肿瘤与代谢PPT课件.pptx

肿瘤与代谢 1 Citricacidcycle Citrate Ketonebodies Acetyl CoA FattyAcyl CoA Ketonebodies FattyAcyl CoA FattyAcid FattyAcidalbumincomplex Fattyacidbiosynthesis Fattyacidoxidatioin FattyAcidTransport FatStorage Fattyacidreleasefromadipocytesintobloodstream ActivatedbycAMP dependentphosphorylation Adipocyte Triacylglyceroltransport Hepatocyte Livercell ActivationInhibitionUnderlong termregulation Freefattyacids Triacylglycerols 2 3 Potentialtargetsforcancertherapyfoundwithinmetabolicpathwaysinvolvedinglucosemetabolism HamanakaRB ChandelNSJExpMed2012 209 211 215 2012HamanakaandChandel 4 突变 Mutation 5 瓦尔堡 Warburg 假说 德国生理学家Otto Warburg 1924年提出 癌症的产生是由于细胞糖无氧酵解增强加上氧消耗量降低造成的 也称为瓦尔堡 Warburg 效应 结果 癌细胞生长很快 过快的生长使得细胞经常处于一种缺氧状态 于是癌细胞就关闭了需要线粒体的有氧氧化 能量则是通过葡萄糖的无氧酵解提供的 6 Warburg效应 Warburg假说或是Warburg效应是说当线粒体功能受损后 细胞则通过增强无氧酵解来提供能量 葡萄糖代谢至丙酮酸 pyruvate 后不再通过线粒体的三羧酸循环进行有氧氧化 而是通过乳酸脱氢酶 LDH 转变成乳酸排出细胞 Warburg认为这个代谢的转变是引起癌症的原因 因此获得了诺贝尔奖 这个假说有着无休止的争论 焦点是这个代谢转变是癌症产生的原因还是癌细胞代谢改变的结果 7 糖酵解的意义 Inadditiontogeneratingenergy glycolysisprovidesthekeycarbonprecursorsneededforthesynthesisofnucleicacids phospholipids fattyacids cholesterolandporphyrins 8 PET原理 18FDGPET是应用18F正电子标记的脱氧葡萄糖 在己糖激酶的作用下 形成的FDG 6磷酸 不参与正常葡萄糖代谢 而在高糖酵解的肿瘤部位有较多的放射性浓集的原理来进行的 肿瘤的恶性程度越高 聚集量越高 因此18FDGPET显像不但用于肿瘤诊断 还可用于良恶性疾病的鉴别诊断 9 Warburgeffect 10 Warburgeffect tumormicroenvironmentandstabilizationofHIF Oncogeneactivationandlossoftumorsuppressorgenes mitochondrialdysfunctionincancercells nuclearDNAmutations epigeneticchanges miRNA glutaminemetabolism post translationalmodifications 11 TumormicroenvironmentandstabilizationofHIF Astumorcellsproliferate theyoutgrowthelocalbloodsupply resultinginhypoxia Asthecancercellsactivateaerobicglycolysis glucoseismetabolizedtolactate TumorcellsareresistanttolowpH Hypoxiaisfoundtobeassociatedwithtumorprogression metastasisandresistancetotherapy 12 Microenvironment 13 Cancercellsareknowntoadapttothehypoxicconditionviathehypoxia induciblefactor1 HIF 1 HIF 1isaheterodimerictranscriptionfactor 14 Oncogenesandtumorsuppressorgenes OneofthemostcommonlyalteredsignalingpathwaysincancercellsisPI3Kpathway whichisactivatedbymutationsinPI3Kcomponentortumorsuppressorgenesorbysignalingfromthereceptortyrosinekinases 15 16 Mitochondrialdysfunction Cancercellspredominantlyproduceenergyfromglycolysiswithaconcomitantsuppressionofmitochondrialmetabolicactivities TheexactmechanismunderlyingmitochondrialimpairmentandanincreasedrateofglycolysisintumorsremainedelusiveformanyyearsuntilrecentstudieselucidatedthelinkbetweenmitochondriaandWarburgphenomenon 17 18 RedoxalterationsinducedbyTCAcycledefects RedoxalterationsinducedbymutationsinSDH FH andIDHareshown LossoffunctionofSDHincreasesROSlevelsleadingtoDNAmutationsandHIF 1 stabilization IDH1andmutationsdecreaseGSHandNADPHlevels PDH脯氨酰羟化酶 19 NuclearDNAmutations SDHandFHaretwoimportantmitochondrialenzymesencodedbynucleargenesandareinvolvedinTCAcycle BothSDHandFHhavetumorsuppressorfunctions 20 21 关于IDH突变 美国杜克大学医学中心和约翰霍普金斯大学的科学家宣称 他们发现了恶性胶质脑瘤最关键的基因突变 这对恶性胶质脑瘤的诊断和治疗具有重大意义 为癌症研究打开了一扇新窗口 六年来我一直在进行脑部肿瘤的基因研究 但我从未见过像这个研究那么显着的基因突变 YanH etal NEnglJMed 2009 360 8 765 22 IDH突变与胶质瘤 异柠檬酸盐脱氢酶 isocitratedehydrogenase1 IDH 突变是恶性胶质脑瘤最原始的基因突变 即癌变组织中每个癌变的细胞内都发生了这一基因突变 IDH1和IDH2基因突变只出现在恶性胶质瘤中 在正常的组织细胞中则没有 增生的星形细胞阴性 阳性是肿瘤 阴性不是一定是增生的的星形细胞 IDH1或IDH2基因发生突变的病人平均能活31个月 相比之下 肿瘤中这两种基因都没有发生突变的患者平均存活时间为15个月 23 IDH1andIDH2MutationsinHumanGliomas YanH etal NEnglJMed 2009 360 8 765 24 SurvivalofAdultPatientswithMalignantGliomaswithorwithoutIDHGeneMutations PutativemechanismsofIDHmutationingliomatumorigenesis miRNA 28 Glutaminemetabolism Buildingcellswithglucoseandglutamine 29 TargetingtheWarburgphenomenonforcancertherapy ReductionofglucoseentryintothecellInhibitionofglycolysisInhibitionofpentosephophatepathwayPromotionofoxidativephosphorylationInhibitionofHIF 1 30 31 Abbreviations 2 DG 2 deoxyglucose LND lonidamine 3 BrPA 3 bromopyruvate 3 PO 3 3 pyridinyl l 4 pyridinyl 2 propen l one 6 AN 6 aminonicotinamide DCA dichloroacetate GA geldanamycin 2ME2 2 m