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簡介：中文中文3070字出處出處SHIAOYH,DANIELABOVO?,GUIDOM,ETALMICROSATELLITEINSTABILITYAND/ORLOSSOFHETEROZYGOSITYINYOUNGGASTRICCANCERPATIENTSINITALYJINTERNATIONALJOURNALOFCANCER,1999,8215962青年胃癌患者的微衛(wèi)星不穩(wěn)定性和青年胃癌患者的微衛(wèi)星不穩(wěn)定性和/或雜和性缺失或雜和性缺失摘要胃癌在40歲前極少。比較40歲和大于40歲的患者，早期胃癌的分子機制可能是微衛(wèi)星不穩(wěn)定性MSI、錯配修復(fù)和雜和性缺失（LOH）。從102例40歲胃癌患者的取出的標(biāo)本,用福爾馬林固定,石蠟包埋后,用PCR非放射篩查法檢測MSI和/或LOH。11/102患者中在1基因座發(fā)現(xiàn)MSI和/或LOH。MSI和/或LOH的發(fā)生率在D11S904基因座要高于D2S119、D2S123、D5S409和IFNA區(qū)域。在老年患者中未發(fā)現(xiàn)D11S904基因座上有優(yōu)先的基因改變。關(guān)于幾個臨床病理參數(shù)，相對于胃竇部和胃體的腫瘤，只有賁門的腫瘤上與MSI和/或LOH有顯著的統(tǒng)計學(xué)聯(lián)系。我們的研究提示，可能有獨特的機制增加了D11S904基因座對MSI和/或LOH的敏感性，特別是在年輕的賁門癌患者。40歲人群胃癌的早期啟動與某些染色體基因座的基因改變，包括D11S904，有關(guān)。正文盡管胃癌的發(fā)病率在下降，但在90年代仍是全世界第二常見的和第二位致死腫瘤PARKINETAL,1993。由于胃癌自然的侵襲性，其總體5年生存率低于20％BREAUXETAL,1990。胃癌一般發(fā)病于大于50歲的患者，只有5％的胃癌患者小于40歲NEUGUTETAL,1996。小于40歲患者的胃癌比老年患者的胃癌更具侵襲性FUJIMOTOETAL,1994。將小于40歲患者的胃癌與老年患者的胃癌比較，可以發(fā)現(xiàn)有特殊的分子機制與腫瘤早期啟動相關(guān)。微衛(wèi)星是短串連DNA重復(fù)序列，普遍存在于哺乳動物的基因中。二、三、四個核酸重復(fù)序列存在于一半以上的人基因中BECKMANANDWEBER,1992。串連的DCDAN尤其豐富。每個位點重復(fù)的數(shù)目不同，如微衛(wèi)星不穩(wěn)定性（MSI），與人類不同的疾病相關(guān)，包括腫瘤SPEICHER,1995。微衛(wèi)星序列的多態(tài)性也很明顯。由于重復(fù)數(shù)目不同引起的多態(tài)性對判斷基因的變化很有用，如雜和性缺失（LOH）。本研究中，我們檢測了5個染色體基因座，在一般人群的胃癌患者和小于40歲的胃癌患者中常在其中發(fā)現(xiàn)MSI和/或LOHRHYUETAL,1994CHONGETAL,1994NAGELETAL,1995TAMURAETAL,1995LINETAL,1995SERUCAETAL,1995BUONSANTIETAL，1997。并對MSI和/或LOH發(fā)生的頻率和其與其他臨床病理數(shù)據(jù)的聯(lián)系進行了討論。材料和方法患者從具有可比性胃癌證據(jù)的多家意大利醫(yī)院中收集了102例小于40歲（平均年齡35歲；范圍16～40）的胃癌患者的福爾馬林固定，石蠟包埋的組織塊。通過協(xié)作研究得到人口統(tǒng)計學(xué)和病理學(xué)資料，包括年齡、性別、腫瘤的位置和腫瘤的TNM分期BEAHRSANDMYERS,1983。腫瘤的位置分為胃竇、胃體和賁門。沒有癌超出胃食管接合部。根據(jù)LAURéN分型（1965），胃癌分為腸型和彌漫型。當(dāng)兩種類型都有的時候，則根據(jù)最具代表性的組織學(xué)表現(xiàn)。胃炎（非萎縮性和萎縮性/化生）的分類根據(jù)HOUSTONUPDATEDSYDNEY系統(tǒng)DIXONETAL,1996。所有的病例均由兩個作者共同分析MCANDMR）。