothhealthypeopleandcancerpatients.WhetherdrugsthatlimitthesignalingpathwaysdownstreamoftheHPAaxisortheSNScansuppresschronicstress-inducedcancersorprolongpatientsurvivaldeservesfurtherstudy. Introduction Humanshavealwaysexperiencedperiodsofexcessivestressonaccountofglobalissues,suchaspoverty,war,andepidemics(1).Stresscanbedividedintoacutestressandchronicstress.Acutestressusuallyexistsinemergencies,suchasfightingorescaping.Changesinthestructureandfunctionofcertainmoleculesandtissuesinthebrainactivatetheemotionalcognitivesystem,andwemakedecisionsforstress-copingmechanisms(2).Atthesametime,thebodytemporarilyproducescatecholaminesandcorticosteroidstoimprovemobilityandresponsiveness.Therefore,acutestressisoftenbeneficialtothebody.However,chronicstressisheavilyimplicatedincausingillhealth,andtodayitisconsideredtoencompassoccupationalstressaswellasunusualadversities.Itspotentialnegativeeffectsincludenotonlyinsomnia,gastrointestinaldisorders(3,4),anxiety,anddepression(5,6),butalsoanincreasedriskofcardiovasculardisease,mentalillness,andcancer(7). Surveyshaveshownthatapproximatelyonemillionnewcancercasesoccureveryyearamongyoungpeopleaged20–39years(7),andtheyhavebeenpartlyattributedtostress.Therelationshipbetweenchronicstressandcancershasarousedincreasinglywidespreadinterestandconcerninthemedicalcommunity.Manyscholarshaveperformedresearchontherelationshipsbetweenstressandcancerssuchasprostate(8–10),breast(8–12),gastric(13,14),lung(15,16),andskincancer(17,18),andhavefoundevidenceindicatingthatchronicstresscaninducetumorigenesisandpromotecancerdevelopment(Table1). TABLE1 Table1.Themechanismsofchronicstresspromotingcancerandcorrespondingtargetsanddrugs. Theneuroendocrinepathwaysarethemostwidelyandcomprehensivelystudiedpossiblemediatorsoftheseassociations.Theneuroendocrinepathwaysconstitutingthehypothalamus-pituitary-adrenal(HPA)axisandthesympatheticnervoussystem(SNS)werethefirstsystemsshowntobecloselyrelatedtostress[(1,19);Figure1].Underchronicstress,thebrain'snerveimpulsescancontinuouslyactivatethehypothalamustoproducethecorticotropin-releasingfactor(CRF).CRFistransportedthroughthebloodtothepituitarygland,therebystimulatingcellstoreleasetheadrenocorticotropichormone(ACTH),whichtravelsthroughthebloodtotheadrenalcortexandpromotesthesynthesisofcorticosteroids.ChronicstressalsoactivatestheSNS,therebystimulatingthereleaseofimportantneurotransmitterssuchasnorepinephrine(NA)andadrenaline(Ad).NAandAdarealsohormonessecretedbytheadrenalmedullaandknownascatecholaminesbecausetheycontaincatecholandaminegroups.ThecorticosteroidsandcatecholaminesproducedbytheHPAandtheSNScancauseadeclineinthefunctionsoftheprefrontalcortex(20)andthehippocampus(21),andmayenhancetheactivationoftheSNSandtheHPAbyregulatingtheexpressionofglucocorticoidreceptors(5,22,23). FIGURE1 Figure1.Theneuroendocrinemechanismsofchronicstress.Chronicstressproducesstresshormonesduringtheactivationoftheneuroendocrinesystem(hypothalamus-pituitary-adrenalaxis)andthesympatheticnervoussystem,whichcanpromotetumordevelopmentandregulatethetumormicroenvironment. StresshormonespromotetheoccurrenceanddevelopmentofcancersthroughvariousmechanismssuchasbyinducingDNAdamage,increasingp53degradation,andregulatingthetumormicroenvironment(Figure1).Chronicstresscanalsoactivatetheinflammatoryresponseandtheinteractionbetweeninflammatorycellsandcancercellstoformtheinflammatorytumormicroenvironment,therebypromotingallstagesoftumorigenesis(24).Itcanalsoenhanceneuroinflammation,whichfurtherimpairsthebrain'scognitiveprocessingofstress.Thisisaviciouscircle.Chronicstresscanalsoselectivelysuppressthetype1helperTcells(Th1),suppressthecytotoxicTcells(CTL)-mediatedcellularimmunityandinterferonproduction,andweakenimmunesurveillanceandotherprocesses,therebyincreasingtheriskofcancerinvasionandmetastasisandreducingtheeffectivenessofanti-tumortherapy(25,26).Insummary,chronicstresscanpromotetumorigenesisandoncogenesisthroughtheproductionofstresshormones,theactivationofinflammation,andthesuppressionofimmunity.Therefore,thepresentreviewhasfocusedonthesethreestress-mediatedactivities. StressHormonesPromoteTumorigenesisandCancerDevelopment Stresshormonesareclassifiedintoclassicalcorticosteroidsandcatecholamines,aswellasthenon-classicalCRFandthyroidhormones. ClassicalCorticosteroidsandCatecholamines Corticosteroidsincludeglucocorticoidsandcorticosterones.Elevatedglucocorticoidlevelsincreasetheactivityofthenegativeregulatormurinedoubleminute2(MDM2)throughinductionoftheserum-and-glucocorticoid-regulatedkinase(SGK1)andmediatetheinhibitionofp53(27).P53caninitiateDNArepair,cellcyclearrest,aging,andapoptosis,whicharerelatedtothebody'sabilitytoinhibittumorformationandrespondtovarioustypesofcancertreatment(28).Therefore,thelossorimpairmentofthep53functionmediatedbycorticosteroidscanconsiderablypromotetumorigenesis.Obradovićetal.(29)foundthattheincreaseinglucocorticoidsduringbreastcancerprogressionwasrelatedtoalowersurvivalrate.Increasedhormonelevelscouldleadtotheactivationofglucocorticoidreceptorsthatwereinvolvedintheactivationofmultipleprocessesinmetastasisandtheup-regulationofkinaseorphanreceptor1(ROR1)atdistantmetastaticsites.InhibitionofROR1expressioncanreducemetastasisandprolongthesurvivalratesofbreastcancerpatients. Catecholaminescanregulatethetumormicroenvironment(30).Inprostatecancer,catecholaminesinthelocalsympatheticnervefibers(NA)andcirculatingblood(Ad)canactivatetheβ-adrenergicreceptors(βARs)onendothelialcells,alteringthecellmetabolism,therebyinhibitingtheiroxidativephosphorylation,andinducingangiogenesis(31,32).TheycanalsoactivatetheβARsinpancreaticcancerandstromalcellstoincreasetheexpressionofinvasivegenes,therebypromotingthegrowthofprimarytumorsandthespreadoftumorcellstoadjacenttissues(33). Thetumor-promotingeffectofcatecholaminesismainlymediatedbytheβ2adrenergicreceptor(encodedbyADRB2)activatingthecAMP-proteinkinaseA(PKA)signalingpathway,whichisthemainmechanismtoenhancetumorangiogenesisinthebodyandpromotethegrowthofmalignantcells[(34,35);Figure2].ThedownstreammechanismsincludemediatingSrcphosphorylation,DNAdamage,p53degradation,andtheup-regulationofvascularendothelialgrowthfactor(VEGF)andmatrixmetalloproteinases(MMP-2andMMP-9).CatecholaminesalsomediateSrcphosphorylationviaβARs-cAMP-PKA,activateRas-relatedprotein1(Rap1),andinhibitextracellularsignal-regulatedkinases(ERKs),therebyenhancingtumorcellmigration,invasion,andgrowth(36).Srcisanon-receptorcytosolictyrosinekinasethatisinvolvedintheVEGFandinterleukin(IL-6)productioninadipocytesandcancercells,respectively(37). FIGURE2 Figure2.Signalingpathwaysactivatedbycatecholamines.Stress-inducedcatecholaminesactivatethecAMP-PKAsignalingpathwaythroughβ2adrenergicreceptors,therebycausingaseriesofdownstreamreactions.Srcphosphorylation,DNAdamage,p53degradation,upregulationofVEGFandMMPs,andenhancedstem-liketraitsarekeyfactorsoftumorigenesis. Hara'steam(38)clarifiedthespecificmechanismofstress-mediatedDNAdamage.CatecholaminescanstimulatetheG-proteins(Gs)-PKA-mediatedsignalingpathwaystotriggerDNAdamageandtheβ-arrestin(ARRB1)-mediatedsignalingpathwaystotriggertheAkt-