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1、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,A
2、ctivated by cAMP-dependent phosphorylation,Adipocyte,Triacylglycerol transport,Hepatocyte (Liver cell),ActivationInhibitionUnder long-term regulation,Free fatty acids,Triacylglycerols,Potential targets for cancer therapy found within metabolic pathways involved in glucose metabolism.,Hamanaka R B ,
3、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
4、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 a
5、cids, 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 sup
6、pressor 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
7、 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-
8、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 rece
9、ptor tyrosine kinases.,Mitochondrial 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
10、many years until recent studies elucidated the link 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 stabi
11、lization. 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
12、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
13、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 me
14、tabolism,Building cells with glucose and glutamine,Targeting the Warburg phenomenon for cancer therapy,Reduction of glucose entry into the cellInhibition of glycolysisInhibition of pentose phophate pathwayPromotion of oxidative phosphorylationInhibition of HIF-1,Abbreviations: 2-DG, 2-deoxyglucose;
15、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.,
