《肺癌的研究現(xiàn)狀分析》3700字

肺癌的研究現(xiàn)狀分析綜述1.1肺癌治療現(xiàn)狀肺癌是全世界最常見的癌癥之一，且是癌癥死亡的主要原因ADDINEN.CITEADDINEN.CITE.DATA[\o"Hirsch,2017#317"1]。大約四分之一的癌癥死亡是由肺癌引起的ADDINEN.CITEADDINEN.CITE.DATA[\o"Islami,2018#129"2]，肺癌的5年生存率僅為21%ADDINEN.CITE<EndNote><Cite><Author>Siegel</Author><Year>2021</Year><RecNum>130</RecNum><DisplayText><styleface="superscript">[3]</style></DisplayText><record><rec-number>130</rec-number><foreign-keys><keyapp="EN"db-id="fefzva2arafxvjeezt3vr2rhx22ervre0wt2"timestamp="1618044807">130</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Siegel,R.L.</author><author>Miller,K.D.</author><author>Fuchs,H.E.</author><author>Jemal,A.</author></authors></contributors><auth-address>SurveillanceandHealthServicesResearch,AmericanCancerSociety,Atlanta,Georgia.</auth-address><titles><title>CancerStatistics,2021</title><secondary-title>CACancerJClin</secondary-title></titles><periodical><full-title>CACancerJClin</full-title></periodical><pages>7-33</pages><volume>71</volume><number>1</number><edition>2021/01/13</edition><keywords><keyword>cancercases</keyword><keyword>cancerstatistics</keyword><keyword>deathrates</keyword><keyword>incidence</keyword><keyword>mortality</keyword></keywords><dates><year>2021</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1542-4863(Electronic) 0007-9235(Linking)</isbn><accession-num>33433946</accession-num><urls><related-urls><url>/pubmed/33433946</url></related-urls></urls><electronic-resource-num>10.3322/caac.21654</electronic-resource-num></record></Cite></EndNote>[\o"Siegel,2021#130"3]。肺癌從組織學(xué)的角度分為非小細(xì)胞肺癌（non-smallcelllungcancer，NSCLC）和小細(xì)胞肺癌（SCLC），其中85%的肺癌屬于NSCLC。NSCLC與SCLC相比，范圍更廣，病因也更加復(fù)雜ADDINEN.CITE<EndNote><Cite><Author>Herbst</Author><Year>2018</Year><RecNum>126</RecNum><DisplayText><styleface="superscript">[4]</style></DisplayText><record><rec-number>126</rec-number><foreign-keys><keyapp="EN"db-id="fefzva2arafxvjeezt3vr2rhx22ervre0wt2"timestamp="1617999207">126</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Herbst,R.S.</author><author>Morgensztern,D.</author><author>Boshoff,C.</author></authors></contributors><auth-address>YaleCancerCenter,YaleSchoolofMedicine,NewHaven,Connecticut,USA. WashingtonUniversitySchoolofMedicine,StLouis,Missouri,USA. Pfizer,Inc.NewYorkCity,NewYork,USA.</auth-address><titles><title>Thebiologyandmanagementofnon-smallcelllungcancer</title><secondary-title>Nature</secondary-title></titles><periodical><full-title>Nature</full-title></periodical><pages>446-454</pages><volume>553</volume><number>7689</number><edition>2018/01/25</edition><keywords><keyword>Carcinoma,Non-Small-CellLung/genetics/*metabolism/pathology/*therapy</keyword><keyword>ClinicalTrialsasTopic</keyword><keyword>Humans</keyword><keyword>Immunotherapy</keyword><keyword>LungNeoplasms/genetics/*metabolism/pathology/*therapy</keyword><keyword>MolecularTargetedTherapy</keyword><keyword>PrecisionMedicine</keyword><keyword>SurvivalRate</keyword><keyword>TumorMicroenvironment/genetics</keyword></keywords><dates><year>2018</year><pub-dates><date>Jan24</date></pub-dates></dates><isbn>1476-4687(Electronic) 0028-0836(Linking)</isbn><accession-num>29364287</accession-num><urls><related-urls><url>/pubmed/29364287</url></related-urls></urls><electronic-resource-num>10.1038/nature25183</electronic-resource-num></record></Cite></EndNote>[\o"Herbst,2018#126"4]。