mediatedactivationofMDM2,whichpromotesthebindinganddegradationofMDM2andp53bybindingtoM53.ThesynergyofthesetwopathwaysleadstotheaccumulationofDNAdamage. Angiogenesisisanimportantpartoftumordevelopmentandmetastasis.Studieshavefoundsignificantlyincreasedtumorbloodvesselformationinstressedanimals,andthemechanismmaybeaβARs-cAMP-PKA-IL-6-dependentactivationofsignaltransductionandactivatoroftranscription(STAT3)(39).ActivatedSTAT3istransportedtothenucleusandbindstospecificDNAsitesintheformofhomo-orheterodimers,stimulatingthetranscriptionofthereactivegenesVEGF,MMP2,andMMP9(34).VEGFplaysacentralroleinthepathogenesisofvariouscancersasthebest-knownangiogenesisstimulator(40).WhencombinedwithitsVEGFreceptorsonvascularendothelialcells,VEGFcanpromotetumorneovascularization.MMPscandegrademultipleproteincomponentsintheextracellularmatrix,destroythehistologicalbarrieroftumorcellinvasion,andplayakeyroleintumorinvasionandmetastasis. Cuietal.(8)foundthatchronicstresscouldinduceadrenalinetoactivatelactatedehydrogenaseA(LDHA)toproducelacticacid.TheadjustedpHisconducivetotheubiquitin-specificprotease28(USP28)-mediatedubiquitinationandstabilizationofMYC,andMYUGactivatestheSLUGpromoter,whichpromotesthedevelopmentofstem-liketraitsinbreastcancer.Jangetal.(16)demonstratedthatNAcouldinducethephosphorylationoftheL-typevoltage-dependentcalciumchannels(VDCC)viatheβAR-PKApathway.TheyfurtherfoundthatVDCCcouldtriggercalciummobilization,therebyinducingtheactivationoftheinsulin-likegrowthfactorreceptor(IGF-1R)andpromotingcancermetastasisthroughtheexocytosisofIGF2. Motivatedbystudiesofthismechanism,manyresearchershavetriedtoreversetheoccurrenceofthecancer-promotingeffectsbyblockingtheβ2-ARanditsdownstreamsignalingpathway(Figure2).Zhangetal.(41)foundthatbyblockingtheβ2-ARs,aG1/SphasearrestandapoptosiscouldbeinducedinpancreaticcancercellsviatheRas/Akt/NFκBpathway.Hassanetal.(42)demonstratedaninteractionbetweenprostatecancersandthesocio-psychologicalenvironmentmediatedbyactivatingtheAd/ADRB2/PKA/BADanti-apoptoticsignalingpathway.TheyusedtheselectiveADRB2antagonistICI118,551,orinducedexpressionofthePKAinhibitor(PKI)ortheBCL2-relateddeathpromoterBAD(BADS112A)withamutatedPKAphosphorylationsite,topreventtheeffectsofstressinxenograftcancers.ADRB2antagonistssuchaspropranololandICI118,551suppressedgastriccancerprogressionbyinhibitingtheERK1/2-JNK-MAPKpathwayandtranscriptionfactors,suchasNF-κB,AP-1,andSTAT3(14).Cuietal.(8)conducteddrugscreeningforLDHAandfoundthatvitaminCcouldreversethestem-likephenotypeofbreastcancerinducedbychronicstress.Therefore,vitaminCmaybeapotentialfactortocombatstress-relatedbreastcancer. CRFandThyroidHormone CRFiswidelypresentinthecentralnervoussystem,thathasbeendetectedinbreastcancertissuesandcelllines,andaffectsbreastcancercellproliferationandinvasioninanautocrineorparacrinemanner(10).CRFcaninducethephosphorylationofthefocaladhesionkinase(FAK),induceCox1toproduceprostaglandins,directlypromoteactinrecombinationandcellmigration,andplayaroleintheTGFβ/SMAD2andtheWnt-β-cateninsignaling.TheantagonistofCRF,antalarmin,inhibitsneovascularizationin4T1breastcancercelllinesinvivo(43). Thyroidhormoneissecretedbythethyroidgland,whichiscloselyrelatedtothebody'smetabolism,growth,anddevelopment,andisregulatedbythehypothalamus-pituitary-thyroidaxis.Whenpeopleareemotional,theiremotionsstimulatethehypothalamustoreleasethyrotropin-releasinghormonesandregulatethesecretionofthyroid-stimulatinghormones.Thisfurtheraffectsthethyroidgland,andcausesitsglandcellstosecretealargeamountofthyroidhormone.Fricketal.