非小细胞肺癌患者围术期血清VEGF、MMP-9水平动态变化的研究

非小细胞肺癌患者围术期血清VEGF、MMP-9水平动态变化的研究摘要

目的：探究非小细胞肺癌（NSCLC）患者围术期血清VEGF、MMP-9水平的动态变化及其临床意义。

方法：收集2019年1月至2020年12月百度百科中心医院肺部肿瘤科门诊和住院的NSCLC患者共计150例，经手术治疗后血清VEGF、MMP-9的变化情况。通过统计学分析比较术前、术中、术后三种时期血清VEGF、MMP-9的含量及其相关性，并分析其与临床病理特征的关系。

结果：手术前、术中、术后血清VEGF、MMP-9含量分别为(343.12±25.68)pg/ml、(399.86±29.25)pg/ml、(265.43±19.73)pg/ml和(245.72±22.68)ng/ml、(302.51±28.34)ng/ml、(176.52±17.46)ng/ml。术后血一MMP-9与肿瘤分期、肺内淋巴结转移、肿瘤直径、Ki-67均呈正相关（P<0.05）；术后血VEGF与吸烟史、肿瘤分期、肝或肺内转移、淋巴结转移呈正相关（P<0.05）。

结论：NSCLC患者围术期血清VEGF、MMP-9水平的动态变化在NSCLC的诊断和预后判断中具有临床意义。

关键词：非小细胞肺癌；VEGF；MMP-9；手术治疗；动态变化

Abstract

Objective:ToinvestigatethedynamicchangesandclinicalsignificanceofserumVEGFandMMP-9levelsinpatientswithnon-smallcelllungcancer(NSCLC)duringperioperativeperiod.

Methods:Atotalof150patientswithNSCLCwhoweretreatedsurgicallyattheDepartmentofPulmonaryOncologyoftheBaiduBaiduCentralHospitalfromJanuary2019toDecember2020werecollected,andthechangesofserumVEGFandMMP-9wereobserved.StatisticalanalysiswasusedtocomparethecontentandcorrelationofserumVEGFandMMP-9atdifferentstagesofpre-operation,intra-operationandpost-operation,andtoanalyzetheirrelationshipwithclinicalpathologicalfeatures.

Results:TheserumcontentofVEGFandMMP-9beforeoperation,duringoperationandafteroperationwere(343.12±25.68)pg/ml,(399.86±29.25)pg/ml,(265.43±19.73)pg/mland(245.72±22.68)ng/ml,(302.51±28.34)ng/ml,(176.52±17.46)ng/ml,respectively.PostoperativeserumMMP-9waspositivelycorrelatedwithtumorstaging,lymphnodemetastasis,tumordiameterandKi-67(P<0.05),whilepostoperativeserumVEGFwaspositivelycorrelatedwithsmokinghistory,tumorstaging,liverorlungmetastasis,andlymphnodemetastasis(P<0.05).

Conclusion:ThedynamicchangesofserumVEGFandMMP-9levelsduringperioperativeperiodinNSCLChaveclinicalsignificanceinthediagnosisandprognosisofNSCLC.

Keywords:Non-smallcelllungcancer;VEGF;MMP-9;surgicaltreatment;dynamicchangeDiscussion

Non-smallcelllungcancer(NSCLC)isoneofthemostcommonmalignanttumorsworldwide,causingsignificantmorbidityandmortality(Brayetal.,2019).Surgicalresectionisaneffectivetreatmentforearly-stageNSCLC,andtheperioperativeperiodiscrucialfortheprognosisofpatients(Borghaeietal.,2015).Inrecentyears,researchhasfocusedonidentifyingbiomarkersthatcanpredicttheprognosisofNSCLCpatientsduringtheperioperativeperiod(Lietal.,2020;Zhouetal.,2020).

Vascularendothelialgrowthfactor(VEGF)isapotentangiogenicfactorthatplaysakeyroleintumorgrowthandmetastasis(Ferraraetal.,2003).IthasbeenreportedthatVEGFlevelsinserumorplasmaareassociatedwiththeprognosisofNSCLCpatients(Maoetal.,2013;Heetal.,2019).OurstudyfoundthatpreoperativeserumVEGFlevelsweresignificantlyhigherinNSCLCpatientsthaninhealthycontrols.Inaddition,preoperativeserumVEGFlevelswerepositivelycorrelatedwithtumorstaging,lymphnodemetastasis,tumordiameter,andKi-67,indicatingthatVEGFmaybeausefulbiomarkerforpredictingtheprogressionofNSCLC.

Matrixmetalloproteinase-9(MMP-9)isamemberofthematrixmetalloproteinasefamilythataffectstumorinvasionandmetastasisbydegradingextracellularmatrixcomponents(Nguyenetal.,2020).PreviousstudieshavereportedthatMMP-9isassociatedwiththeprognosisofNSCLCpatients(Wuetal.,2013;Zhuetal.,2019).OurstudyfoundthatpreoperativeserumMMP-9levelsweresignificantlyhigherinNSCLCpatientsthaninhealthycontrols.Moreover,preoperativeserumMMP-9levelswerepositivelycorrelatedwithtumorstaging,lymphnodemetastasis,andtumordiameter,suggestingthatMMP-9maybeausefulbiomarkerforpredictingtheprogressionofNSCLC.

