腫瘤與代謝課件

腫瘤與代謝葉菁第四軍醫(yī)大學(xué)病理學(xué)與病理生理學(xué)教研室2013年1月腫瘤與代謝葉菁Page

1CitricacidcycleCitrateKetonebodiesAcetyl-CoAFattyAcyl-CoAKetonebodiesFattyAcyl-CoAFattyAcidFattyAcidalbumincomplexFattyacidbiosynthesisFattyacidoxidatioinFattyAcidTransportFatStorageFattyacidreleasefromadipocytesintobloodstreamActivatedbycAMP-dependentphosphorylationAdipocyteTriacylglyceroltransportHepatocyte(Livercell)ActivationInhibitionUnderlong-termregulationCitrateSmoothERPalmitateStearateOleatePalmitateMalonyl-CoAAcetyl-CoAFattyAcidSynthaseInhibitedbycAMP-dependentphosphorylationActivatedbyinsulin-dependentdephosphorylationAcetyl-CoAcarboxylaseVerylowdensitylipoprotein(VLDL)TriacylglycerolLipoproteinlipaseFreefattyacidsTriacylglycerols“hormone-sensitive”lipaseCitricacidcycleCitrateKetonePage

2腫瘤與代謝課件Page

3Potentialtargetsforcancertherapyfoundwithinmetabolicpathwaysinvolvedinglucosemetabolism.HamanakaRB,ChandelNSJExpMed2012;209:211-215?2012HamanakaandChandelPotentialtargetsforcancertPage

4突變（Mutation）？突變（Mutation）？Page

5瓦爾堡(Warburg)假說德國生理學(xué)家Otto.Warburg，1924年提出，癌癥的產(chǎn)生是由于細(xì)胞糖無氧酵解增強(qiáng)加上氧消耗量降低造成的，也稱為瓦爾堡(Warburg)效應(yīng)。結(jié)果：癌細(xì)胞生長很快，過快的生長使得細(xì)胞經(jīng)常處于一種缺氧狀態(tài)，于是癌細(xì)胞就關(guān)閉了需要線粒體的有氧氧化，能量則是通過葡萄糖的無氧酵解提供的。

瓦爾堡(Warburg)假說德國生理學(xué)家Otto.WarPage

6Warburg效應(yīng)Warburg假說或是Warburg效應(yīng)是說當(dāng)線粒體功能受損后，細(xì)胞則通過增強(qiáng)無氧酵解來提供能量，葡萄糖代謝至丙酮酸(pyruvate)后不再通過線粒體的三羧酸循環(huán)進(jìn)行有氧氧化，而是通過乳酸脫氫酶（LDH），轉(zhuǎn)變成乳酸排出細(xì)胞。Warburg認(rèn)為這個代謝的轉(zhuǎn)變是引起癌癥的原因，因此獲得了諾貝爾獎。這個假說有著無休止的爭論。焦點(diǎn)是這個代謝轉(zhuǎn)變是癌癥產(chǎn)生的原因還是癌細(xì)胞代謝改變的結(jié)果。

Warburg效應(yīng)Warburg假說或是Warburg效應(yīng)是Page

7糖酵解的意義Inadditiontogeneratingenergy,glycolysisprovidesthekeycarbonprecursorsneededforthesynthesisofnucleicacids,phospholipids,fattyacids,cholesterolandporphyrins.糖酵解的意義InadditiontogeneratinPage

8PET原理18FDGPET是應(yīng)用18F正電子標(biāo)記的脫氧葡萄糖，在己糖激酶的作用下，形成的FDG-6磷酸，不參與正常葡萄糖代謝，而在高糖酵解的腫瘤部位有較多的放射性濃集的原理來進(jìn)行的。腫瘤的惡性程度越高，聚集量越高，因此18FDGPET顯像不但用于腫瘤診斷，還可用于良惡性疾病的鑒別診斷。PET原理18FDGPET是應(yīng)用18F正電子標(biāo)記的脫氧葡萄Page

9WarburgeffectWarburgeffectPage

10WarburgeffecttumormicroenvironmentandstabilizationofHIF；Oncogeneactivationandlossoftumorsuppressorgenes；

mitochondrialdysfunctionincancercells；nuclearDNAmutations；epigeneticchanges；miRNA；glutaminemetabolism；post-translationalmodifications.WarburgeffecttumormicroenvirPage