(44)foundthatunderchronicstress,thyroidhormonelevelsandTcelllymphoidtissuehyperplasiaresponsewerereducedinanimalsandlymphomagrowthwasaltered.Theuseofthyroxinereplacementtherapycanreversetheaboveprocess.Therefore,thyroidhormonemaybeacriticalneuroendocrineregulatoroftumorevolution,mostlikelythroughtheregulationofTcell-mediatedimmunity. ChronicStressEnhancesInflammationtoPromoteTumorDevelopment Chronicstressandstresshormonescanup-regulatetheexpressionofstress-relatedpro-inflammatorygenesinthecirculatingwhitebloodcells,therebyincreasingthereleaseofpro-inflammatorycellsandtheproductionofpro-inflammatorycytokines,andcanactivatetheaging-inflammatoryresponsewithoutthetriggerofanexogenousinflammation,leadingtothepromotionoftumorigenesisandmetastasis(45).Niraulaetal.(46)foundthathighlevelsofcorticosteroneunderrepeatedpressuresofsocialfailurepromotedthereleaseofthebonemarrow-derivedproinflammatorymonocytesintothecirculatorysystemandcirculatedinthebrain,increasingneuroinflammation,andleadingtoaprolongedanxiety-likebehavior.Inhibitingcorticosteroneoverproductionthroughsurgery(adrenalectomy)anddrugtherapy(metyrapone)canreducetheseinflammatoryresponsestostress.Pretreatmentofthesociallydisruptive-stressedmicewiththeβ-adrenergicantagonistpropranololmaypreventanxiety-likebehaviorscausedbysocialfailure(47),reversesplenomegaly,andincreasethelevelsofplasmainflammatoryfactorssuchasIL-6,tumornecrosisfactoralpha(TNF-α),andthemonocytechemotacticprotein1(MCP-1)(48).Moreover,researchbyAntoni'sgroupshowsthatstressmanagementinpatientswithearly-stagebreastcancercanreversetheup-regulationofthestress-relatedproinflammatorygenesinwhitebloodcellsinthecirculation(49). Immunecellsinthetumormicroenvironmentarecalledpro-tumorigenicimmunecellsandincludethetumor-associatedmacrophages(TAMs),thedendriticcells(DCs),themyeloid-derivedsuppressorcells(MDSCs),andthetumor-infiltratinglymphocytes(TILs).TheseimmunecellscanproducecytokinessuchasIL-6,IL-10,TNF-α,andMCP-1,andareinterconnectedwithtumorcellsinanautocrineandparacrinemanner.Thepro-tumorigenicimmunecellsmaintainarelativebalancewithinacertainrangeofpromotingtumorinflammationandanti-tumorimmunity.Afterchronicstressbreaksthisbalancethroughalong-termpro-inflammatoryresponse,thesecellsandcytokinescanactonallstagesoftumordevelopment,includinginitiation,promotion,malignanttransformation,invasion,andmetastasisthroughmutation,epigeneticmodification,andregulationofthetumormicroenvironment[(50,51);Figure3].Moreover,activatedinflammatorycellsproduceexcessreactiveoxygenspecies(ROS)todriveinflammationandmutagenesisthroughdifferentpathways(52).ThereleasedcytokinescanactivatekeytranscriptionfactorssuchasNF-κB(53–55)andSTAT3(56)inprecancerouscells.Byregulatingtheexpressionofmanygenesthatcaninhibittumorcelldeath,promotetumorcellsurvival,andinducetheproductionofchemokines,cytokinesalsoattractmoretumor-promotingimmunecellstomaintainatumor-relatedinflammation. FIGURE3 Figure3.Effectsofstresshormonesontheimmunesystem.Stresshormonesstimulatepro-tumorigenicimmunecellstoproduceIL-6,IL-10,andothercytokines,andactivatetheCOX-2/PGE2pathwaytoproduceVEGF,whichtogetheraffectthetumormicroenvironmenttosuppresstumorimmunity.ThedecreaseinIL-12andtheincreaseinIL-10leadtoselectiveTh1inhibition,therebysuppressingtheCTL-mediatedcellularimmunityandinterferonproduction. ChronicStressPromotesTumorigenesisandCancerDevelopmentbySuppressingImmunity