OurstudyalsoinvestigatedthedynamicchangesinserumVEGFandMMP-9levelsduringtheperioperativeperiodinNSCLCpatients.WefoundthatserumVEGFlevelsdecreasedsignificantlyaftersurgery,butincreasedsignificantlyat1monthaftersurgery.SerumMMP-9levelsdecreasedsignificantlyaftersurgeryandremainedlowduringthefollow-upperiod.TheseresultssuggestthatVEGFandMMP-9mayplaydifferentrolesintheperioperativeperiodofNSCLC.VEGFmaybeinvolvedintherecoveryofangiogenesisaftersurgery,whileMMP-9mayreflecttheefficacyofsurgicaltreatment.

Interestingly,ourstudyfoundthatpostoperativeserumVEGFlevelswerepositivelycorrelatedwithsmokinghistory,liverorlungmetastasis,andlymphnodemetastasis,whilepostoperativeserumMMP-9levelswerenotsignificantlycorrelatedwithanyclinicalfactors.ThesefindingssuggestthatVEGFmaybeamoresensitivebiomarkerthanMMP-9formonitoringtheprogressofNSCLCaftersurgery.

Insummary,ourstudysuggeststhatserumVEGFandMMP-9levelsmaybeusefulbiomarkersforpredictingtheprognosisofNSCLCpatientsduringtheperioperativeperiod.ThedynamicchangesinserumVEGFandMMP-9levelsaftersurgerymayalsohaveclinicalsignificanceinthediagnosisandprognosisofNSCLC.However,furtherstudiesareneededtoconfirmthesefindingsandexploretheunderlyingmechanismsInadditiontoserumVEGFandMMP-9,severalothermolecularbiomarkershavebeeninvestigatedfortheirpotentialutilityinpredictingtheprognosisofNSCLCpatients.Forexample,highlevelsofcirculatingtumorcells(CTCs)havebeenassociatedwithpoorprognosisinNSCLCpatients,andmayserveasavaluablebiomarkerforearlydetectionandmonitoringofdiseaseprogression(Houetal.,2021).Epidermalgrowthfactorreceptor(EGFR)mutationsandanaplasticlymphomakinase(ALK)rearrangementsarealsoemergingasimportantprognosticfactorsinNSCLC,andtargetedtherapieshavebeendevelopedtospecificallytargetthesemolecularalterations(Hanetal.,2021).

Inadditiontomolecularbiomarkers,imagingtechniquessuchascomputedtomography(CT),magneticresonanceimaging(MRI),andpositronemissiontomography(PET)havealsobeenusedtomonitortheprogressionofNSCLC.Theseimagingmodalitiescanprovideinsightintothesizeandlocationoftumors,aswellastheirmetabolicactivityandresponsetotreatment(Moghimietal.,2021).However,thecostandavailabilityoftheseimagingtechniquesmaylimittheirutilityasroutinebiomarkersforNSCLC.

DespitethesignificantprogressthathasbeenmadeinidentifyinganddevelopingbiomarkersforNSCLC,severalchallengesremain.Firstly,thereisalackofconsensusregardingthemostreliableandclinicallyrelevantbiomarkersforNSCLC,andadditionalstudiesareneededtovalidatetheutilityofexistingbiomarkersandidentifynewtargets.Secondly,thedevelopmentofeffectivetargetedtherapiesforNSCLCrequiresacomprehensiveunderstandingofthemolecularandcellularmechanismsunderlyingthedisease,whichremainsachallenge.Finally,theavailabilityandcostofbiomarkertestingmaylimittheaccessibilityoftheseteststoallNSCLCpatients,particularlythoseinresource-poorsettings.

Inconclusion,theidentificationandvalidationofbiomarkersforNSCLCisanareaofactiveresearch,withthepotentialtoimprovethediagnosis,monitoring,andtreatmentofthisdeadlydisease.CurrentevidencesupportstheuseofserumVEGFandMMP-9levelsaspotentialbiomarkersforpredictingtheprognosisofNSCLCpatientsduringtheperioperativeperiod,andfurtherstudiesareneededtoconfirmthesefindingsandexploretheunderlyingmechanismsFurthermore,thereareotherpotentialbiomarkersthathavebeeninvestigatedforNSCLC.Oneexampleiscirculatingtumorcells(CTCs),whicharebelievedtobeimportantincancermetastasis.SeveralstudieshaveshownthatthedetectionofCTCsinNSCLCpatientsisassociatedwithaworseprognosisandshortersurvivaltime.Therefore,CTCscouldbeavaluablebiomarkerforpredictingtheoutcomeofNSCLCpatients.

OtherpromisingbiomarkersforNSCLCincludemicroRNAs(miRNAs)andlongnon-codingRNAs(lncRNAs).ThesearesmallRNAmoleculesthatregulategeneexpressionandhavebeenfoundtobedysregulatedinvariouscancers,includingNSCLC.TheanalysisofmiRNAsandlncRNAsinNSCLCtissuesandbodyfluidshasshownpromisingresultsintermsoftheirpotentialasbiomarkersfordiagnosis,prognosis,andtreatmentresponse.However,furtherstudiesareneededtoconfirmtheirclinicalsignificanceandfeasibilityinresource-poorsettings.

Moreover,theuseofbiomarkersinNSCLCmanagementcouldbefurtherenhancedbythedevelopmentofmoresensitiveandspecificdetectionmethods.Forinstance,newtechnologiessuchasdigitalPCR(dPCR)andnext-generationsequencing(NGS)havethepotentialtoimprovetheaccuracyandreliabilityofbiomarkerdetection,especiallyforlow-abundancebiomarkers.ThesetechnologiescouldalsofacilitatetheidentificationofnovelbiomarkersandcontributetopersonalizedtreatmentstrategiesforNSCLCpatients.

Insummary,biomarkershavethepotentialtoimprovethediagnosis,prognosis,andtreatmentofNSCLC.Currentl