1、第四军医大学第四军医大学 Fourth Military Medical UniversityFourth Military Medical UniversityGlobal Action Against CancerUpdate Edition 2005Global(Year)7.6 millionDeaths10.9 millionNew Cases5Liver1Lung7Esopha-geal3Colon2Breast4Gastric6CervicalCancer第四军医大学第四军医大学 Fourth Military Medical UniversityFourth Military
2、Medical UniversityDisease Control Division,Ministry of Health of PRC,2008Cancer6Cervical5Colon8Nasopharyn-geal1Lung2Liver7Breast3Gastric4Esopha-gealCity 24.41(2nd)Incidence 2,000,000Mortality 1,500,000CancerCountryside 26.93(1st)Liver CancerMortality/100,000Against Cancer in China第四军医大学第四军医大学 Fourth
3、 Military Medical UniversityFourth Military Medical University第四军医大学第四军医大学 Fourth Military Medical UniversityFourth Military Medical University增生增生 异常异常 Inherited susceptibility Chemical carcinogens Radiation Infectious agents DNA repair system General health(diet,stress,etc)Immune systemCancer Cell
4、:Contributing FactorsCancer EtiologyMultiple CarcinogenCancer:Three Characteristics第四军医大学第四军医大学 Fourth Military Medical UniversityFourth Military Medical UniversityDysplasiaCarcinomain situCellPrimary cancer Metastasis(2nd Cancer)genomic DNAtranscriptiontranslationpost-transcriptionpost translationM
5、ultiple Stages第四军医大学第四军医大学 Fourth Military Medical UniversityFourth Military Medical UniversityEMBO reports 1,2,115-119,2000Multiple Gene Mutation第四军医大学第四军医大学 Fourth Military Medical UniversityFourth Military Medical UniversityCancer Initiation&InvasionFour Mechanisms第四军医大学第四军医大学 Fourth Military Med
6、ical UniversityFourth Military Medical UniversityMining the cancer genomeTobias Sjoblom,et al.Science 314:268-274,2006Cancer Genome AtlasSequencing:13,023 genesremoving errors,normal variantsBreast cancer 11 SamplesColon cancer 11 Samples1149 mutation genes(Individual tumors:average 90)(Significant
7、frequency:189 genes)(Significant frequency:average 11 per tumor)Cancer MolecularBalance&Mutation第四军医大学第四军医大学 Fourth Military Medical UniversityFourth Military Medical UniversitySohrab P.Shah,et al.Nature 461:809-813,2009Mutational evolution in a lobular breast tumour profiled at single nucleotide re
8、solutionRecent advances in next generation sequencing 1,2,3,4 have made it possible to precisely characterize all somatic coding mutations that occur during the development and progression of individual cancers.We found 32 somatic non-synonymous coding mutations present in the metastasis.Five of the
9、 32 mutations(in ABCB11,HAUS3,SLC24A4,SNX4 and PALB2)were prevalent in the DNA of the primary tumour removed at diagnosis 9 years earlier,six(in KIF1C,USP28,MYH8,MORC1,KIAA1468 and RNASEH2A)were present at lower frequencies(113%),19 were not detected in the primary tumour,and two were undetermined.S
10、ohrab P.Shah,Ryan D.Morin,Jaswinder Khattra,Leah Prentice,Trevor Pugh,Angela Burleigh,Allen Delaney,Karen Gelmon,Ryan Guliany,Janine Senz,Christian Steidl,Robert A.Holt,Steven Jones,Mark Sun,Gillian Leung,Richard Moore,Tesa Severson,Greg A.Taylor,Andrew E.Teschendorff,Kane Tse,Gulisa Turashvili,Rich
11、ard Varhol,Ren L.Warren,Peter Watson,Yongjun Zhao,Carlos Caldas,David Huntsman,Martin Hirst,Marco A.Marra&Samuel AparicioCancer Genome Atlas第四军医大学第四军医大学 Fourth Military Medical UniversityFourth Military Medical UniversityTravelIntravasationPrimary tumor (Cell escape)InvasionExtravasationTransportGro
12、wth(2nd tumor)MigrationInvasion&Metastasis Main Death Causes第四军医大学第四军医大学 Fourth Military Medical UniversityFourth Military Medical UniversityMesenchymal cell-like movementAmoeba-like movementA little long cellNeed proteaseForm of pseudopodiumA little rely onproteaseMyosin strongContractionA little c
13、ircle cellRac/WAVE2 signalRho/ROCK signalCell.2008 Oct 31;135(3):510-523Adhesion Movement第四军医大学第四军医大学 Fourth Military Medical UniversityFourth Military Medical UniversityG1SG2MRControl of cell cycleG1:DNA pre-synthesisS:DNA synthesisG2:DNA post-synthesisM:Cell divisionGO:OncogenesSTOP:Tumor superess
14、or第四军医大学第四军医大学 Fourth Military Medical UniversityFourth Military Medical UniversityEpithelial lining cellsTransformed epithelial cellsTumor fbTissueMartrixMatrix Degradation MMPs第四军医大学第四军医大学 Fourth Military Medical UniversityFourth Military Medical Universityo Tumor2-3mm:Need vesselso Key Molecular:
15、MMPs,VEGF,bFGF,PDGFo Tumor vessels density is a marker for early diagnosis and prognosis Nature Rev Cancer,4,2004Angiogenesis第四军医大学第四军医大学 Fourth Military Medical UniversityFourth Military Medical UniversityCancer:Wounds that fail to healNature,420,2002The Chain of Inflammation&CancerTumor Developmen
16、t第四军医大学第四军医大学 Fourth Military Medical UniversityFourth Military Medical UniversityCancerChronic inflammationBacterialH pylori幽门螺杆菌幽门螺杆菌VirusEB,HCVParasiteflukes,schistosomes吸虫，血吸虫吸虫，血吸虫Chemial irritisPMA 佛波酯佛波酯Nondigestible Particles asbestos,silica石棉纤维，矽石棉纤维，矽Strong association:inflammation and can
17、cer 第四军医大学第四军医大学 Fourth Military Medical UniversityFourth Military Medical UniversityOxidative Stress氧化应激氧化应激 Aldehydes醛醛 Oxidized DNA nucleosides氧化脱氧核苷酸氧化脱氧核苷酸 DNA mutation Peroxynitrite过氧亚硝基过氧亚硝基ROS活性氧活性氧DNA damage P53、Rb DNA repairDNA repairRNS活性氮活性氮Chronic inflammation第四军医大学第四军医大学 Fourth Militar
18、y Medical UniversityFourth Military Medical UniversityInflammatory cytokines&OncogenesOncogenesInflammatorycytokinesRASIL-1a,IL-1b,IL-6,CXCL8,IL-11MYCIL-1b,CCL2,CCL5,CCL7,CXCL1,CXCL2RET tyrosine kinaseCXCL8,CXCR4,CCL2,MCP-1,GM-CSFEGFRCXCL8proto-oncogene Tpl2NF-kBOncomiRs,miR-155Inflammatory mediator
19、s in macrophages and in monocytesCancer Letters,267,2008Tumor inflammation environment第四军医大学第四军医大学 Fourth Military Medical UniversityFourth Military Medical UniversityROSHIFBlood vesselCancer cellMacrophageCytokinesChemokinesCD147CypAErk1/2P38ProliferationAnti-apoptosisAngiogenesisCypAHypoxiaOur stu
20、dyNot confirmedReportedPI3KSignal TransductionThe Seven Hallmarks of Cancer and Their Links to Tumor MetabolismCancer Cell.13:472-482,2008凋亡凋亡血管血管生成生成无限无限增殖增殖侵袭转移侵袭转移抵抗抵抗抑瘤抑瘤免疫免疫逃避逃避增生增生环路环路Tumor Metabolism第四军医大学第四军医大学 Fourth Military Medical UniversityFourth Military Medical UniversityJ Clin Invest
