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肿瘤生物学与转化医学 Cancer Biology & Translation Medicine 第四军医大学 陈志南 Zhi-Nan Chen.

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Presentation on theme: "肿瘤生物学与转化医学 Cancer Biology & Translation Medicine 第四军医大学 陈志南 Zhi-Nan Chen."— Presentation transcript:

1 肿瘤生物学与转化医学 Cancer Biology & Translation Medicine 第四军医大学 陈志南 Zhi-Nan Chen

2 第四军医大学 Fourth Military Medical University Global Action Against Cancer Update Edition 2005 Global (Year) 7.6 million Deaths 10.9 million New Cases 5 Liver 1 Lung 7 Esopha- geal 3 Colon 2 Breast 4 Gastric 6 Cervical Cancer

3 第四军医大学 Fourth Military Medical University Disease Control Division, Ministry of Health of PRC, 2008 Cancer 6 Cervical 5 Colon 8 Nasopharyn- geal 1 Lung 2 Liver 7 Breast 3 Gastric 4 Esopha- geal City (2 nd ) Incidence 2,000,000 Mortality 1,500,000 Cancer Countryside (1 st ) Liver Cancer Mortality/100,000 Against Cancer in China

4 第四军医大学 Fourth Military Medical University The third time investigation of death causes: cancer ranks second with a mortality rate of 22.32%. cancer ranks second with a mortality rate of 22.32%. ——Ministry of Health, April 2008

5 第四军医大学 Fourth Military Medical University 增生 异常 Inherited susceptibility Chemical carcinogens Radiation Infectious agents DNA repair system General health (diet, stress, etc) Immune system Cancer Cell: Contributing Factors Cancer Etiology Multiple Carcinogen Cancer: Three Characteristics

6 第四军医大学 Fourth Military Medical University TumorInitiationDevelopmentInvasionMetastasisTumorInitiationDevelopmentInvasionMetastasis Dysplasia Carcinoma in situ Cell Primary cancer Metastasis (2nd Cancer) genomic DNA transcription translation post-transcription post translation Multiple Stages

7 第四军医大学 Fourth Military Medical University EMBO reports 1, 2, , 2000 Loss of genomic integrity and imbalance of molecules are mechanism for the cancer incidence Multiple Gene Mutation

8 第四军医大学 Fourth Military Medical University Cancer Initiation & Invasion Four Mechanisms Cancer Initiation & Invasion Four Mechanisms

9 第四军医大学 Fourth Military Medical University Mining the cancer genome Tobias Sjoblom, et al. Science 314: , 2006 Cancer Genome Atlas Sequencing: 13,023 genes removing errors, normal variants Breast cancer 11 SamplesColon cancer 11 Samples 1149 mutation genes (Individual tumors: average 90) (Significant frequency: 189 genes) (Significant frequency: average 11 per tumor) Cancer Molecular Balance & Mutation

10 第四军医大学 Fourth Military Medical University Sohrab P. Shah, et al. Nature 461: , 2009 Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution Recent 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 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 (1–13%), 19 were not detected in the primary tumour, and two were undetermined. Sohrab 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, Richard Varhol, René L. Warren, Peter Watson, Yongjun Zhao, Carlos Caldas, David Huntsman, Martin Hirst, Marco A. Marra & Samuel Aparicio Cancer Genome Atlas

11 第四军医大学 Fourth Military Medical University Travel Intravasation Primary tumor (Cell escape) Invasion Extravasation Transport Growth (2nd tumor) Migration Invasion & Metastasis — Main Death Causes

12 第四军医大学 Fourth Military Medical University Mesenchymal cell-like movement Amoeba-like movement A little long cell Need protease Form of pseudopodium A little rely on protease Myosin strong Contraction A little circle cell Rac/WAVE 2 signal Rho/ROCK signal Cell Oct 31; 135 (3): Adhesion Movement

13 第四军医大学 Fourth Military Medical University G1 → S → G2 → M R Control of cell cycle G1: DNA pre-synthesis S: DNA synthesis G2: DNA post- synthesis M: Cell division GO: Oncogenes STOP: Tumor superessor

14 第四军医大学 Fourth Military Medical University Epithelial lining cells Transformed epithelial cells Tumor fb Tissue Martrix Transformed epithelial cells MMP-7, 13 (9) Epithelial cells of tumor angiogenesis MMP-1, 2, 14 Tumor fb MMP- 1, 2, 3, 11, 14 Matrix degradation: Structural base of tumor invasion & metastasis Structural base of tumor invasion & metastasis Matrix degradation: Structural base of tumor invasion & metastasis Structural base of tumor invasion & metastasis Matrix Degradation —— MMPs

15 第四军医大学 Fourth Military Medical University  Tumor>2-3mm: Need vessels  Key Molecular: MMPs, VEGF, bFGF, PDGF  Tumor vessels density is a marker for early diagnosis and prognosis Nature Rev Cancer, 4, 2004 Angiogenesis

16 第四军医大学 Fourth Military Medical University Cancer: Wounds that fail to heal Nature, 420, 2002 The Chain of Inflammation & Cancer Tumor Development

