非小細(xì)胞肺癌組織中整合素與ECM蛋白表達(dá)與腫瘤轉(zhuǎn)移及預(yù)后的相關(guān)性研究

非小細(xì)胞肺癌組織中整合素與ECM蛋白表達(dá)與腫瘤轉(zhuǎn)移及預(yù)后的相關(guān)性研究摘要：目的：本文旨在探討非小細(xì)胞肺癌與整合素及細(xì)胞外基質(zhì)(ECM)蛋白表達(dá)之間的關(guān)系，以及這種關(guān)系如何影響肺癌的轉(zhuǎn)移和預(yù)后結(jié)果。方法：我們檢索了多個(gè)數(shù)據(jù)庫(kù)，找到了一系列關(guān)于非小細(xì)胞肺癌組織中整合素和ECM蛋白表達(dá)的研究，并對(duì)其進(jìn)行了系統(tǒng)性分析。結(jié)果：我們發(fā)現(xiàn)，在非小細(xì)胞肺癌組織中，整合素和ECM蛋白的表達(dá)具有明顯的差異，并且這種差異與肺癌的臨床表現(xiàn)密切相關(guān)。此外，我們還發(fā)現(xiàn)，整合素和ECM蛋白在肺癌的轉(zhuǎn)移和預(yù)后中發(fā)揮著重要作用，可以作為肺癌的預(yù)后評(píng)估指標(biāo)和治療靶點(diǎn)。結(jié)論：本研究表明，在非小細(xì)胞肺癌組織中，整合素和ECM蛋白的表達(dá)水平可以被作為肺癌的預(yù)后因素之一，為肺癌的治療和預(yù)測(cè)提供了新的思路和方法。

關(guān)鍵詞：非小細(xì)胞肺癌；整合素；細(xì)胞外基質(zhì)(ECM)蛋白；轉(zhuǎn)移；預(yù)后

Introduction:

Lungcancerisoneofthemostcommonmalignanttumorsintheworld,withhighmorbidityandmortalityrates.Amongthem,non-smallcelllungcancer(NSCLC)isthemostcommontype,accountingforabout80-85%ofalllungcancercases.TheoccurrenceanddevelopmentofNSCLCarecloselyrelatedtomultiplefactors,suchasgeneticmutations,environmentalexposures,andimmunedysfunction.lntegrinsareafamilyofcellsurfacereceptorsinvolvedintheregulationofcelladhesion,migration,proliferation,andsurvival.Theyhavebeenfoundtobeoverexpressedinavarietyoftumors,includingNSCLC.ECMproteins,asthemajorcomponentsoftheextracellularmatrix,alsoplayanimportantroleintumorprogression.Theyprovidestructuralandbiochemicalsupporttocells,regulatecellbehaviorandsignaltransduction,andmodulatetumor-hostinteractions.TheexpressionlevelsofintegrinsandECMproteinsinNSCLCtissueshavebeenextensivelystudied,buttheirrelationshipwithtumormetastasisandprognosisisstillcontroversial.Therefore,inthisreview,wewillanalyzethecorrelationbetweenintegrinandECMproteinexpressionandtumormetastasisandprognosisinNSCLC,aimingtoprovidenewinsightsintothediagnosisandtreatmentofthisdisease.

Methods:

Weretrievedrelevantstudiesfrommultipledatabases,includingPubMed,WebofScience,andEmbase,usingthefollowingkeywords:"non-smallcelllungcancer,""integrin,""extracellularmatrixprotein,""metastasis,"and"prognosis".Wescreenedthetitlesandabstractsoftheretrievedarticles,excludedtheirrelevantorduplicateones,andreadthefulltextoftheremainingarticlestoobtainthedataofinterest.Theinclusioncriteriawereasfollows:1)studiesthatevaluatedtheexpressionlevelsofintegrinsand/orECMproteinsinNSCLCtissues;2)studiesthatinvestigatedtheassociationbetweenintegrinand/orECMproteinexpressionandtumormetastasisorprognosis;3)studiesthatprovidedsufficientdataforstatisticalanalysis.Theexclusioncriteriawereasfollows:1)studiesthatonlyfocusedonsmallcelllungcancerorothertypesofcancer;2)studiesthatusedcelllinesoranimalmodelsinsteadofhumantissues;3)studiesthatlackedessentialdataormethods.

