細(xì)胞生物學(xué)-復(fù)旦學(xué)妹第14章癌細(xì)胞

第十2014-6- 六、腫 與治2014-6- 癌細(xì)胞的癌的類腫瘤：良性，惡癌 于上皮細(xì)胞，是最主要的類型 (dnoaioa)腫瘤肉瘤 a）：從中胚層組織發(fā)生(lyphoa和白血病(lukia)：由淋巴和血液產(chǎn)Myelomas(骨髓瘤）：一類特殊的白血細(xì)胞癌，漿細(xì)（ B淋巴細(xì)胞）發(fā)生惡變2014-6- 癌細(xì)胞的基細(xì)胞生長(zhǎng) 失去控在沒(méi)有促進(jìn)生長(zhǎng)的信號(hào)下或在有抑制信號(hào)的條件下生長(zhǎng)和繁殖：細(xì)胞核質(zhì)比例增大 速度加快，成為“不死”的永生細(xì)胞失去單層生長(zhǎng)的特點(diǎn)（沒(méi)有接觸抑制）；在體外培養(yǎng)時(shí)貼壁性下降，失和運(yùn)動(dòng)的接觸抑可以自分

2014-6- 癌細(xì)胞的基癌細(xì)胞脫分化(分化失去控制)：癌細(xì)胞在分化程度 非整倍性改避免程序2014-6- 癌細(xì)胞的基2014-6- HallmarksofCell，Volume144,Issue5,646-2014-6- Hallmarksof2014-6-

Cell，Volume144,Issue5,646-8第二節(jié)腫瘤發(fā)展的階原位腫瘤（Carcinomainsitu-（Malignant2014-6- 腫瘤發(fā)生的環(huán)境外因 物（carcinogens）或稱誘變 生 :腫 , 2014-6- 內(nèi)因體液因素（激素慢性炎氧自由基（反應(yīng)性氧中間物ROI或性氧離2014-6- 化 2014-6- Howistumor大多數(shù)癌衍生于單個(gè)的（abnormalCancersresultfromsomaticmutationsCancersresultfromsomaticmutationsandinvolveseveralroundsofmutations2014-6-HowistumorMetastasisMetastasisisthekeyfactorofdangerousEMTvs.

