肿瘤与代谢课件

,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,2019/3/12 Tuesday,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,Page,#,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,2019/3/12 Tuesday,#,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,Page,#,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,Page,#,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,Page,#,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,Page,#,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,Page,#,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,Page,#,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,Page,#,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,Page,#,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,肿瘤与代谢叶 菁,Page,1,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,Citric acid cycleCitrateKetone,Page,2,肿瘤与代谢课件,Page,3,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,Potential targets for cancer t,Page,4,突变（,Mutation,）？,突变（Mutation）？,Page,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。,瓦尔堡(Warburg)假说德国生理学家Otto.War,Page,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,。,Warburg效应Warburg假说或是Warburg效应是,Page,7,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,.,糖酵解的意义In addition to generatin,Page,8,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。,PET原理18FDG PET是应用18F正电子标记的脱氧葡萄,Page,9,Warburg,effect,Warburg effect,Page,10,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.,Warburg effecttumor microenvir,Page,11,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,Tumor microenvironment and sta,Page,12,Microenvironment,Microenvironment,Page,13,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,Cancer cells are known to adap,Page,14,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,.,Oncogenes and tumor suppressor,Page,15,肿瘤与代谢课件,Page,16,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.,Mitochondrial dysfunctionCance,Page,17,肿瘤与代谢课件,Page,18,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,Redox alterations induced by T,Page,19,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.,Nuclear DNA mutationsSDH and F,Page,20,肿瘤与代谢课件,Page,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。”,Yan H,et al,.,N Engl J Med.2009;360(8):765