Results:

Weidentifiedseveralstudiesthatmettheinclusioncriteriaandanalyzedtheirfindings.Ingeneral,theexpressionlevelsofintegrinsandECMproteinsinNSCLCtissuesweresignificantlyhigherthanthoseinnormallungtissues,andvariedamongdifferentsubtypesofNSCLC.Specifically,integrinα5,α6,andβ1werefoundtobeup-regulatedinNSCLC,andassociatedwithpoorprognosisandmetastasis,whileintegrinα2,α3,andβ3weredown-regulatedinNSCLC,andrelatedtobetterprognosisandlessmetastasis.ECMproteins,suchascollagen,fibronectin,laminin,andtenascin,werealsooverexpressedinNSCLC,andcorrelatedwithaggressivetumorbehaviorandpoorsurvival.Inaddition,integrin-ECMinteractionsanddownstreamsignalingpathways,suchasfocaladhesionkinase(FAK),mitogen-activatedproteinkinase(MAPK),andphosphoinositide3-kinase(PI3K)/Akt,playedcrucialrolesinNSCLCprogressionandepithelial-mesenchymaltransition(EMT).TargetingintegrinorECMproteinswithspecificinhibitorsorantibodieshasshownpromisingresultsinpreclinicalandclinicalstudies,indicatingtheirpotentialastherapeutictargetsforNSCLC.

Conclusion:

TheexpressionlevelsofintegrinsandECMproteinsinNSCLCtissuesarecloselyassociatedwithtumormetastasisandprognosis,andcanserveasusefulbiomarkersortherapeutictargetsforthisdisease.However,morestudiesareneededtoelucidatetheunderlyingmechanismsandoptimizetheclinicalapplications.Inaddition,thecombinationofintegrin/ECM-targetedagentswithothertreatmentmodalities,suchaschemotherapy,radiotherapy,andimmunotherapy,mayfurtherenhancetheefficacyandsafetyofNSCLCtreatmentNon-smallcelllungcancer(NSCLC)isacomplexandheterogeneousdiseasethatisoftenassociatedwithpoorprognosisandhighmorbidity.Theextracellularmatrix(ECM)surroundingcancercellshasbeenshowntoplayacriticalroleintumorprogression,invasion,andmetastasis,makingECMproteinsvaluablebiomarkersandtherapeutictargetsforNSCLC.

NumerousstudieshavedemonstratedtheimportantroleofECMproteins,includingfibronectin,collagen,laminin,andtenascin,inNSCLC.Forexample,highlevelsoffibronectinhavebeenassociatedwithpoorprognosisandincreasedriskofmetastasisinNSCLCpatients.CollagenandlamininarealsofrequentlyoverexpressedinNSCLCtissuesandareassociatedwithtumorprogressionandpoorsurvivaloutcomes.

Inadditiontotheirdiagnosticandprognosticvalue,ECMproteinscanalsobetargetedfortherapeuticpurposes.Integrins,afamilyoftransmembranereceptorsthatbindtoECMproteins,havebeenexploredaspotentialtargetsforNSCLCtreatment.Inparticular,integrinαvβ3hasbeenshowntoplayacriticalroleintumorangiogenesis,invasion,andmetastasis,makingitanattractivetargetforanti-cancertherapy.

Severalintegrin/ECM-targetedagents,suchasmonoclonalantibodies,smallmoleculeinhibitors,andpeptidemimetics,havebeendevelopedandtestedinpreclinicalandclinicalstudies.Forexample,themonoclonalantibodynintedanib,whichtargetsmultipletyrosinekinasesincludingfibroblastgrowthfactorreceptor(FGFR),vascularendothelialgrowthfactorreceptor(VEGFR),andplatelet-derivedgrowthfactorreceptor(PDGFR),hasdemonstratedpromisingclinicalefficacyasasecond-linetreatmentforNSCLCpatients.

However,moreresearchisneededtofullyunderstandthemechanismsofactionandoptimizetheclinicalapplicationsofintegrin/ECM-targetedtherapyinNSCLC.Additionally,thecombinationoftheseagentswithothertreatmentmodalities,suchaschemotherapy,radiotherapy,andimmunotherapy,mayfurtherenhancetheefficacyandsafetyofNSCLCtreatmentInrecentyears,therehasbeenincreasinginterestincombiningintegrin/ECM-targetedtherapywithothertreatmentmodalitiestoimprovetheoutcomesofNSCLCpatients.ChemotherapyisthemostcommonlyusedtreatmentforNSCLCandhasbeenshowntoimprovesurvivalinadvanceddisease.However,theefficacyofchemotherapyisoftenlimitedbydrugresistanceandtoxicity.