DNA的提取腫瘤和鄰近的非瘤組織用顯微切割的方法從未染色的福爾馬林固定，石蠟包埋的切片中分離，進行去石蠟作用、蛋白激酶K消化和DNA純化SHIAOETAL,1994。顯微切割的瘤組織至少包含50％的腫瘤細胞?？赡軙r，淋巴結(jié)作為對照的非瘤細胞。PCR選擇5個帶有CAN二核苷酸重復(fù)D2S119,D2S123,D5S409,IFNAANDD11S904的染色101MSI1ND,NOTDETERMINED2,NODETECTABLEMSIAND/ORLOHTABLETABLEIIIICOMPARISONCOMPARISONOFOFTHETHEFREQUENCYFREQUENCYOFOFMSIMSIAND/ORAND/ORLOHLOHBETWEENBETWEENYOUNGYOUNGTHISTHISSTUDYSTUDYANDANDELDERLYELDERLYPATIENTSPATIENTSREFERENCEREFERENCED2S119D2S119D2S123D2S123D5S409D5S409IFNAIFNAD11S904D11S904THISSTUDY1/9610/8702/9921/10119/1009RHYUETAL199411/522115/5229NDND9/5217CHONGETAL1994ND117/7523NDNDNDNAGELETAL1995ND7/1937NDNDNDTAMURAETAL1995ND3/23137/23306/2326NDLINETAL1995ND16/5927NDNDNDSERUCAETAL1995NDNDNDND4/2417BUONSANTIETAL1997NDNDNDND2/8251ND,NOTDETERMINEDFIGUREFIGURE11ANALYSISOFMSIAND/ORLOHATTHED11S904LOCUSUSINGANONRADIOACTIVEMETHODN,NORMALC,CANCER

簡介：CYTOKINEDRIVENREGULATIONOFNKCELLFUNCTIONSINTUMORIMMUNITYROLEOFTHEMICANKG2DSYSTEMNORBERTOWZWIRNER,MERCEDESBFUERTES,MARI′AVICTORIAGIRART,CAROLINAIDOMAICA,LUCASEROSSILABORATORIODEINMUNOGENE′TICA,HOSPITALDECLI′NICAS‘‘JOSE′DESANMARTI′N’’,ANDDEPARTAMENTODEMICROBIOLOGI′A,FACULTADDEMEDICINA,UNIVERSIDADDEBUENOSAIRES,BUENOSAIRES,ARGENTINAAVAILABLEONLINE26FEBRUARY2007ABSTRACTNATURALKILLERNKCELLSARECRITICALPLAYERSDURINGTUMORGROWTHCONTROLINIMMUNOCOMPETENTHOSTSTHESECELLSALSOESTABLISHACROSSTALKWITHDENDRITICCELLSDCSANDPROMOTEATH1MEDIATEDIMMUNITYNKG2DISAPIVOTALRECEPTORTHATDIRECTSTHETUMORICIDALACTIVITYOFNKCELLSTHROUGHTHERECOGNITIONOFAGROUPOFLIGANDSSUCHASMICAWIDELYEXPRESSEDONDIFFERENTTUMORSHEREWEWILLREVIEWTHEMOSTIMPORTANTTUMORIMMUNEESCAPEMECHANISMSTHATCOMPROMISETHEFUNCTIONALITYOFNKG2DANDITSCOGNATELIGANDS,INCLUDINGTGFBSECRETION,TUMORSHEDDINGOFSOLUBLEMICA,ANDADDITIONALMECHANISMSTHATCOMPROMISETHETUMORICIDALACTIVITYOFNKG2DEXPRESSINGCELLSSUCHMECHANISMSMAYALSODAMPENTHECROSSTALKBETWEENNKCELLSANDDCSDURINGTHEANTITUMORIMMUNERESPONSESRECENTKNOWLEDGEMAYLEADTOINNOVATIVEAPPROACHESTOPROMOTEEFFICIENTNKCELLMEDIATEDANTITUMORIMMUNERESPONSES2007ELSEVIERLTDALLRIGHTSRESERVEDKEYWORDSMHCNKG2DNKCELLSMICATUMOR1INTRODUCTIONTUMORTRANSFORMATIONANDGROWTHISAMULTISTEPPROCESSTHATINVOLVESTHEACCUMULATIONOFMUTATIONSANDRESULTSINAGENETICINSTABILITY,LOSSOFCELLCYCLECONTROL,RESISTANCETOAPOPTOSIS,UNLIMITEDSELFRENEWALCAPACITYANDTHESELECTIONOFTUMORVARIANTSWITHTHEABILITYTOINVADELOCALANDDISTANTTISSUESHOWEVER,INIMMUNOCOMPETENTHOSTSTUMORSAREFORCEDTOGROWUNDERTHEPERMANENTPRESSUREOFANIMMUNESYSTEMTHATIMPOSESANIMMUNOLOGICALPRESSURETHISOBSERVATIONHASLEDTOTHEPOSTULATIONOFTHEIMMUNOSURVEILLANCEHYPOTHESISCURRENTLY,WEKNOWTHATMANYIMMUNEMEDIATEDCELLDESTRUCTIONMECHANISMSAREACTIVATEDTOELIMINATETUMORCELLSTHEPROGRESSMADEDURINGTHELASTTWODECADESINTHEAREAOFCELLULARANDMOLECULARIMMUNOLOGYANDONCOLOGYHASGREATLYCONTRIBUTEDTOADEEPERKNOWLEDGEABOUTTHETUMORHOSTRELATIONSHIPNEWIDEASHAVEBEENPROPOSEDTOEXPLAINTHECOMPLEXNATUREOFTHEEFFECTOFTHEIMMUNESYSTEMONTHETUMORCELLSANDTHEMECHANISMSDEVELOPEDBYTUMORSTOESCAPEDIFFERENTIMMUNEEFFECTORMECHANISMSALTHOUGHNOTMUTUALLYEXCLUSIVE,TWOMAINLINESOFTHINKINGWEREPOSTULATED1,2INTHEFIRSTCASE,ITWASPROPOSEDTHATTUMORGROWTHISACONSEQUENCEOFANIMMUNOEDITINGPROCESSACHIEVEDBYTHEIMMUNESYSTEMONTUMORCELLS1ACCORDINGLY,TUMORGROWTHANDMETASTASISINIMMUNOCOMPETENTHOSTSISACONSEQUENCEOFTHREESTAGESTHE‘‘THREEES’’OFIMMUNOEDITINGFIRST,THEIMMUNESYSTEMACHIEVESELIMINATIONOFSUSCEPTIBLETUMORCELLSIMMUNOSURVEILLANCESECONDLY,EQUILIBRIUMBETWEENTHEIMMUNESYSTEMANDTHESURVIVINGRESISTANTTUMORCELLSISREACHED,THUSSCULPTINGTHETUMORPHENOTYPEFINALLY,SURVIVINGTUMORCELLSENTERTHETUMORESCAPEPHASETHATISOFTENACCOMPANIEDBYTHEESTABLISHMENTOFMETASTASISOTHERAUTHORSHAVEPROPOSEDTHATTUMORSGROWWWWELSEVIERCOM/LOCATE/CYTOGFRCYTOKINEFAX541159508758EMAILADDRESSNWZSINECTISCOMARNWZWIRNER13596101/–SEEFRONTMATTER2007ELSEVIERLTDALLRIGHTSRESERVEDDOI101016/JCYTOGFR200701013THEABILITYOFNKG2DENGAGEMENTALONETOTRIGGERIFNGSECRETIONHASBEENQUESTIONEDBYTHEOBSERVATIONTHATENGAGEMENTOFTHISRECEPTORBYSOMESOLIDPHASEIMMOBILIZEDNKG2DSPECIFICMABSCOULDELICITCYTOTOXICGRANULERELEASEANDTARGETCELLKILLINGBUTNOTIFNGSECRETION13,16,19,23INSOMECASES,THISDIFFERENTIALRESPONSEHASBEENATTRIBUTEDTOADIFFERENTIALSPLICINGOFNKG2DINMOUSEBUTNOTHUMANNKCELLSANDTOADIFFERENTIALASSOCIATIONWITHTHEDAP10ANDDAP12ADAPTERPROTEINS24,25HOWEVER,RECENTEXPERIMENTALEVIDENCEINDICATESTHATMOUSENKG2DASSOCIATESWITHBOTHADAPTERPROTEINSINNKCELLSTOTRIGGERANACTIVATIONSIGNAL26INSOMECASES,THEDISCREPANCYINTHEABILITYOFNKG2DTOPROMOTEIFNGSECRETIONMIGHTBEDUETOTHEUSEOFSOLIDPHASEIMMOBILIZEDMABSAGAINSTNKG2DSINCEINTHESEEXPERIMENTS,IFNGSECRETIONWASINDUCEDBYENGAGEMENTOFNKG2DWITHSOLIDPHASEIMMOBILIZEDCHIMERICMOLECULESTHATRESEMBLENKG2DLS,SUCHASMICAFCANDULBP1FC16INADDITION,ITISLIKELYTHATINORDERTOTRIGGERIFNGSECRETIONTHROUGHNKG2D,NKCELLSREQUIRETHECOENGAGEMENTOFOTHERRECEPTORS12,13,23THEREFORE,INTERPRETATIONOFTHERESULTSOBTAINEDUPONSTIMULATIONOFNKCELLSTHROUGHNKG2DDURINGTHEINITIATIONOFCYTOTOXICITYANDCYTOKINEPRODUCTIONSHOULDBECAUTIOUSCONSIDERINGTHATTHEDISTINCTOUTCOMESDEPENDONTHECELLTYPE,ACTIVATIONSTATEOFTHECELLS,SPECIESANALYZEDHUMANORMOUSEANDTHESPECIFICLIGANDBEINGTESTEDTWOPOPULATIONSOFHUMANNKCELLSHAVEBEENIDENTIFIEDTHEMAJORPOPULATIONABOUT90ISCYTOTOXICANDSHOWSACD56DIMCD16PHENOTYPE,WHEREASTHEREMAINING10OFTHENKCELLSAREASOURCEOFIMMUNOREGULATORYCYTOKINESANDPRESENTACD56BRIGHTCD16DIMORCD56BRIGHTCD16?PHENOTYPE27ALTHOUGHNKG2DEXPRESSIONSEEMSTOBESLIGHTLYHIGHERINCD56DIMTHANINCD56BRIGHTNKCELLS,THESEDIFFERENCESDONOTAPPEARTOBEINVOLVEDINTHEDIFFERENTIALIFNGPRODUCTIONANDPROLIFERATIONOFTHESENKCELLSUBSETSUPONACTIVATIONBYDENDRITICCELLSDCS28INHUMANSANDMICE,NKG2DISPROMISCUOUSINTERMSOFLIGANDRECOGNITIONHUMANNKG2DLIGANDSNKG2DLSARETHEMHCCLASSIRELATEDCHAINGENESAANDBMICAANDMICB15,ANDAGROUPOFGLYCOSYLPHOSPHATIDYLINOSITOLGPIBOUNDSURFACEMOLECULESCALLEDUL16BINDINGPROTEINULBP1,2,3AND418