21、.118(12):3835-3837,2008Intratumoral hypoxia and metabolic symbiosis or Aerobic stromal cell 第四军医大学第四军医大学 Fourth Military Medical UniversityFourth Military Medical UniversityMolecular Mechanisms of Cancer-Specific Metabolic Reprogramming葡萄糖转运葡萄糖转运糖原分解糖原分解乳酸产生乳酸产生氧化磷酸化降低氧化磷酸化降低脂类合成脂类合成氧化抑制氧化抑制第四军医大学第四
22、军医大学 Fourth Military Medical UniversityFourth Military Medical UniversityLeland H.Hartwell,et al.Nat Biotech,24(8),2006p高危评估高危评估 Risk assessmentp早期诊断早期诊断 Noninvasive screening for early-stage diseasep检测定位检测定位 Detection and localizationp预后判断预后判断 Disease stratification and prognosis p治疗反应治疗反应 Response
23、 to therapyp复发监测复发监测 Screening for disease recurrenceCancer Biomarker -A Systems Approach第四军医大学第四军医大学 Fourth Military Medical UniversityFourth Military Medical UniversityBiomarker Discovery:Expression Mapping(Modification mapping)Functional proteomics:interaction of the proteins Epitope mapping(acti
24、ve core)Seperation and identification of mixture sample Ab array,Cell array,Tissue array,Co-IP(pull-down),Biosence,etc.Comparative proteomics 2DE,2DELC-MS Validation peptides sequence of protein MALDI-MS,SELDI-MS,LC-MSMS,ESI-MS(m/z)Analysis of the databasesHow Identified Cancer Biomarker?第四军医大学第四军医大
25、学 Fourth Military Medical UniversityFourth Military Medical UniversitySystem Biology Approaches“-omic”Technologies(Preclinical or Clinical Utilization)Trends Biotechnol.23(11),544-546,2005第四军医大学第四军医大学 Fourth Military Medical UniversityFourth Military Medical UniversityWhat is an Ideal Cancer Biomark
26、er?o Screening a healthy population or a high risk population for the presence of cancero Making a diagnosis of cancer or of a specific type of cancero Determining the prognosis in a patiento Monitoring the course in a patient in remission or while receiving surgery,radiation,chemotherapy,or biother
27、apyo Screening a healthy population or a high risk population for the presence of cancero Making a diagnosis of cancer or of a specific type of cancero Determining the prognosis in a patiento Monitoring the course in a patient in remission or while receiving surgery,radiation,chemotherapy,or biother
28、apy第四军医大学第四军医大学 Fourth Military Medical UniversityFourth Military Medical UniversityApplication of Cancer BiomarkeroIdentification and diagnosisnIndividuals affected with diseasenPeople who may be at risk but do not yet exhibit symptomsoMonitor progress of diseaseoMonitor effects of treatmentoRemiss
29、ionoFollow-upnCancers found in early stage:low morbidity and recurrence ratesnCancers identified in late stage:high recurrence and mortality rates第四军医大学第四军医大学 Fourth Military Medical UniversityFourth Military Medical UniversityCancer Biomarker and Types of Cancer:statistically significant associatio
30、n between a particular cancer and the associated cancer marker(s)AFP=alpha fetoproteinCEA=carcinogenic embryonic antigenCA 15-3=carbohydrate antigen 15-3CA 19-9=carbohydrate antigen 19-9CA 125=carbohydrate antigen 125PSA=free prostate specific antigen+prostate specific antigen-alpha(1)antichymotryps