肺癌主要的治療手段包括手術(shù)、化療、激光消融、放射治療、光動(dòng)力療法（Photodynamictherapy，PDT）和光熱療法（PTT）等ADDINEN.CITEADDINEN.CITE.DATA[\o"Azar,2017#127"5]。因腫瘤內(nèi)異質(zhì)性的存在使得癌癥治療手段趨向個(gè)體化。NSCLC被發(fā)現(xiàn)時(shí)大多已處于晚期，因此放化療等全身療法被廣泛用于肺癌治療。然而，因放化療存在腫瘤選擇性差且易引起高毒副作用等缺點(diǎn)，刺激了其他治療手段的發(fā)展ADDINEN.CITE<EndNote><Cite><Author>Mayekar</Author><Year>2017</Year><RecNum>128</RecNum><DisplayText><styleface="superscript">[6]</style></DisplayText><record><rec-number>128</rec-number><foreign-keys><keyapp="EN"db-id="fefzva2arafxvjeezt3vr2rhx22ervre0wt2"timestamp="1617999291">128</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Mayekar,M.K.</author><author>Bivona,T.G.</author></authors></contributors><auth-address>DepartmentofMedicine,UniversityofCalifornia,SanFrancisco,SanFrancisco,USA. DepartmentofCellularandMolecularPharmacology,UniversityofCalifornia,SanFrancisco,SanFrancisco,USA. HelenDillerFamilyComprehensiveCancerCenter,UniversityofCalifornia,SanFrancisco,SanFrancisco,USA.</auth-address><titles><title>CurrentLandscapeofTargetedTherapyinLungCancer</title><secondary-title>ClinPharmacolTher</secondary-title></titles><periodical><full-title>ClinPharmacolTher</full-title></periodical><pages>757-764</pages><volume>102</volume><number>5</number><edition>2017/08/09</edition><keywords><keyword>AntineoplasticAgents/*administration&dosage/metabolism</keyword><keyword>ClinicalTrialsasTopic/methods</keyword><keyword>ErbBReceptors/antagonists&inhibitors/metabolism</keyword><keyword>Humans</keyword><keyword>LungNeoplasms/*drugtherapy/genetics/metabolism</keyword><keyword>MolecularTargetedTherapy/methods/*trends</keyword><keyword>Mutation/genetics</keyword></keywords><dates><year>2017</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1532-6535(Electronic) 0009-9236(Linking)</isbn><accession-num>28786099</accession-num><urls><related-urls><url>/pubmed/28786099</url></related-urls></urls><electronic-resource-num>10.1002/cpt.810</electronic-resource-num></record></Cite></EndNote>[\o"Mayekar,2017#128"6]。針對早期NSCLC患者的主要推薦治療方式是手術(shù)ADDINEN.CITEADDINEN.CITE.DATA[\o"Besse,2014#166"7]。Meta分析結(jié)果顯示，相比于傳統(tǒng)的開胸肺葉切除，接受胸腔鏡手術(shù)（Video-assistedthoracicsurgery）的NSCLC患者長期生活質(zhì)量明顯提高，且整體并發(fā)癥顯著減少ADDINEN.CITE<EndNote><Cite><Author>Cao</Author><Year>2013</Year><RecNum>180</RecNum><DisplayText><styleface="superscript">[8]</style></DisplayText><record><rec-number>180</rec-number><foreign-keys><keyapp="EN"db-id="fefzva2arafxvjeezt3vr2rhx22ervre0wt2"timestamp="1618472834">180</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Cao,C.</author><author>Manganas,C.</author><author>Ang,S.C.</author><author>Peeceeyen,S.</author><author>Yan,T.D.</author></authors></contributors><auth-address>CollaborativeResearch(CORE)Group,Sydney,Australia.