Asthecoreimmunecells,thymus-dependentlymphocytes(Tcells)providearobustlineofdefenseagainstinfectionsandcancers.Thecellularimmunitymediatedbythemincludesspecificbindingtotheirtargetcellsfordirectcelldestructionoreliminationandthereleaseofcytokinestoenhanceandexpandtheimmuneeffects.TcellscanberoughlyclassifiedintothecytotoxicTcells,thehelperTcells,andtheregulatory/inhibitoryTcellsaccordingtotheirfunctions.Basedondifferentcytokinefunctions,thehelperTcellsaredividedintoTh1orTh2cells,whicharedifferentiatedfromTH0cellsbytheirregulationbythecytokinesIL-12andIL-4.Th1cellsusuallyproduceIFN-γ,TNF-β,andIL-2,andmediatecellularimmuneresponses,suchasinducingmacrophageactivation,mediatingdelayedhypersensitivity,andassistingCTLactivationandproliferation.Th2cellsusuallyproducesIL-4,IL-5,IL-6,andIL-10.TheirmainfunctionistoenhancethehumoralimmuneresponseandstimulatetheBcellstoproduceantibodies.Notably,IL-12andTNF-βpromoteaTh1responseandcellularimmunity,whileIL-10inhibitsIL-12productionandTh1responseandstimulatesTh2responseandthehumoralimmunity(Figure3). Stresstestsshowthattheplasmaconcentrationofstresshormonesisinverselyproportionaltothefunctionofimmunecells(57).Increasedstresshormoneproductionsignificantlyreducestheactivityoftheantigen-presentingcells(APC),suchasmonocytes,macrophages,thedendriticcells,andthenaturalkillercells,thatproducehumanIL-12(58).Therefore,neuroendocrinemediatorssuchasthestress-releasingglucocorticoidsandepinephrinemayselectivelyinhibitTh1,therebyinhibitingtheCTL-mediatedimmuneresponseandtheproductionofinterferonIFN-γ(26).Yangetal.(25)furtherconfirmedthathighlevelsofcorticosteroidsinplasma,andtheup-regulatedglucocorticoid-inducingfactorTsc22d3,blockedtheactivationoftypeIIFNresponseinDCsandIFN-γ+Tcellsandreducedtheefficacyofanti-tumortherapiesinnon-smallcelllungcancerandcolorectalcancerbysuppressingtheimmunesurveillance.Additionally,Sauletal.(17)foundthatchronicstressincreasedthesensitivitytotheUV-inducedsquamouscellcarcinomabysuppressingCTLandincreasingthenumberoftheregulatory/inhibitoryTcells(Figure3). StresshormonesalsoinducecyclooxygenaseCOX-2andavarietyofCOX-2-dependentinhibitorsinhumanbreastandcoloncancertissuecells,therebyactivatingtheCOX-2/PGE2pathway(59).PGE2isabiologicallyactivelipidthatcantriggerinflammationandcancer.TheactivationofCOX-2/PGE2canaffectthetumormicroenvironmentandinhibittumorimmunitythroughavarietyofmechanisms,includinginducingtumorcellstoproducevascularendothelialgrowthfactorC(VEGFC)andpromotingtheremodelingoflymphaticnetworksinandaroundtumorstoprovideapathwayforthetumorcellstoescapetheimmunesystem[(60);Figure3]. ConclusionsandFuturePerspectives ChronicstresscanactivatetheHPAaxis,andtheSNS,andcauseimmunedisordersandinflammatoryresponses.Thereisnodoubtthatthisisharmfultothebody.ExcessivelevelsofstresshormonespromotecarcinogenesisbyinducingDNAdamageaccumulation,increasingp53degradation,andother,relatedpathways.Excessivestresshormonesalsopreventimmunecellsfromeffectivelycontrollingcancercellsbyincreasinginflammationandsuppressingimmunity.Further,theycanactontumorandstromalcellsinthetumormicroenvironmenttopromotetumorgrowth,invasion,andmetastasis.Inadditiontothesepathways,emergingtrendsincludeinvestigationofthecorrelationbetweenchronicstressandthemicrobiota-gut-brainaxis(61–63),anditsimpactonintestinaldiseases(64). Theeffectsofdailystressontheneuroendocrineandimmunefunctionofhealthyhumanindividuals,whichmaybemodulatedbytheindividual'spersonality,havebeenconfirmed,forexample,byBiondietal.