,29MICEHAVEADIFFERENTSETOFNKG2DLS,WHICHCOMPRISETHERETINOICACIDEARLYINDUCIBLEGENERAE1FAMILYAGROUPOFGPIANCHORED,CELLSURFACEGLYCOPROTEIN,THEMINORHISTOCOMPATIBILITYANTIGENH60ANINTEGRALTRANSMEMBRANEPROTEINS,ANDTHEMURINEUL16BINDINGPROTEINLIKETRANSCRIPT1MULT1,ALLOFWHICHEXHIBITLOWSEQUENCEHOMOLOGYWITHTHEIRHUMANCOUNTERPARTS18,29HOWEVER,HUMANNKG2DBINDSMOUSENKG2DLSANDMOUSENKG2DCANRECOGNIZESOMEHUMANNKG2DLS,MOSTLIKELYREFLECTINGASELECTIVEADVANTAGEOFPRESERVINGTHENKG2DRECEPTORINBOTHSPECIESTHEMICAANDMICBGENESWEREDESCRIBEDIN1994ASAGROUPOFGENESTHATMAPWITHINTHEMHCCLASSIREGION,BUTEXHIBITALOWHOMOLOGYWITHTHECLASSICALMHCCLASSIGENES30,31EXPRESSIONOFMICAHASBEENOBSERVEDINHUMANEPITHELIALANDFIBROBLASTCELLLINES32,33,INPRIMARYCULTURESOFENDOTHELIALCELLSANDFIBROBLASTS34,TUMORSOFDIFFERENTHISTOTYPES12,35,THYMICMEDULLA36,ANDGASTROINTESTINALEPITHELIUM32EXPRESSIONOFMICAWASALSOOBSERVEDINCULTUREDHUMANKERATINOCYTES37,BUTTHISEXPRESSIONWASNOTOBSERVEDONTHECELLSURFACE34ALSO,ACTIVATEDCD4ANDCD8TCELLSWERESHOWNTOEXPRESSMICA38–40,ALTHOUGHLOWLEVELSOFTHISNKG2DLAREEXPRESSEDONTHECELLSURFACE41THEGENERALIZEDEXPRESSIONOFMICAOBSERVEDINMANYTUMORS35,42–46SUGGESTSTHATITSEXPRESSIONISACONSEQUENCEOFTHEMALIGNANTNEOTRANSFORMATIONHOWEVER,RECENTEVIDENCEINDICATESTHATEXPRESSIONOFMICAANDOTHERNKG2DLSISINDUCEDBYTHEDNADAMAGEPATHWAYINRESPONSETOGENOTOXICINSULTS,WHICHISACRITICALSTEPDURINGTHENEOTRANSFORMATION47HOWEVER,ALTHOUGHTHETUMORSUPPRESSORP53ANTIONCOGENHASBEENINVOLVEDINTHEPROTECTIONAGAINSTMALIGNTRANSFORMATION48,P53DOESNOTAPPEARTOBEINVOLVEDINUPREGULATIONOFMICAANDSUBSEQUENTACQUISITIONOFSUSCEPTIBILITYTONKG2DMEDIATEDCYTOTOXICITYALSO,EXPRESSIONOFMICAINACTIVATEDTCELLSINDICATESTHATTHISNKG2DLCANALSOBEINDUCEDBYCELLACTIVATIONCOINCIDENTALLY,CELLACTIVATIONANDNEOTRANSFORMATIONARETWOCELLULARPROCESSESREGULATEDBYNFKB49EXPERIMENTALEVIDENCEACCUMULATEDDURINGTHELASTYEARSINDICATESTHATTHEMICANKG2DSYSTEMPARTICIPATESINDIFFERENTASPECTSOFTHEIMMUNERESPONSE15,32,50–56,BUTTHATTHISINTERACTIONISPARTICULARLYIMPORTANTDURINGTUMORIMMUNITY42,43,57–60THEANTITUMOREFFECTORMECHANISMSUSEDBYNKCELLSCOMPRISETHECYTOTOXICITYAGAINSTSUSCEPTIBLETARGETCELLSANDTHESECRETIONOFIFNGANDOTHERPROINFLAMMATORYCYTOKINESTHEMECHANISMSOFNKCELLMEDIATEDCYTOTOXICITYHAVEBEENREVIEWEDELSEWHERE61,62INMOSTCASES,NKCELLSLYSESUSCEPTIBLETARGETCELLSSECRETINGCYTOTOXICGRANULESTHATCONTAINGRANZYMESANDPERFORINHOWEVER,STUDIESINPERFORIN,GRANZYMESORNKCELLDEFICIENTMICEANDSTUDIESWITHHUMANCELLSREVEALEDTHATNKCELLSCANALSOLYSETARGETCELLSBYDEATHRECEPTORMEDIATEDCYTOTOXICITYSUCHASTHEFASFASLSYSTEMANDTHETNFRELATEDAPOPTOSISINDUCINGLIGANDTRAIL63INMICE,NKCELLPERFORINMEDIATEDCYTOTOXICITY,BUTNOTPRODUCTIONOFIFNGWASCRITICALFORTHEREJECTIONOFRAE1BEXPRESSINGTUMORCELLSINVIVO22ANDFORTHEESTABLISHMENTOFTUMORMETASTASIS64,SUGGESTINGTHATPERFORINGRANZYMESECRETIONISTHEMAJOREFFECTORMECHANISMSOFTHENKG2DDEPENDENT,NKCELLMEDIATEDANTITUMORRESPONSETHEREFORE,CURRENTEVIDENCEINDICATESTHATTHEMECHANISMSTHROUGHWHICHNKG2DTRIGGERSNKCELLMEDIATEDCYTOTOXICITYRELIESONTHEGRANULESECRETIONPATHWAY,BUTITREMAINSANOPENQUESTIONWHETHERNKG2DENGAGEMENTCANALSOELICITFASANDTRAILMEDIATEDAPOPTOSISOFSUSCEPTIBLETARGETSTHEMOLECULARDISSECTIONOFRECEPTORSANDEFFECTORMOLECULESINVOLVEDINNKCELLMEDIATEDTUMORCELLDESTRUCTIONMAYLEADTOTHENWZWIRNERETAL/CYTOKINEGROWTHFACTORREVIEWS182007159–170161

簡介：中文中文9169字出處出處ZWIRNERN,FUERTESM,GIRARTM,ETALCYTOKINEDRIVENREGULATIONOFNKCELLFUNCTIONSINTUMORIMMUNITYROLEOFTHEMICANKG2DSYSTEMJCYTOKINEGROWTHFACTORREVIEWS,2007,181215970腫瘤免疫中腫瘤免疫中NK細胞功能的細胞因子驅(qū)使調(diào)節(jié)細胞功能的細胞因子驅(qū)使調(diào)節(jié)MICANKG2D系統(tǒng)的作用系統(tǒng)的作用NZWIRNER，MFUERTES，MGIRART，CDOMAICA，LROSSI摘要NK細胞在免疫活性宿主的腫瘤生長調(diào)控中起著關(guān)鍵作用。NK細胞還和樹突細胞相互，并且促進了TH1介導(dǎo)的免疫活動。NKG2D是指導(dǎo)NK細胞殺滅腫瘤作用的樞紐受體，它通過識別如MICA這樣的廣泛表達于不同腫瘤內(nèi)的一組配體發(fā)揮作用。這里我們將論述最重要的腫瘤免疫逃逸機制，即NKG2D的功能和它的相關(guān)配體，包括TGFB分泌物，腫瘤的可溶性MICA脫落物，及其他機制即NKG2D表達細胞的殺滅腫瘤作用。