</auth-address><titles><title>Video-assistedthoracicsurgeryversusopenthoracotomyfornon-smallcelllungcancer:ameta-analysisofpropensityscore-matchedpatients</title><secondary-title>InteractCardiovascThoracSurg</secondary-title></titles><periodical><full-title>InteractCardiovascThoracSurg</full-title></periodical><pages>244-9</pages><volume>16</volume><number>3</number><edition>2012/11/22</edition><keywords><keyword>Carcinoma,Non-Small-CellLung/mortality/pathology/*surgery</keyword><keyword>Chi-SquareDistribution</keyword><keyword>Humans</keyword><keyword>LengthofStay</keyword><keyword>LungNeoplasms/mortality/pathology/*surgery</keyword><keyword>OddsRatio</keyword><keyword>PostoperativeComplications/etiology</keyword><keyword>PropensityScore</keyword><keyword>*ThoracicSurgery,Video-Assisted/adverseeffects/mortality</keyword><keyword>*Thoracotomy/adverseeffects/mortality</keyword><keyword>TimeFactors</keyword><keyword>TreatmentOutcome</keyword></keywords><dates><year>2013</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1569-9285(Electronic) 1569-9285(Linking)</isbn><accession-num>23169877</accession-num><urls><related-urls><url>/pubmed/23169877</url></related-urls></urls><custom2>PMC3568798</custom2><electronic-resource-num>10.1093/icvts/ivs472</electronic-resource-num></record></Cite></EndNote>[\o"Cao,2013#180"8]。若臨床Ⅰ階段NSCLC患者拒絕手術(shù)或有手術(shù)禁忌的可以選擇高腫瘤控制率與低毒性的立體定向身體放射治療（Stereotacticbodyradiationtherapy，SBRT）ADDINEN.CITEADDINEN.CITE.DATA[\o"Timmerman,2010#167"9,\o"Shinde,2018#168"10]，SBRT對早期NSCLC的治療效果良好，3年腫瘤控制率能達(dá)到98%。表皮生長因子受體（EGFR）基因的激活突變是在NSCLC患者中占比最高的一種突變，現(xiàn)已有多種針對EGFR突變的分子靶向藥物，如吉非替尼（Gefitinib）、厄洛替尼（Erlotinib）等靶向EGFR的酪氨酸激酶抑制劑（EGFR-TKI），然而幾乎所有使用EGFR-TKI靶向治療后患者都不可避免地產(chǎn)生了獲得性耐藥，使進(jìn)一步治療變得困難，因此耐藥性是靶向治療的一大障礙，導(dǎo)致靶向治療的5年生存率僅約為20%ADDINEN.CITE<EndNote><Cite><Author>Siegel</Author><Year>2021</Year><RecNum>130</RecNum><DisplayText><styleface="superscript">[3]</style></DisplayText><record><rec-number>130</rec-number><foreign-keys><keyapp="EN"db-id="fefzva2arafxvjeezt3vr2rhx22ervre0wt2"timestamp="1618044807">130</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Siegel,R.L.</author><author>Miller,K.D.</author><author>Fuchs,H.E.</author><author>Jemal,A.</author></authors></contributors><auth-address>SurveillanceandHealthServicesResearch,AmericanCancerSociety,Atlanta,Georgia.</auth-address><titles><title>CancerStatistics,2021</title><secondary-title>CACancerJClin</secondary-title></titles><periodical><full-title>CACancerJClin</full-title></periodical><pages>7-33</pages><volume>71</volume><number>1</number><edition>2021/01/13</edition><keywords><keyword>cancercases</keyword><keyword>cancerstatistics</keyword><keyword>deathrates</keyword><keyword>incidence</keyword><keyword>mortality</keyword></keywords><dates><year>2021</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1542-4863(Electronic) 0007-9235(Linking)</isbn><accession-num>33433946</accession-num><urls><related-urls><url>/pubmed/33433946</url></related-urls></urls><electronic-resource-num>10.3322/caac.21654</electronic-resource-num></record></Cite></EndNote>[\o"Siegel,2021#130"3]。靶向治療產(chǎn)生耐藥性的確切機(jī)制非常復(fù)雜且是多因素的ADDINEN.CITEADDINEN.CITE.DATA[\o"Jing,2019#124"11]，不僅包括了各種基因的二次突變（圖1-1），還包括腫瘤微環(huán)境（Tumormicroenvironment，TME）的改變等。靶向治療的獲得性耐藥還可能來源于微小殘留病變（minimalresidualdisease），這是因?yàn)楦鞣N療法雖令癌癥患者緩解了病況，然而它們?nèi)詴?huì)保留著引起復(fù)發(fā)的微小殘留病變，這種情況不僅在EGFR-TKI治療肺癌中出現(xiàn)，還在慢性骨髓性白血病、鼠肉瘤病毒癌基因同源物B1（BRAF）突變的黑色素瘤等中存在ADDINEN.CITEADDINEN.CITE.DATA[\o"Luskin,2018#170"12]。圖1-1第一代和第二代EGFR-TKI獲得性耐藥的已知分子機(jī)制ADDINEN.CITEADDINEN.CITE.DATA[\o"Lim,2019#260"13]。