(65).Therefore,weneedtoactivelymanagestress(66,67).Alargeamountofclinicalevidenceshowsthatsupportivepsychologicaltherapyhasapositiveeffectonanticancertreatmentandprognosisofcancerpatients(68,69).Inadditiontoincreasingexercise(70)andpsychologicalintervention(71–74)toregulatethepatients'stress,wecanalsousedrugsthatlimitthetransmissionoftheHPAaxisandthedownstreamsignalingpathwaysoftheSNS,suchastheβ-adrenergicreceptorantagonists[(9);Figure2],COX2inhibitors(COX2i)[(59,75);Figure3],anti-VEGFCtherapeutics(αVEGFC)ordopamine(76)(aninhibitorycatecholamine).Thesedrugshavebeenshowninanimalexperimentstonotonlysignificantlyimproveanxiety-likebehavior(47,48),andinhibitchronictumor-promotingtumorgrowth,butalsotoblockastress-inducedincreaseinangiogenesisandlymphaticmetastasis(60).Atthesametime,wesuggestthatstresshormonesshouldbeusedwithcaution,especiallyglucocorticoids(77)totreatpatientswithcancerandrelatedcomplications.Finally,itisnotablethatβ-blockershavebeenrelativelywidelyusedinclinicalresearch(78,79)andareoftenadministeredasadjuvantsincancertreatmentinrecentyears[(80–84);Table2],especiallyinbreastcancertreatment.Thoughotherrelateddrugshaveshownpromisefortreatingcancer,thereremainsinsufficientevidencefortheirclinicalapplication. TABLE2 Table2.Clinicaltrialsofstress-inducedcancersinrecentyears. AuthorContributions SD,YM,andYWcollectedtherelatedpaperandfinishedthemanuscript,tables,andfigures.YL,WX,GL,CG,andZZgaveconstructiveguidanceandmadecriticalrevisions.BX,QL,MZ,andXLparticipatedinthedesignofthisreview.Allauthorsreadandapprovedthefinalmanuscript. Funding ThisworkwassupportedpartiallybygrantsfromtheNationalNaturalScienceFoundationofChina(81972776,81872278,81772928,81702907,and81672683)andtheNaturalScienceFoundationofHunanProvince(2018SK21210,2018SK21211,2018JJ3704,and2017SK2105). ConflictofInterest Theauthorsdeclarethattheresearchwasconductedintheabsenceofanycommercialorfinancialrelationshipsthatcouldbeconstruedasapotentialconflictofinterest. Abbreviations AR,adrenergicreceptor;ACTH,adrenocorticotropichormone;Ad,adrenaline;APC,antigen-presentingcell;ARRB1,β-arrestin;CRF,corticotropinreleasingfactor;DC,dendriticcell;FAK,focaladhesionkinase;HPA,hypothalamic-pituitary-adrenal;IGF-1R,insulin-likegrowthfactorreceptor;IL,interleukin;LDHA,lactatedehydrogenaseA;MCP-1,monocytechemotacticprotein1;MDM2,negativeregulatormurinedoubleminute2;MDSC,myeloid-derivedsuppressorcell;MMPs,matrixmetalloproteinases;NA,norepinephrine;PKA,cAMP-proteinkinaseA;ROR1,receptortyrosinekinase-likeorphanreceptor1;ROS,reactiveoxygenspecies;SGK1,serum-and-glucocorticoid-regulatedkinase;SNS,sympatheticnervoussystem;STAT3,signaltransductionandactivatoroftranscription;Tcell,thymus-dependentlymphocyte;TAM,tumor-associatedmacrophage;Th1,type1helperTcell;TIL,tumor-infiltratinglymphocyte;TNF-α,tumornecrosisfactoralpha;VDCC,voltage-dependentcalciumchannel;VEGF,vascularendothelialgrowthfactor. 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Editedby:SridharMuthusami,KarpagamAcademyofHigherEducation,India Reviewedby:RaviManoharan,UniversityofMadras,IndiaAruljothiMuralidharan,UniversityofCaliforniaSchoolofMedicine,Riverside,UnitedStates Copyright©2020Dai,Mo,Wang,Xiang,Liao,Zhou,Li,Li,Xiong,Li,GuoandZeng.Thisisanopen-accessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(CCBY).Theuse,distributionorreproductioninotherforumsispermitted,providedtheoriginalauthor(s)andthecopyrightowner(s)arecreditedandthattheoriginalpublicationinthisjournaliscited,inaccordancewithacceptedacademicpractice.Nouse,distributionorreproductionispermittedwhichdoesnotcomplywiththeseterms. *Correspondence:ZhaoyangZeng,[email protected] COMMENTARY ORIGINALARTICLE Peoplealsolookedat SuggestaResearchTopic>