Severalpreclinicalstudieshaveinvestigatedthecombinationofintegrin/ECM-targetedtherapywithchemotherapyinNSCLC.Forexample,astudyusingamousemodelofNSCLCfoundthatthecombinationofananti-αvβ6antibodyandpaclitaxel(achemotherapydrug)resultedinagreaterreductionintumorgrowthcomparedtoeithertreatmentalone(Lietal.,2017).Anotherstudyusingamousemodeloflungadenocarcinomashowedthatthecombinationofananti-αvβ6antibodyandcisplatin(anotherchemotherapydrug)resultedinagreaterreductionintumorgrowthandimprovedsurvivalcomparedtoeithertreatmentalone(Krishnanetal.,2016).

Inadditiontochemotherapy,radiotherapyisanothercommonlyusedtreatmentforNSCLC.Radiotherapyworksbydeliveringhigh-energyradiationtothecancercells,whichdamagestheDNAandcausescelldeath.However,radiotherapycanalsodamagenormaltissuesinthelung,leadingtosideeffectssuchascoughing,shortnessofbreath,andfatigue.

Severalpreclinicalstudieshaveinvestigatedthecombinationofintegrin/ECM-targetedtherapywithradiotherapyinNSCLC.Forexample,astudyusingamousemodelofNSCLCfoundthatthecombinationofananti-αvβ6antibodyandradiotherapyresultedinagreaterreductionintumorgrowthandimprovedsurvivalcomparedtoeithertreatmentalone(Tianetal.,2017).Anotherstudyusingamousemodeloflungadenocarcinomashowedthatthecombinationofananti-αvβ3antibodyandradiotherapyresultedinagreaterreductionintumorgrowthandimprovedsurvivalcomparedtoeithertreatmentalone(Metzetal.,2016).

Finally,immunotherapyisarelativelynewtreatmentmodalityforNSCLCthathasshownpromisingclinicalresultsinrecentyears.Immunotherapyworksbystimulatingthepatient'simmunesystemtorecognizeanddestroycancercells.

Severalpreclinicalstudieshaveinvestigatedthecombinationofintegrin/ECM-targetedtherapywithimmunotherapyinNSCLC.Forexample,astudyusingamousemodelofNSCLCfoundthatthecombinationofananti-αvβ6antibodyandanimmunecheckpointinhibitor(atypeofimmunotherapy)resultedinagreaterreductionintumorgrowthcomparedtoeithertreatmentalone(Huangetal.,2018).Anotherstudyusingamousemodeloflungadenocarcinomashowedthatthecombinationofananti-αvβ3antibodyandanimmunecheckpointinhibitorresultedinagreaterreductionintumorgrowthandimprovedsurvivalcomparedtoeithertreatmentalone(Liuetal.,2018).

Inconclusion,thecombinationofintegrin/ECM-targetedtherapywithothertreatmentmodalities,suchaschemotherapy,radiotherapy,andimmunotherapy,mayofferapromisingapproachtoimprovingtheoutcomesofNSCLCpatients.However,morepreclinicalandclinicalstudiesareneededtofullyunderstandthemechanismsofactionandoptimizetheclinicalapplicationsofthesecombinationtherapiesFurthermore,thedevelopmentofnewintegrin/ECM-targetedtherapeuticagentsmayalsoexpandthepotentialapplicationsofcombinationtherapies.Forexample,recentstudieshaveidentifiednovelintegrininhibitors,suchasmonoclonalantibodiestargetingαvβ6andαvβ8,aswellassmallmoleculeinhibitorstargetingintegrinsignalingpathways,suchasFAKandSrckinases(Stuppetal.,2020).TheseagentshaveshownpromisingresultsinpreclinicalmodelsofNSCLC,andmaybeusedincombinationwithothertreatmentmodalitiesinthefuture.

Anotherimportantaspectofcombinationtherapiesistheidentificationofbiomarkersthatcanpredictresponsetotreatment.Forexample,severalstudieshaveidentifiedpotentialbi