免疫檢查點(diǎn)抑制劑（ICIs）的引入改善了NSCLC治療格局。細(xì)胞程序性死亡-配體1（PD-L1）在各種癌癥包括肺癌中過度表達(dá)，它是一種關(guān)鍵的免疫檢查點(diǎn)，與受體程序性死亡受體1（PD-1）作用可以逃脫T細(xì)胞的免疫反應(yīng)，因此，阻斷PD-L1/PD-1的信號(hào)通路是免疫療法的重要手段ADDINEN.CITEADDINEN.CITE.DATA[\o"Osmani,2018#169"14-16]。納武單抗（Nivolumab），派姆單抗（Pembrolizumab）等ICIs已被美國食品藥品監(jiān)督管理局（FDA）批準(zhǔn)用來治療NSCLCADDINEN.CITEADDINEN.CITE.DATA[\o"Kazandjian,2016#174"17]。除了單劑免疫治療，免疫治療藥物還常與化療藥物聯(lián)合使用ADDINEN.CITEADDINEN.CITE.DATA[\o"Proto,2019#176"18]。1.2肺癌的生物學(xué)特點(diǎn)（1）肺癌的分類肺癌分為NSCLC和SCLC，NSCLC在全部肺癌中約占85%，其中40%是肺腺癌（Lungadenocarcinoma，LUAD），25~30%是肺鱗狀細(xì)胞癌（Lungsquamouscellcarcinoma，LUSC），其余是大細(xì)胞癌（圖1-2）ADDINEN.CITEADDINEN.CITE.DATA[\o"Rami-Porta,2014#177"19-21]。圖1-2肺癌的組織學(xué)分類及NSCLC的亞型ADDINEN.CITE<EndNote><Cite><Author>Schabath</Author><Year>2019</Year><RecNum>261</RecNum><DisplayText><styleface="superscript">[22]</style></DisplayText><record><rec-number>261</rec-number><foreign-keys><keyapp="EN"db-id="fefzva2arafxvjeezt3vr2rhx22ervre0wt2"timestamp="1619185909">261</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Schabath,M.B.</author><author>Cote,M.L.</author></authors></contributors><auth-address>DepartmentofCancerEpidemiology,H.LeeMoffittCancerCenterandResearchInstitute,Tampa,Florida.Matthew.Schabath@M. DepartmentofThoracicOncology,H.LeeMoffittCancerCenterandResearchInstitute,Tampa,Florida. DepartmentofOncology,WayneStateUniversitySchoolofMedicine,Detroit,Michigan. BarbaraAnnKarmanosCancerInstitute,Detroit,Michigan.</auth-address><titles><title>CancerProgressandPriorities:LungCancer</title><secondary-title>CancerEpidemiolBiomarkersPrev</secondary-title></titles><periodical><full-title>CancerEpidemiolBiomarkersPrev</full-title></periodical><pages>1563-1579</pages><volume>28</volume><number>10</number><edition>2019/10/03</edition><keywords><keyword>EarlyDetectionofCancer/methods/mortality</keyword><keyword>Genomics/methods</keyword><keyword>Humans</keyword><keyword>Immunotherapy/methods</keyword><keyword>LungNeoplasms/*diagnosis/epidemiology/mortality/*therapy</keyword><keyword>MolecularTargetedTherapy/methods</keyword><keyword>Prognosis</keyword><keyword>RiskFactors</keyword><keyword>SurvivalRate</keyword><keyword>UnitedStates/epidemiology</keyword></keywords><dates><year>2019</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1538-7755(Electronic) 1055-9965(Linking)</isbn><accession-num>31575553</accession-num><urls><related-urls><url>/pubmed/31575553</url></related-urls></urls><custom2>PMC6777859</custom2><electronic-resource-num>10.1158/1055-9965.EPI-19-0221</electronic-resource-num></record></Cite></EndNote>[\o"Schabath,2019#261"22]。肺癌最常見的病因是吸煙，然而肺癌的組織學(xué)亞型中與吸煙的相關(guān)性有別，其中LUAD是不吸煙肺癌患者中的主要組織學(xué)類型ADDINEN.CITEADDINEN.CITE.DATA[\o"Sun,2007#181"23]，其亞克隆突變分?jǐn)?shù)可能導(dǎo)致患者術(shù)后復(fù)發(fā)，腫瘤內(nèi)異質(zhì)性的增加也帶來更大的腫瘤轉(zhuǎn)移傾向ADDINEN.CITEADDINEN.CITE.DATA[\o"Zhang,2014#182"24]。與LUAD相比，LUSC中的受體酪氨酸激酶的活性突變明顯更少ADDINEN.CITE<EndNote><Cite><Author>Reck</Author><Year>2017</Year><RecNum>185</RecNum><DisplayText><styleface="superscript">[25]</style></DisplayText><record><rec-number>185</rec-number><foreign-keys><keyapp="EN"db-id="fefzva2arafxvjeezt3vr2rhx22ervre0wt2"timestamp="1618488057">185</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Reck,M.