這些機制可能緩解了NK細胞和樹突細胞在抗腫瘤免疫反應(yīng)中的相互作用。最近的研究可能產(chǎn)生一種新的方法來促進有效的NK細胞介導(dǎo)的抗腫瘤免疫反應(yīng)。關(guān)鍵詞MHC；NKG2D；NK細胞；MICA；腫瘤11序論序論腫瘤轉(zhuǎn)化和生長是一個多步驟過程，包括突變的積累和導(dǎo)致遺傳不穩(wěn)定性，細胞周期調(diào)控的喪失，抗凋亡，無限自我增殖能力和具有入侵局部和遠處組織能力的腫瘤突變體的選擇。盡管如此，在免疫活性宿主中，腫瘤一直在一個免疫系統(tǒng)給予的免疫壓力下生長。這種觀點已經(jīng)引出免疫監(jiān)視假說。如今，我們知道有許多免疫介導(dǎo)的細胞破壞機制被激活來消滅腫瘤細胞。在過去二十年中，細胞和分子免疫學(xué)及腫瘤學(xué)領(lǐng)域中的進展已經(jīng)很大程度地促進了腫瘤和宿主之間聯(lián)系的深入研究。已經(jīng)有新的觀點被提出來解釋免疫系統(tǒng)對腫瘤細胞的作用的復(fù)雜本質(zhì)以及腫瘤逃避不同免疫效應(yīng)機制的機理。盡管不是互相排斥，這種觀點的兩條主要思路依然是假說。第一種思路提出腫瘤生長是免疫系統(tǒng)對腫瘤細胞的一個免疫編輯過程的結(jié)果。而且，腫瘤在免疫活性宿主的生長和轉(zhuǎn)移是三個步驟的結(jié)果。第一步，免疫系統(tǒng)實現(xiàn)對敏感腫瘤細胞的消除（免疫監(jiān)視）。第二步，免疫系統(tǒng)和存活腫瘤細胞之間達到平衡，從而腫瘤表型出現(xiàn)。最后，存活腫瘤細胞進入腫瘤逃逸階段，該階段經(jīng)常伴隨有腫瘤轉(zhuǎn)移。其他專家也有提出腫瘤在活性免疫系統(tǒng)不斷給予的固定選擇壓力下生長。這種觀點認為，只有那些對免疫系統(tǒng)的免疫破壞和攻擊耐受的腫瘤細胞才會成為過度生長的腫瘤細胞。這些特性共同賦予腫瘤不受控制生長和轉(zhuǎn)移的潛力。盡管如此，腫瘤生長其實是一個更為復(fù)雜的過程，因為在腫瘤生長中，一系列血管生成和抗血管生成因子也參與形成腫瘤表型。；另外，細胞外基質(zhì)在腫瘤生長中的重要作用最近也已經(jīng)被認識到。不管有多少作用因素，無可爭議的是，免疫系統(tǒng)對腫瘤生長的調(diào)控很關(guān)鍵。細胞毒性細胞，特別是NK細胞及致炎細胞因子促進了免疫抗腫瘤作用。在這篇綜述中，我們將集中于腫瘤免疫中NK細胞功能的細胞因子驅(qū)使調(diào)節(jié)研究的新方面，特別是MICANKG2D系統(tǒng)在腫瘤逃逸中的作用。關(guān)于T淋巴細胞在腫瘤免疫中的作用以及細胞因子如何參與形成這些機制，將在另一篇優(yōu)秀的綜述中論述。2NK細胞，受體和配體細胞，受體和配體在過去幾十年的研究中已經(jīng)明確NK細胞呈現(xiàn)細胞毒性，分泌致炎細胞因子如IFNG,TNFA,TNFB,IL13,IL10ANDGMCSF與敏感腫瘤靶細胞接觸。例如，活體內(nèi)NK細胞缺失會導(dǎo)致腫瘤生長的不受控制。而且，化學(xué)方法誘發(fā)的腫瘤在NK細胞缺陷的小鼠體內(nèi)被迅速排斥，而移植入NK細胞充分的小鼠體內(nèi)則腫瘤發(fā)展平衡。最近，NK細胞還被證明參與形成小鼠和人類的適應(yīng)性免疫反應(yīng)。NK細胞對靶細胞的識別是通過種系密碼，細胞表面抑制和活化受體實現(xiàn)的。我們知和MICB，以及一組叫UL16結(jié)合蛋白1，2，3，4的糖基磷脂酰肌醇錨定表面分子。小鼠有一組不同的NKG2D配體，其中包含了維甲酸早期誘導(dǎo)基因I家族，次要組織相容性抗原H60，及小鼠UL16結(jié)合蛋白類轉(zhuǎn)錄子。盡管如此，人類NKG2D能結(jié)合小鼠的NKG2DLS，而小鼠的NKG2D也能識別一些人類NKG2DLS，這一現(xiàn)象最有可能反映的是NKG2D受體在人類和小鼠中的選擇性保存優(yōu)勢，MICA和MICB基因在1994年被描述為一組基因，定位于MHC類別I區(qū)域，但和經(jīng)典MHC類別I基因呈現(xiàn)低同源性。MICA的表達已經(jīng)在人類上皮和成纖維細胞系中發(fā)現(xiàn)，首先是在上皮細胞和成纖維細胞，不同組織分型的腫瘤，胸腺髓質(zhì)，胃腸上皮組織的培養(yǎng)系中發(fā)現(xiàn)的。