11TumormicroenvironmentandstabilizationofHIFAstumorcellsproliferate,theyoutgrowthelocalbloodsupply,resultinginhypoxia.Asthecancercellsactivateaerobicglycolysis,glucoseismetabolizedtolactate.TumorcellsareresistanttolowpH.Hypoxiaisfoundtobeassociatedwithtumorprogression,metastasisandresistancetotherapyTumormicroenvironmentandstaPage

12MicroenvironmentMicroenvironmentPage

13Cancercellsareknowntoadapttothehypoxicconditionviathehypoxia-induciblefactor1(HIF-1).HIF-1isaheterodimerictranscriptionfactorCancercellsareknowntoadapPage

14OncogenesandtumorsuppressorgenesOneofthemostcommonlyalteredsignalingpathwaysincancercellsisPI3Kpathway,whichisactivatedbymutationsinPI3Kcomponentortumorsuppressorgenesorbysignalingfromthereceptortyrosinekinases.OncogenesandtumorsuppressorPage

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16MitochondrialdysfunctionCancercellspredominantlyproduceenergyfromglycolysiswithaconcomitantsuppressionofmitochondrialmetabolicactivities.TheexactmechanismunderlyingmitochondrialimpairmentandanincreasedrateofglycolysisintumorsremainedelusiveformanyyearsuntilrecentstudieselucidatedthelinkbetweenmitochondriaandWarburgphenomenon.MitochondrialdysfunctionCancePage

17腫瘤與代謝課件Page

18RedoxalterationsinducedbyTCAcycledefects.RedoxalterationsinducedbymutationsinSDH,FH,andIDHareshown.LossoffunctionofSDHincreasesROSlevelsleadingtoDNAmutationsandHIF-1αstabilization.IDH1andmutationsdecreaseGSHandNADPHlevels.PDH脯氨酰羥化酶RedoxalterationsinducedbyTPage

19NuclearDNAmutationsSDHandFHaretwoimportantmitochondrialenzymesencodedbynucleargenesandareinvolvedinTCAcycle.BothSDHandFHhavetumorsuppressorfunctions.NuclearDNAmutationsSDHandFPage

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21關(guān)于IDH突變美國杜克大學(xué)醫(yī)學(xué)中心和約翰霍普金斯大學(xué)的科學(xué)家宣稱，他們發(fā)現(xiàn)了惡性膠質(zhì)腦瘤最關(guān)鍵的基因突變，這對惡性膠質(zhì)腦瘤的診斷和治療具有重大意義，為癌癥研究打開了一扇新窗口?！傲陙砦乙恢痹谶M(jìn)行腦部腫瘤的基因研究，但我從未見過像這個研究那么顯著的基因突變。”YanH,etal.NEnglJMed.2009;360(8):765關(guān)于IDH突變美國杜克大學(xué)醫(yī)學(xué)中心和約翰霍普金斯大學(xué)的科學(xué)家Page

22IDH突變與膠質(zhì)瘤異檸檬酸鹽脫氫酶（isocitratedehydrogenase1，IDH）突變是惡性膠質(zhì)腦瘤最原始的基因突變，即癌變組織中每個癌變的細(xì)胞內(nèi)都發(fā)生了這一基因突變；IDH1和IDH2基因突變只出現(xiàn)在惡性膠質(zhì)瘤中，在正常的組織細(xì)胞中則沒有，增生的星形細(xì)胞陰性（陽性是腫瘤，陰性不是一定是增生的的星形細(xì)胞）；IDH1或IDH2基因發(fā)生突變的病人平均能活31個月，相比之下，腫瘤中這兩種基因都沒有發(fā)生突變的患者平均存活時間為15個月。IDH突變與膠質(zhì)瘤異檸檬酸鹽脫氫酶（isocitratedPage

23IDH1andIDH2MutationsinHumanGliomasYanH,etal.NEnglJMed.2009;360(8):765IDH1andIDH2MutationsinHumPage

24SurvivalofAdultPatientswithMalignantGliomaswithorwithoutIDHGeneMutationsSurvivalofAdultPatientswit腫瘤與代謝課件PutativemechanismsofIDHmutationingliomatumorigenesis.PutativemechanismsofIDHmutmiRNAmiRNAPage

28GlutaminemetabolismBuildingcellswithglucoseandglutamineGlutaminemetabolismBuildingcPage

29TargetingtheWarburgphenomenonforcancertherapyReductionofglucoseentryintothecellInhibitionofglycolysisInhibitionofpentosephophatepathwayPromotionofoxidativephosphorylationInhibitionofH