</author><author>Rabe,K.F.</author></authors></contributors><auth-address>FromLungenClinicGrosshansdorfandAirwayResearchCenterNorth,Grosshansdorf(M.R.,K.F.R.),theGermanCenterforLungResearch,Giessen(M.R.,K.F.R.),UniversityofLubeck,Lubeck(M.R.),andChristianAlbrechtsUniversityKiel,Kiel(K.F.R.)-allinGermany.</auth-address><titles><title>PrecisionDiagnosisandTreatmentforAdvancedNon-Small-CellLungCancer</title><secondary-title>NEnglJMed</secondary-title></titles><periodical><full-title>NEnglJMed</full-title></periodical><pages>849-861</pages><volume>377</volume><number>9</number><edition>2017/08/31</edition><keywords><keyword>Algorithms</keyword><keyword>AntineoplasticAgents/*therapeuticuse</keyword><keyword>Bronchoscopy/methods</keyword><keyword>Carcinoma,Non-Small-CellLung/*diagnosis/*drugtherapy/genetics/pathology</keyword><keyword>Genes,erbB-1</keyword><keyword>Humans</keyword><keyword>*Immunotherapy</keyword><keyword>LungNeoplasms/*diagnosis/*drugtherapy/genetics/pathology</keyword><keyword>Mutation</keyword><keyword>NeoplasmStaging</keyword><keyword>Ultrasonography</keyword></keywords><dates><year>2017</year><pub-dates><date>Aug31</date></pub-dates></dates><isbn>1533-4406(Electronic) 0028-4793(Linking)</isbn><accession-num>28854088</accession-num><urls><related-urls><url>/pubmed/28854088</url></related-urls></urls><electronic-resource-num>10.1056/NEJMra1703413</electronic-resource-num></record></Cite></EndNote>[\o"Reck,2017#185"25]。（2）基因突變LUAD中最常見的突變基因包括鼠肉瘤病毒癌基因同源物（KRAS）和EGFR，KRAS和EGFR基因突變通常被發(fā)現(xiàn)在腫瘤原始克隆中表達(dá)。腫瘤原始克隆在腫瘤發(fā)生發(fā)展中扮演著重要的角色，它通過積累突變而變得異常以至惡性，雖然腫瘤中存在的干系克隆和旁系克隆導(dǎo)致了腫瘤內(nèi)異質(zhì)性，但原始克隆主導(dǎo)著腫瘤發(fā)展的方向ADDINEN.CITE<EndNote><Cite><Author>Tu</Author><Year>2012</Year><RecNum>268</RecNum><DisplayText><styleface="superscript">[26]</style></DisplayText><record><rec-number>268</rec-number><foreign-keys><keyapp="EN"db-id="fefzva2arafxvjeezt3vr2rhx22ervre0wt2"timestamp="1619251662">268</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>MingTu,Shi</author></authors></contributors><titles><title>OriginofCancer:FounderClones</title><secondary-title>Chemotherapy:OpenAccess</secondary-title></titles><periodical><full-title>Chemotherapy:OpenAccess</full-title></periodical><volume>01</volume><number>05</number><dates><year>2012</year><pub-dates><date>01/01</date></pub-dates></dates><isbn>21677700</isbn><urls></urls><electronic-resource-num>10.4172/2167-7700.1000e115</electronic-resource-num></record></Cite></EndNote>[\o"MingTu,2012#268"26]。KRAS和EGFR在肺癌中的表達(dá)對治療是極具幫助且有吸引力的。但是一般情況下EGFR和KRAS的突變是互相排斥的，當(dāng)這兩者共同存在時(shí)，KRAS突變可能會(huì)對EGFR抑制劑產(chǎn)生耐藥性ADDINEN.CITEADDINEN.CITE.DATA[\o"Pao,2005#183"27]。LUSC中最常見的突變包括腫瘤蛋白P53基因（TP53）和多重腫瘤抑制基因（MTS1），其中TP53存在于90%以上的LUSC中，MTS1存在于70%以上的LUSC中，這兩種抑癌基因的失活對LUSC形成發(fā)展至關(guān)重要ADDINEN.CITEADDINEN.CITE.DATA[\o"Ding,2008#269"28]。吸煙者的基因組具有更高的突變頻率，它們的突變主要是由胞嘧啶到腺嘌呤的轉(zhuǎn)換和非活性的改變，比如KRAS和TP53；不吸煙者通常包含胞嘧啶到胸腺嘧啶的突變以及可操作的驅(qū)動(dòng)基因改變，比如激活EGFR突變，C-ros原癌基因1?