31、in complexPSAF=free prostate specific antigenPSAC=prostate specific antigen-alpha(1)antichymotrypsin complexPAP=prostatic acid phosphatasehTG=human thyroglobulinhCGb=human chorionic gonadotropin betaFerr=FerritinNSE=neuron specific enolaseIL-2=interleukin 2IL-6=interleukin 6A2M=alpha 2 macroglobulin
32、B2M=beta 2 microglobulin 第四军医大学第四军医大学 Fourth Military Medical UniversityFourth Military Medical UniversityProblems of Cancer BiomarkeroNo cancer biomarker is absolutely specificoNo cancer biomarker test is free of false negativesoNo cancer biomarker test is free of false positivesoNo cancer biomarke
33、r is absolutely specificoNo cancer biomarker test is free of false negativesoNo cancer biomarker test is free of false positives第四军医大学第四军医大学 Fourth Military Medical UniversityFourth Military Medical UniversityAntibody Based Cancer BiomarkersCancer MarkerAntibodyCancerCA125OC 125ovarian cancerCA 15-3
34、DF3,115D8breast cancer,ovarian cancerCA 549BC4E549,BC4N154breast cancer,ovarian cancerCA 27-29B27.29breast cancerMCAb-12breast cancer,ovarian cancerDU-PAN-2Du-PAN-2pancreatic cancer,ovarian cancer,gastrointestinal cancers,lung cancerCA 19-919-9pancreatic cancer,liver cancer,gastrointestinal cancersC
35、A 19-519-5pancreatic cancer,ovarian cancer,gastrointestinal cancersCA 50C50pancreatic cancer,rectal cancer,gastrointestinal cancersCA 72-4B27.3,cc49gastric carcinoma,pancreatic cancer,ovarian cancerCA 242C242gastrointestinal cancerspancreatic cancerHer-2/neuHerceptinbreast cancer第四军医大学第四军医大学 Fourth
36、Military Medical UniversityFourth Military Medical UniversityAntibody Based Cancer BiomarkersHuman genome is 2.91-billion base pairs in length(1990)There are about 25,000 genes exist in the human genome(42%have an unknown function)Approximately 12,000 genes that appear to have the capacity to make s
37、ecreted proteins,all the genes have been determined the entire nucleotide sequences(3141 genes locus on the first chromosome)At May 2006,the first chromosome sequences were completed,at least 1,000 new genes were found.This is the end of 16 years Human Genomic Plan.This has empowered more direct mea
38、ns of target identification,e.g.by expanding protein databases and enabling the mapping of novel cancer-associated genes(Venter et al.2001).第四军医大学第四军医大学 Fourth Military Medical UniversityFourth Military Medical UniversityAntibody Based Cancer BiomarkersComplete genome sequences have provided a pleth
39、ora of potential drug targets.But the hard task of finding their weak spots is just beginning(about 5000 genes can be used as drug target)A challenging new development in the field of drug-target discovery is systems biology,or the recognition that genes,or better the gene products,are part of,and f
40、unction,in large complex networks.Nature,428,225-231,2004.第四军医大学第四军医大学 Fourth Military Medical UniversityFourth Military Medical University第四军医大学第四军医大学 Fourth Military Medical UniversityFourth Military Medical University EA.Zerhouni，NIH路线图计划（路线图计划（NIH Roadmap），），2003 将医学生物学基础研究成果迅速有效的转化为可在临床实际将医学生物学