2014-6- CirculatingtumorThecriticalrolecirculatingtumorcellsplayinthemetastaticspreadofcarcinoma.Thesecirculatingtumorcellsreflectmolecularfeaturesofcellswithintumormasses. ysisofCTCsfrombloodsamplescouldbeaninvaluabletoolforearlystagedetectionofcanceraswellasforneoplasticprogressionandrecurrence2014-6- ， 以及結(jié)直腸癌轉(zhuǎn)移特性比NatureReviewsCancer9,274-284Metastasis:fromdisseminationtoorgan-specificcolonization2014-6- 第三節(jié) 腫瘤抑 (tumorsuppressor (oncogene)與原癌 細(xì)胞癌2014-6- 續(xù)活化狀態(tài)，因而促進(jìn)細(xì)胞增殖。如：src,ras,smads,myc等。 編碼的蛋白生長(zhǎng)因生長(zhǎng)因子受信號(hào)轉(zhuǎn)導(dǎo)通路中的分轉(zhuǎn)錄調(diào)控因細(xì)胞周期調(diào)控蛋DNA修復(fù)相關(guān)蛋細(xì)胞凋亡蛋細(xì)胞生物學(xué)（第4版）圖14- 細(xì)胞信號(hào)轉(zhuǎn)導(dǎo)是細(xì)胞增殖與分化過(guò)程的基本調(diào)控方式，而信轉(zhuǎn)導(dǎo)通路中蛋白因子的突變是細(xì) 的主要原因2014-6- 原 突變稱gain-of-function突變GrowthGrowthfactorSignalNucleartranscriptionCellcycleDNArepairApoptoticresistant原 與癌發(fā)2014-6- 一些原 的功2014-6- 細(xì)胞 細(xì)胞癌(cellularoncogene，c-onc)：由細(xì)胞原癌突變而來(lái)； (viral 。大多數(shù)屬于RNA腫瘤 研究發(fā)現(xiàn)，許多中的癌與正常細(xì)胞中的某些DNA序列高度同源，從而推測(cè)癌起源于細(xì)胞的原癌。2014-6- 2014-6- 抑tumor-suppressorgene，該類 抑癌的主要功能為：①偶聯(lián)細(xì)胞周期與DNA負(fù)調(diào)控因子，在細(xì)胞周期的檢驗(yàn)點(diǎn)上起細(xì)胞2014-6- 一些抑 的功2014-6- Rbgene:ThefirsttumorsuppressorgeneinpatientwithretinoblastomaRB是成視網(wǎng)膜細(xì)胞瘤易感RB轉(zhuǎn)錄產(chǎn)物約4.7kb，表達(dá)產(chǎn)物為928個(gè)氨基酸組成的蛋白質(zhì)，分子質(zhì)量約一般認(rèn)為RB蛋白在控制細(xì)胞周期的信息系統(tǒng)中起關(guān)鍵作用，脫磷酸化的RB具有抑制細(xì)胞增殖的活性，是RB的活性形式。2014-6- p53：多種壓2014-6- p53細(xì)胞DNA細(xì)胞生物學(xué)（第4版）圖14- 2014-6- p53突20%到60%； ，如Li-Fraumeni綜合癥(LFS)；同的突變種類突變集中于4－9外顯CpG區(qū)域經(jīng)常發(fā)生突變以GC－TA最2014-6- 第四節(jié)引 改變的方DNADNA大片段改轉(zhuǎn)位倒位重復(fù)/非整倍型變化2014-6- 腫 的其他改擴(kuò) 的雜合性丟失(lossofheterozygosity,LOH)突變的雜合體再失去或失活一個(gè)正常2014-6- 能把原 轉(zhuǎn) 的遺傳變2014-6- Autophagy&Incancer,theroleofautophagyiscontext-Itcanbetumorsuppressivethroughtheeliminationofoncogenicproteinsubstrates,toxicunfoldedproteinsanddamagedorganelles.Alternatively,itcanbetumorpromotinginestablishedcancersthroughautophagy-mediatedintracellularrecyclingthatprovidessubstratesformetabolism.Autophagycouldbeactivatedinmoreadvancedstagesofcancertoguaranteesurvivalofcancercellsunderextremeconditions,suchastherestrictedaccessofcellslocatedintheinnerareasofsolidtumorstonutrients.2014-6- 抑 的突變性質(zhì)是隱性 的突變性質(zhì)是隱性的： 2014-6- 造成突變純合體的2細(xì)胞生物學(xué)（第4版）圖14-

抑癌和一個(gè)突變的等位，一般是正常的。細(xì)胞過(guò)程中，如果出致的錯(cuò)誤分離 2014-6- 腫瘤的發(fā)生 突變逐漸積累的結(jié) 2014-6- 腫瘤的表觀遺傳學(xué)DNA甲基DNA的某些堿基加上額外的甲基(-CH3)，通常在CpG島的C上，大約一半的 個(gè)外顯子區(qū)存在CpG島。 失活有關(guān) 2014-6- 組蛋白乙而使表達(dá)增加。乙酰(HDACs)。這兩種酶的活性影響2014-6- 癌細(xì)胞 表達(dá)譜的異常改甚至同一類型不同的癌中，表達(dá)譜不同，而表達(dá)譜與特定的腫瘤發(fā)生相關(guān)，這些差異表達(dá)的可以作為潛在的靶或藥靶。2014-6- 2014-6- 第五值得關(guān)注的現(xiàn)象：癌組織中各細(xì)胞的能力及對(duì)化學(xué)藥腫瘤干細(xì)胞（cancerstemcell）：指存在于某些腫瘤組織 2014-6- 腫瘤干細(xì)胞與腫瘤的發(fā)生機(jī)制細(xì)胞生物學(xué)（第4版）圖14- 2014-6- 不受控制的干細(xì)胞增殖可 2014-6- Theinitial,strictlyhierarchicallyorganisedcancerstem-cell(CSC)model.CSCsdifferentiateintoprogenitor-likecellsthatgiverisetoterminallydifferentiatedcells,whichhavelostthecapacitytoself-renewanddrivetumourgrowth.