受體酪氨酸激酶（ROS1）和間變性淋巴瘤激酶（ALK）易位等ADDINEN.CITE<EndNote><Cite><Author>CancerGenomeAtlasResearch</Author><Year>2014</Year><RecNum>184</RecNum><DisplayText><styleface="superscript">[29]</style></DisplayText><record><rec-number>184</rec-number><foreign-keys><keyapp="EN"db-id="fefzva2arafxvjeezt3vr2rhx22ervre0wt2"timestamp="1618487743">184</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>CancerGenomeAtlasResearch,Network</author></authors></contributors><titles><title>Comprehensivemolecularprofilingoflungadenocarcinoma</title><secondary-title>Nature</secondary-title></titles><periodical><full-title>Nature</full-title></periodical><pages>543-50</pages><volume>511</volume><number>7511</number><edition>2014/08/01</edition><keywords><keyword>Adenocarcinoma/*genetics/*pathology</keyword><keyword>AdenocarcinomaofLung</keyword><keyword>CellCycleProteins/genetics</keyword><keyword>Female</keyword><keyword>GeneDosage</keyword><keyword>GeneExpressionRegulation,Neoplastic</keyword><keyword>*Genomics</keyword><keyword>Humans</keyword><keyword>LungNeoplasms/*genetics/*pathology</keyword><keyword>Male</keyword><keyword>MolecularTyping</keyword><keyword>Mutation/genetics</keyword><keyword>Oncogenes/genetics</keyword><keyword>SexFactors</keyword><keyword>Transcriptome/genetics</keyword></keywords><dates><year>2014</year><pub-dates><date>Jul31</date></pub-dates></dates><isbn>1476-4687(Electronic) 0028-0836(Linking)</isbn><accession-num>25079552</accession-num><urls><related-urls><url>/pubmed/25079552</url></related-urls></urls><custom2>PMC4231481</custom2><electronic-resource-num>10.1038/nature13385</electronic-resource-num></record></Cite></EndNote>[\o"CancerGenomeAtlasResearch,2014#184"29]。基因突變比如抑癌基因絲氨酸/蘇氨酸激酶11（STK11）的失活也會(huì)對TME產(chǎn)生影響，使其向免疫抑制中性粒細(xì)胞的聚集和PD-L1表達(dá)的丟失傾斜ADDINEN.CITEADDINEN.CITE.DATA[\o"Koyama,2016#186"30]。（3）生物標(biāo)志物由細(xì)胞內(nèi)成分、蛋白酶、生長因子和細(xì)胞外基質(zhì)等組成的TME是一個(gè)有機(jī)整體，它的存在也為腫瘤提供了生物標(biāo)志物。相比于正常組織或細(xì)胞，實(shí)體瘤或腫瘤細(xì)胞總是包含許多異常且獨(dú)特的標(biāo)志，比如多種癌癥中的缺氧、肺癌中的EGFR突變等。腫瘤細(xì)胞會(huì)分泌兩種獨(dú)特的抗原，一種為腫瘤相關(guān)抗原（Tumorassociatedantigens，TAA），這些抗原在腫瘤細(xì)胞中過度表達(dá)，但在正常細(xì)胞中也存在，包括CD19、CD44、PRAME、MAGE、ERBB2、p53、L2A5等ADDINEN.CITEADDINEN.CITE.DATA[\o"Barfoed,2000#250"31-37]。擁有這些過表達(dá)抗原的腫瘤對免疫檢查點(diǎn)阻斷（ICB）的反應(yīng)更低。另一組為腫瘤特異性抗原（Tumorspecificantigens），是腫瘤特有的，也是腫瘤細(xì)胞突變積累的結(jié)果ADDINEN.CITEADDINEN.CITE.DATA[\o"Li,2018#257"38]。突變頻率高的腫瘤具有大量新抗原（neoantigens），對ICB反應(yīng)更加敏感ADDINEN.CITE<EndNote><Cite><Author>Yarchoan</Author><Year>2017</Year><RecNum>259</RecNum><DisplayText><styleface="superscript">[39]</style></DisplayText><record><rec-number>259</rec-number><foreign-keys><keyapp="EN"db-id="fefzva2arafxvjeezt3vr2rhx22ervre0wt2"timestamp="1619163967">259</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Yarchoan,M.</author><author>Hopkins,A.</author><author>Jaffee,E.M.</author></authors></contributors><auth-address>SidneyKimmelComprehensiveCancerCenteratJohnsHopkins,Baltimore,MDejaffee@.</auth-address><titles><title>TumorMutationalBurdenandResponseRatetoPD-1Inhibition</title><secondary-title>NEnglJMed</secondary-title><alt-title>TheNewEnglandjournalofmedicine</alt-title></titles><periodical><full-title>NEnglJMed</full-title></periodical><pages>2500-2501</pages><volume>377</volume><number>25</number><edition>2017/12/21</edition><keywords><keyword>AntineoplasticAgents/therapeuticuse</keyword><keyword>B7-H1Antigen/*antagonists&inhibitors</keyword><keyword>Biomarkers,Tumor</keyword><keyword>DNAMutationalAnalysis</keyword><keyword>Humans</keyword><keyword>Models,Genetic</keyword><keyword>*Mutation</keyword><keyword>Neoplasms/drugtherapy/*genetics</keyword><keyword>ProgrammedCellDeath1Receptor/*antagonists&inhibitors</keyword></keywords><dates><year>2017</year><pub-dates><date>Dec21</date></pub-dates></dates><isbn>1533-4406(Electronic) 