肿瘤与代谢.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Inhibited bycAMP-dependent phosphorylation Activated by insulin-dependent dephosphorylation “hormone-sensitive” lipaseFatty acid biosynthesisFatty acid oxidatioinHepatocyte (Liver cell)ActivationInhibitionUnder long-term regulationCitrateKetone bodiesAcetyl-CoACitric acid cycleAcetyl-CoA carboxylaseKetone bodiesMalonyl-CoACitrateFatty Acid SynthaseAcetyl-CoAPalmitateFatty Acyl-CoAPalmitateFatty Acyl-CoASmooth ERStearateOleateFatty AcidTriacylglycerol transportTriacylglycerolFatty Acid TransportVery low density lipoprotein (VLDL)Fatty Acid albumin complexFatty acid release from adipocytes into bloodstreamFat StorageLipoprotein lipaseFree fatty acidsActivated by cAMP-dependent phosphorylationTriacylglycerolsAdipocytePotential 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 effectWarburg effecttumor 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 HIFAs tumor cells proliferate, th