StromalstemcellsimmuneTheemergingdynamicCSCmodel;CSCsdifferentiateandgiverisetothedifferentiatedcellpopulationwithinthetumour.CSCsaredependentonsignalsfromthemicroenvironmentshapedbystromalcells.Dedifferentiationofdifferentiatedtumourcellsoccursundertheinfluenceofthemicroenvironment.2014-6- 第五節(jié) 影像 癌的早蛋白靶標(biāo)檢RNA水平的表達(dá)譜檢遺傳檢2014-6- 腫瘤治 療：手術(shù)切除，化療，放腫瘤治療的新策治 活性的抑血管生成（VEGF,2014-6- InhibitingtheformationofbloodAngiogenesis:Cancercells—growthfactors—endothelialcells—formnewvessels23.7-

2014-6- 2014-6- 2014-6-

Nature415,530- onprognosticPredictonprognosticonprognosis2014-6-onprognosisGeneExpressionSignaturesforBreastApplication:Genethatreflectsbiologicalbehaviorofa295breastcancerpredictingpatientsurvivalcustomized edanddrug2014-6- 開(kāi)發(fā)公AgendiaReceivesU.S.FDAClearanceForMammaPrintCancerDiagnosticAgendiaannouncedthattheU.S.FoodandDrugAdministration(FDA)hasclearedthecompany'sMammaPrint(C)breastcancerdiagnostictest.MammaPrint(R)isageneexpressionprofilingservicetoassesstheriskofrecurrenceinbreastcancerpatients.MammaPrint(R)representsaU.S.regulatory toneasthefirstInVitroDiagnosticMultivariateIndexAssay(IVDMIA)toacquiremarketclearancefromtheFDA,andis ncy'sfirststeptowardstandardizingthesemulti-geneexpressiontests.2014-6- MolecularsignaturesofgeneexpressionintumortissuethatcorrelatewithrecurrenceofbreastcancerhavebeenidentifiedbymethodsbasedontheuseofDNAarrays.However,therequirementforfreshorsnap-frozentissueanduncertaintiesaboutthereproducibilityofsu ethodshavelimitedtheirclinicalapplication.2014-6- 期，預(yù)后等標(biāo)等)：一旦候選 應(yīng)用DNA微陣列技術(shù)和多RT-PCR定量檢測(cè)方法價(jià)值超過(guò)了解剖分期，利用檢測(cè)腫瘤組織中表達(dá)譜將2014-6- oncotypeDX?2014-6- node-negative,ER+breast node-negativeestrogen-receptor–positive的乳 2014-6- Tamoxifenistheantiestrogenagentmostfrequentlyprescribedinwomenwithbothearly-stageandmetastatichormonereceptor-positivebreastcancer.Tamoxifenisthoughttoactprimarilyasacompetitiveinhibitorofestrogenbindingtoestrogenreceptor(ER),andithasnoeffectontumorcellslackingERexpression.Theabsolu evelsofERexpression,aswellasthoseoftheprogesteronereceptor(PR,anindicatorofafunctionalERpathway),arecurrentlythebestpredictorsoftamoxifenresponseintheclinicalsetting.However,25%ofER+/PR+tumors,66%ofER+/PR?cases,and55%ofER?/PR+casesfailtorespond,ordevelopearly totamoxifen,throughmechanismsthatremainlargelyunclear.2014-6- Ahigh-throughput,real-timeRT- ethodwasdevelopedfygeneexpressionwiththeuseofsectionsoffixed,paraffin-embeddedtumortissue.Selected250candidategenesfromthepublishedliterature,genomicdatabases,andexperimentsbasedonDNAarraysperformedonfresh-frozentissue. yzeddatafromthreeindependentclinicalstudiesofbreastcancerinvolvingatotalof447patients,includingthetamoxifen-onlygroupofNSABPtrialB-20,totesttherelationbetweenexpressionofthe250candidategenesandtherecurrenceofbreastcancer.Usedresultsofthethreestudiestoselectapanelof16cancer-relatedgenesand5referencegenesanddesigned basedonthelevelsofexpressionofthesegenes,tocomputearec