0028-4793(Linking)</isbn><accession-num>29262275</accession-num><urls><related-urls><url>/pubmed/29262275</url></related-urls></urls><custom2>PMC6549688</custom2><custom6>NIHMS1018553</custom6><electronic-resource-num>10.1056/NEJMc1713444</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[\o"Yarchoan,2017#259"39]。腫瘤細(xì)胞中的過表達(dá)受體為正常和惡性組織的選擇性提供了理想的靶點(diǎn)ADDINEN.CITE<EndNote><Cite><Author>Mattheolabakis</Author><Year>2012</Year><RecNum>264</RecNum><DisplayText><styleface="superscript">[40]</style></DisplayText><record><rec-number>264</rec-number><foreign-keys><keyapp="EN"db-id="fefzva2arafxvjeezt3vr2rhx22ervre0wt2"timestamp="1619231250">264</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Mattheolabakis,G.</author><author>Rigas,B.</author><author>Constantinides,P.P.</author></authors></contributors><auth-address>DivisionofCancerPrevention,DepartmentofMedicine,StonyBrookUniversity,StonyBrook,NY,USA.</auth-address><titles><title>Nanodeliverystrategiesincancerchemotherapy:biologicalrationaleandpharmaceuticalperspectives</title><secondary-title>Nanomedicine(Lond)</secondary-title><alt-title>Nanomedicine(London,England)</alt-title></titles><periodical><full-title>Nanomedicine(Lond)</full-title><abbr-1>Nanomedicine(London,England)</abbr-1></periodical><alt-periodical><full-title>Nanomedicine(Lond)</full-title><abbr-1>Nanomedicine(London,England)</abbr-1></alt-periodical><pages>1577-90</pages><volume>7</volume><number>10</number><edition>2012/11/15</edition><keywords><keyword>AntineoplasticAgents/pharmacokinetics/*therapeuticuse</keyword><keyword>Humans</keyword><keyword>Hydrogen-IonConcentration</keyword><keyword>*Nanostructures</keyword><keyword>TissueDistribution</keyword></keywords><dates><year>2012</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1748-6963(Electronic) 1743-5889(Linking)</isbn><accession-num>23148540</accession-num><urls><related-urls><url>/pubmed/23148540</url></related-urls></urls><electronic-resource-num>10.2217/nnm.12.128</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[\o"Mattheolabakis,2012#264"40],這些癌癥生物標(biāo)志物也是癌癥細(xì)胞篩選、檢測、診斷、預(yù)后、預(yù)測、癌癥發(fā)展和疾病復(fù)發(fā)監(jiān)測所必需的。許多細(xì)胞表面標(biāo)記物，包括CD133、CD24和CD44等，負(fù)責(zé)腫瘤的啟動(dòng)、進(jìn)展、轉(zhuǎn)移和耐藥性的產(chǎn)生ADDINEN.CITE<EndNote><Cite><Author>Nguyen</Author><Year>2012</Year><RecNum>266</RecNum><DisplayText><styleface="superscript">[41]</style></DisplayText><record><rec-number>266</rec-number><foreign-keys><keyapp="EN"db-id="fefzva2arafxvjeezt3vr2rhx22ervre0wt2"timestamp="1619232683">266</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Nguyen,L.V.</author><author>Vanner,R.</author><author>Dirks,P.</author><author>Eaves,C.J.</author></authors></contributors><auth-address>TerryFoxLaboratory,BritishColumbiaCancerAgencyandtheUniversityofBritishColumbia,675West10thAvenue,Vancouver,BritishColumbia,V5Z1L3,Canada.