肿瘤与代谢ppt课件.pptx

肿瘤与代谢,叶 菁,第四,军医大学病理学与病理生理学教研室,2013,年,1,月,Citric acid cycle,Citrate,Ketone bodies,Acetyl-CoA,Fatty Acyl-CoA,Ketone bodies,Fatty Acyl-CoA,Fatty Acid,Fatty Acid albumin complex,Fatty acid biosynthesis,Fatty acid oxidatioin,Fatty Acid Transport,Fat Storage,Fatty acid release from adipocytes into bloodstream,Activated by cAMP-dependent phosphorylation,Adipocyte,Triacylglycerol transport,Hepatocyte(Liver cell,),Activation,Inhibition,Under long-term regulation,Citrate,Smooth ER,Palmitate,Stearate,Oleate,Palmitate,Malonyl-CoA,Acetyl-CoA,Fatty Acid Synthase,Inhibited by cAMP-dependent phosphorylation,Activated by insulin-dependent dephosphorylation,Acetyl-CoA carboxylase,Very low density lipoprotein(VLDL),Triacylglycerol,Lipoprotein lipase,Free fatty acids,Triacylglycerols,“hormone-sensitive”lipase,Potential targets for cancer therapy found within metabolic pathways involved in glucose metabolism.,Hamanaka R B,Chandel N S J Exp Med 2012;209:211-215,2012 Hamanaka and Chandel,突变（,Mutation,）？,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。,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,。,糖酵解的意义,In addition to generating energy,glycolysis,provides the,key carbon,precursors needed for the synthesis of,nucleic acids,phospholipids,fatty,acids,cholesterol and,porphyrins,.,PET,原理,18FDG,PET,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,18FDG PET,显像不但用于肿瘤诊断，还可用于良恶性疾病的鉴别,诊断。,Warburg,effect,Warburg effect,tumor,microenvironment,and stabilization,of,HIF,；,Oncogene,activation and loss of tumor,suppressor genes,；,mitochondrial,dysfunction in cancer,cells,；,nuclear DNA mutations,；,epigenetic changes,；,miRNA,；,glutamine metabolism,；,post-translational,modifications.,Tumor,microenvironment and stabilization of HIF,As tumor cells proliferate,they,outgrow,the local blood supply,resulting,in,hypoxia,.,As the cancer,cells activate aerobic glycolysis,glucose is metabolized,to,lactate,.Tumor,cells are resistant to low pH.,Hypoxia,is found to be associated with tumor,progression,metastasis and,resistance to therapy,Microenvironment,Cancer cells are known to adapt to the hypoxic condition via the hypoxia-inducible factor 1(HIF-1).HIF-1 is a heterodimeric transcription factor,Oncogenes,and tumor suppressor genes,One,of the most commonly altered signaling pathways in,cancer cells,is,PI3K pathway,which is activated by mutations in PI3K,component or,tumor suppressor genes or by signaling from the receptor,tyrosine kinases,.,M,itochondrial,dysfunction,Cancer cells,predominantly,produce energy,from,glycolysis,with a,concomitant suppression of,mitochondrial metabolic,activities,.,The,exact,mechanism underlying mitochondrial impairment,and an increased rate of glycolysis in,tumors remained,elusive for many years until recent studies elucidated,the l,ink,between mitochondria and Warburg phenomenon.,Redox,alterations induced by TCA cycle defects.Redox alterations induced by mutations in SDH,FH,and IDH are shown.Loss of function of SDH increases ROS levels leading to DNA mutations and HIF-1,stabilization.IDH1 and,mutations,decrease GSH and NADPH levels.,PDH,脯,氨酰羟化酶,Nuclear DNA mutations,SDH and FH are two important,mitochondrial enzymes,encoded by nuclear genes and are involved in TCA cycle.,Both SDH,and FH have tumor suppressor,functions.,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。”,Yan H,et al,.,N Engl J Med.2009;360(8):765,IDH,突变与胶质瘤,异柠檬酸,盐脱氢酶（,isocitrate dehydrogenase,1,，,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。,IDH1,and,IDH2,Mutations in Human Gliomas,Yan H,et al,.,N Engl J Med.2009;360(8):765,Survival of Adult Patients with Malignant Gliomas with or without IDH Gene Mutations,Putative mechanisms of IDH mutation in glioma tumorigenesis.,miRNA,Glutamine metabolism,Building cells with glucose and glutamine,Targeting the Warburg phenomenon for cancer therapy,Reduction of glucose entry into the,cell,Inhibition,of,glycolysis,Inhibition of pentose,phophate pathway,Promotion of oxidative,phosphorylation,Inhibition of HIF-1,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-methoxyoestradiol;PX-478,S-2-amino-,3-4-N,N,-bis(2-chloroethyl)aminophenyl propionic acid N-oxide dihydrochloride.,2-DG(2-deoxyglucose),Reduction of glucose entry into the cell,2-deoxyglucose,Px-478,ONCOTHYREON INC.,