MICA的表達也在人工培養(yǎng)的人類角質(zhì)化細胞中發(fā)現(xiàn)，但是這種表達不是發(fā)生在細胞表面。而且，活化的CD4和CD8T細胞也被證明表達MICA，盡管低水平的這種NKG2DL是表達在細胞表面。MICA在許多腫瘤上發(fā)現(xiàn)有表達，這表明它的表達是腫瘤惡性轉(zhuǎn)化的結(jié)果。盡管如此，最近的證據(jù)表明MICA和其他NKG2DLS的表達是適應(yīng)遺傳毒性損傷的DNA破壞途徑導(dǎo)致的，這是轉(zhuǎn)化中的關(guān)鍵步驟。雖然抑癌基因P53參與保護對抗惡性轉(zhuǎn)化，P53并不涉及MICA的上調(diào)及隨后NKG2D介導(dǎo)的細胞毒性敏感性的獲得。另外，MICA在活化T細胞的表達表明NKG2DL也能由細胞活化導(dǎo)致。同時，細胞活化和轉(zhuǎn)化是兩個受NFKB調(diào)控的細胞過程。去年的實驗證據(jù)表明MICANKG2D系統(tǒng)參與免疫反應(yīng)的不同方面，但是這種相互作用在腫瘤免疫中尤其重要。NK細胞的抗腫瘤效應(yīng)物機制包含對可疑靶細胞的細胞毒性，IFN的分泌和其他致炎細胞因子。NK細胞介導(dǎo)的細胞毒性機制已經(jīng)在別處進行了綜述。在大多數(shù)實驗中，NK細胞溶解敏感靶細胞分泌細胞毒性顆粒，其中包含粒酶和穿孔素。盡管如此，對于穿孔素，粒酶或者NK細胞缺陷小鼠和人類細胞的研究表明NK細胞也能通過死亡受體介導(dǎo)（TRAIL）的細胞毒性溶解靶細胞。在小鼠體內(nèi)，NK細胞穿孔素介導(dǎo)的細胞毒性，但不是IFN的產(chǎn)生對于體內(nèi)RAE1B表達的腫瘤細胞的排斥和腫瘤轉(zhuǎn)移的建議是置關(guān)重要的，這表明穿孔素粒酶分泌是NKG2D依賴性的，NK細胞介導(dǎo)的抗腫瘤反應(yīng)的主要效應(yīng)物機制。因此，當(dāng)前證據(jù)表明，NKG2D啟動NK細胞介導(dǎo)的細胞毒性機制依賴于顆粒分泌途徑，但關(guān)于NKG2D配對是否也能引起FAS和TRAIL介導(dǎo)的可疑靶細胞的凋亡依然是個疑問。對于受體和效應(yīng)分子的分子解析涉及NK細胞介導(dǎo)的腫瘤細胞破壞，可能促進抑制腫瘤生長和轉(zhuǎn)移的新方法的發(fā)展。3NK3NK細胞的細胞因子刺激及和樹突細胞的相互細胞的細胞因子刺激及和樹突細胞的相互NK細胞的分化和刺激是受巨噬細胞和樹突細胞如IL2，IL12，IL15，IL18，IL21，IL23和IFNA/B分泌的不同細胞因子的控制的。這些致炎細胞因子有差別地促進NK細胞活化標(biāo)記的表達，IFN的分泌和/或啟動NK細胞介導(dǎo)的細胞毒性，促進他們的腫瘤殺傷功能。特別是，樹突細胞通過依賴于可溶性因子和細胞細胞連接的相互作用的建立，在活化NK細胞中發(fā)揮了關(guān)鍵的作用，在小鼠體內(nèi)引出了強烈的抗腫瘤免疫反應(yīng)。盡管一種類似的相互作用也被證明發(fā)生在人類DC和NK細胞之間，但可以觀察到的是不同的樹突細胞亞群促進NK細胞活化，增殖，發(fā)揮細胞毒性的能力也不同。DC刺激NK細胞的能力不僅依賴于IL12，還依賴于其他細胞因子比如IFNA/BANDIL18,ANDCELL–CELL相互作用在人類中，涉及DCNK細胞相互作用的主要的NK細胞受體是NKP30，該受體導(dǎo)致了不成熟DC的殺傷而不是成熟DC。這種差別抵抗的潛在機制并沒有被完全弄清楚，但它可能和成熟DC比非成熟DC表達更高水平的MHCI型分子有關(guān)。而且，一些證據(jù)表明NKP46和NKP44，NKG2D在DC和NK細胞相互作用中有少量參與，盡管其他也可能無法證明NKP46和NKG2D的涉及。NKG2D確實可能涉及這種相互作用，因為一些科研人員報道，MICA在DC的表達上調(diào)導(dǎo)致IL15或者IFN或者微生物組成的成熟。而且，因為DC能被相關(guān)的有害復(fù)合物如TOLL類受體或TLRS促效藥刺激，以及考慮到最近出現(xiàn)的證據(jù)表明甚至連NK細胞也表達功能性TLRS。在DC和NK細

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