</auth-address><titles><title>Cancerstemcells:anevolvingconcept</title><secondary-title>NatRevCancer</secondary-title><alt-title>Naturereviews.Cancer</alt-title></titles><periodical><full-title>NatRevCancer</full-title></periodical><pages>133-43</pages><volume>12</volume><number>2</number><edition>2012/01/13</edition><keywords><keyword>Animals</keyword><keyword>GenomicInstability</keyword><keyword>Humans</keyword><keyword>Mice</keyword><keyword>NeoplasticStemCells/*cytology</keyword><keyword>StochasticProcesses</keyword><keyword>Transplantation,Heterologous</keyword></keywords><dates><year>2012</year><pub-dates><date>Jan12</date></pub-dates></dates><isbn>1474-1768(Electronic) 1474-175X(Linking)</isbn><accession-num>22237392</accession-num><urls><related-urls><url>/pubmed/22237392</url></related-urls></urls><electronic-resource-num>10.1038/nrc3184</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[\o"Nguyen,2012#266"41]。更深入地剖析肺癌的生物學(xué)特點(diǎn)，可以更有效地制定治療策略。1.3CD44與肺癌分化抗原簇蛋白44（clusterofdifferentiation44，CD44）是一種廣泛表達(dá)的非激酶轉(zhuǎn)膜糖蛋白，也被稱為多功能細(xì)胞表面粘附受體。CD44在細(xì)胞中貫穿細(xì)胞膜，含有細(xì)胞外區(qū)域、膜臨近區(qū)域、跨膜域和細(xì)胞質(zhì)尾ADDINEN.CITE<EndNote><Cite><Author>Idzerda</Author><Year>1989</Year><RecNum>189</RecNum><DisplayText><styleface="superscript">[42]</style></DisplayText><record><rec-number>189</rec-number><foreign-keys><keyapp="EN"db-id="fefzva2arafxvjeezt3vr2rhx22ervre0wt2"timestamp="1618645056">189</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Idzerda,R.L.</author><author>Carter,W.G.</author><author>Nottenburg,C.</author><author>Wayner,E.A.</author><author>Gallatin,W.M.</author><author>StJohn,T.</author></authors></contributors><auth-address>BasicSciencesDivision,FredHutchinsonCancerResearchCenter,Seattle,WA98104.</auth-address><titles><title>IsolationandDNAsequenceofacDNAcloneencodingalymphocyteadhesionreceptorforhighendothelium</title><secondary-title>ProcNatlAcadSciUSA</secondary-title></titles><periodical><full-title>ProcNatlAcadSciUSA</full-title></periodical><pages>4659-63</pages><volume>86</volume><number>12</number><edition>1989/06/01</edition><keywords><keyword>AminoAcidSequence</keyword><keyword>Animals</keyword><keyword>BaseSequence</keyword><keyword>CellLine</keyword><keyword>*Cloning,Molecular</keyword><keyword>DNA/*genetics/isolation&purification</keyword><keyword>Endothelium,Vascular/*physiology</keyword><keyword>Epitopes/analysis</keyword><keyword>Lymphocytes/*physiology</keyword><keyword>MolecularSequenceData</keyword><keyword>Papio</keyword><keyword>ProteinConformation</keyword><keyword>Receptors,Immunologic/*genetics/immunology</keyword><keyword>Receptors,LymphocyteHoming</keyword></keywords><dates><year>1989</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0027-8424(Print) 0027-8424(Linking)</isbn><accession-num>2471974</accession-num><urls><related-urls><url>/pubmed/2471974</url></related-urls></urls><custom2>PMC287330</custom2><electronic-resource-num>10.1073/pnas.86.12.4659</electronic-resource-num></record></Cite></EndNote>[\o"Idzerda,1989#189"42]（圖1-3a）。圖1-3CD44的蛋白質(zhì)和基因結(jié)構(gòu)。a：CD44糖蛋白結(jié)構(gòu)；b：CD44基因結(jié)構(gòu)ADDINEN.CITEADDINEN.CITE.DATA[\o"Chen,2018#262"43]。CD44由人類11號(hào)染色體和小鼠2號(hào)染色體上的一個(gè)基因編碼。在人類中，CD44由19個(gè)外顯子編碼，其中前5個(gè)和后5個(gè)外顯子在所有亞型中都是相同的，由這10個(gè)不變的外顯子編