41、基础研究成果迅速有效的转化为可在临床实际应用的理论、技术、方法和药物应用的理论、技术、方法和药物 基础研究基础研究临床应用，实验室成果临床应用，实验室成果产业化产业化 在实验室到病房（在实验室到病房（Bench to Bedside,B2B）之间架起一条）之间架起一条快速通道快速通道 双向、开放：双向、开放：基础研究提供新疗法、新药物基础研究提供新疗法、新药物 临床研究者对疾病的进程和特性提供反馈意见临床研究者对疾病的进程和特性提供反馈意见“驱动临床研究引擎的激发器驱动临床研究引擎的激发器”第四军医大学第四军医大学 Fourth Military Medical UniversityFourt
42、h Military Medical University 美国已经在美国已经在38所大学建立了转化医学研究中心，在所大学建立了转化医学研究中心，在2012年以年以前将会达到前将会达到60个以上，个以上，NIH每年资助经费达每年资助经费达5亿美元亿美元 英国已投入英国已投入4.5亿英镑用于转化医学研究，并启动世界上首个亿英镑用于转化医学研究，并启动世界上首个转化医学合作研究中心转化医学合作研究中心 欧洲共同体为转化医学计划投入欧洲共同体为转化医学计划投入60亿欧元亿欧元 Science Translational Medicine、Journal of Translational Medici
43、ne和和Translational Research三本国际性专业杂志三本国际性专业杂志第四军医大学第四军医大学 Fourth Military Medical UniversityFourth Military Medical University 转化医学战略研讨会转化医学战略研讨会 2009，中国工程院，中国工程院 2010，中国科学院，中国科学院 转化医学中心转化医学中心 中南大学中南大学 上海交通大学上海交通大学 同济大学同济大学 成果转化率：成果转化率：25%，商品化：，商品化：15%第四军医大学第四军医大学 Fourth Military Medical UniversityFo
44、urth Military Medical UniversityPredictive Medicine 预测医学预测医学Preventive Medicine 预防医学预防医学Personalized Medicine 个体化医学个体化医学Participate Medicine 参与医学参与医学第四军医大学第四军医大学 Fourth Military Medical UniversityFourth Military Medical UniversityPersonalized Prevention&Early Detection Lifestyle changesScreeningChem
45、opreventionProphylactic Surgery Average ModerateHighVery HighRISK第四军医大学第四军医大学 Fourth Military Medical UniversityFourth Military Medical UniversityPersonalized Medicine 个体化治疗个体化治疗 No“one size fits all”drug Most drugs work for 30%to 70%of patients Multiple factors determine drug responses Phamacogenet
46、ics is essential for individualized therapy第四军医大学第四军医大学 Fourth Military Medical UniversityFourth Military Medical UniversityHerceptin,the first marketed personalized medicine,was approved using a coordinated drug/diagnostic approval process that will become more common.Personalized Medicine 个体化治疗个体化
47、治疗第四军医大学第四军医大学 Fourth Military Medical UniversityFourth Military Medical UniversityOur StudyMolecular DockingHAb18G&Its AntibodiesHAb18G/CD147&HAb18,6H8,5A12 AntibodiesHAb18G/CD147 I Set第四军医大学第四军医大学 Fourth Military Medical UniversityFourth Military Medical UniversityOur StudyCrystal Structure of HAb
48、18G/CD147C2IXiao-Ling Yu,Zhi-Nan Chen,J Biol Chem,283(26),2008National patent:200710018514.XPCT patent:PCT/CN2007/003034 PDB ID:3B5HHAb18G/CD147Our StudyTissue Atlas-HAb18G/CD147HAb18G/CD147Our StudyTissue Atlas-HAb18G/CD147第四军医大学第四军医大学 Fourth Military Medical UniversityFourth Military Medical Unive
49、rsityOur StudyTissue Atlas-HAb18G/CD147Shao-Hui Hu,Zhi-Nan Chen,et al.Proteomics,7(13),2007LungLiverFetalNormalCancerCasePositivePositive Rate(%)PFetal6711.490.0001Normal196168.160.0001Cancer15651040第四军医大学第四军医大学 Fourth Military Medical UniversityFourth Military Medical UniversityYu Li,Zhi-Nan Chen,e
50、t al.Histopathology,2009Our StudyTissue Atlas-HAb18G/CD147组织类型组织类型病例数病例数阳性率阳性率灵敏度灵敏度（真阳性率）（真阳性率）特异度特异度（真阴性率）（真阴性率）肝肝 癌癌147例例77.66%77.66%100%良性病变肝组织良性病变肝组织44例例0.00%肺肺 癌癌186例例95.04%95.04%98%良性肺疾病良性肺疾病100例例2.00%乳腺癌乳腺癌200例例65.35%65.35%91%良性乳腺疾病良性乳腺疾病100例例9.00%食管癌食管癌199例例86.22%86.22%97.5%良性食管疾病良性食管疾病80例例