17 第四军医大学 Fourth Military Medical University Cancer Chronic inflammation Bacterial H pylori 幽门螺杆菌 Bacterial H pylori 幽门螺杆菌 Virus EB, HCV Virus EB, HCV Parasite flukes, schistosomes 吸虫,血吸虫 Parasite flukes, schistosomes 吸虫,血吸虫 Chemial irritis PMA 佛波酯 Chemial irritis PMA 佛波酯 Nondigestible Particles asbestos, silica 石棉纤维,矽 Nondigestible Particles asbestos, silica 石棉纤维,矽 Strong association: inflammation and cancer

18 第四军医大学 Fourth Military Medical University Oxidative Stress 氧化应激 Aldehydes 醛 Oxidized DNA nucleosides 氧化脱氧核苷酸 Oxidized DNA nucleosides 氧化脱氧核苷酸 DNA mutation Peroxynitrite 过氧亚硝基 Peroxynitrite 过氧亚硝基 ROS 活性氧 ROS 活性氧 DNA damage P53 、 Rb DNA repair RNS 活性氮 RNS 活性氮 Chronic inflammation

19 第四军医大学 Fourth Military Medical University Inflammatory cytokines & Oncogenes Oncogenes Inflammatory cytokines RAS IL-1a, IL-1b, IL-6, CXCL8, IL-11 MYC IL-1b, CCL2, CCL5, CCL7, CXCL1, CXCL2 RET tyrosine kinase CXCL8, CXCR4, CCL2, MCP-1, GM-CSF EGFRCXCL8 proto-oncogene Tpl2NF-kB OncomiRs, miR-155 Inflammatory mediators in macrophages and in monocytes Cancer Letters, 267, 2008 Tumor inflammation environment

20 第四军医大学 Fourth Military Medical University ROS HIF Blood vessel Cancer cell Macrophage CytokinesChemokines CD147 CypA Erk1/2P38 Proliferation Anti-apoptosis Angiogenesis CypA Hypoxia Our study Not confirmed Reported PI3K Signal Transduction

21 The Seven Hallmarks of Cancer and Their Links to Tumor Metabolism Cancer Cell. 13: , 2008 凋亡 血管 生成 无限 增殖 侵袭转移 抵抗 抑瘤 免疫 逃避 增生 环路 Tumor Metabolism

22 第四军医大学 Fourth Military Medical University J Clin Invest. 118 (12): , 2008 Intratumoral hypoxia and metabolic symbiosis or Aerobic stromal cell Anaerobic glycolysis

23 第四军医大学 Fourth Military Medical University Molecular Mechanisms of Cancer-Specific Metabolic Reprogramming 葡萄糖转运 糖原分解 乳酸产生 氧化磷酸化降低 脂类合成 氧化抑制

24 第四军医大学 Fourth Military Medical University Leland H. Hartwell, et al. Nat Biotech, 24 (8), 2006  高危评估 Risk assessment  早期诊断 Noninvasive screening for early-stage disease  检测定位 Detection and localization  预后判断 Disease stratification and prognosis  治疗反应 Response to therapy  复发监测 Screening for disease recurrence Cancer Biomarker -- A Systems Approach Cancer Biomarker -- A Systems Approach

25 第四军医大学 Fourth Military Medical University Biomarker Discovery: Expression Mapping (Modification mapping) Functional proteomics: interaction of the proteins Epitope mapping (active core) Biomarker Discovery: Expression Mapping (Modification mapping) Functional proteomics: interaction of the proteins Epitope mapping (active 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 databases 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 databases How Identified Cancer Biomarker?

26 第四军医大学 Fourth Military Medical University System Biology Approaches “-omic” Technologies (Preclinical or Clinical Utilization) System Biology Approaches “-omic” Technologies (Preclinical or Clinical Utilization) Trends Biotechnol. 23 (11), , 2005 Amplichip Cyp 450 Test Global SNP Arrays MicroarraySAGE MALDI-MS/MS 2D Gels- MS NMRGC-MSLC-MSFT-IR

27 第四军医大学 Fourth Military Medical University What is an Ideal Cancer Biomarker?  Screening a healthy population or a high risk population for the presence of cancer  Making a diagnosis of cancer or of a specific type of cancer  Determining the prognosis in a patient  Monitoring the course in a patient in remission or while receiving surgery, radiation, chemotherapy, or biotherapy  Screening a healthy population or a high risk population for the presence of cancer  Making a diagnosis of cancer or of a specific type of cancer  Determining the prognosis in a patient  Monitoring the course in a patient in remission or while receiving surgery, radiation, chemotherapy, or biotherapy

28 第四军医大学 Fourth Military Medical University Application of Cancer Biomarker  Identification and diagnosis Individuals affected with disease People who may be at risk but do not yet exhibit symptoms  Monitor progress of disease  Monitor effects of treatment  Remission  Follow-up Cancers found in early stage: low morbidity and recurrence rates Cancers identified in late stage: high recurrence and mortality rates  Identification and diagnosis Individuals affected with disease People who may be at risk but do not yet exhibit symptoms  Monitor progress of disease  Monitor effects of treatment  Remission  Follow-up Cancers found in early stage: low morbidity and recurrence rates Cancers identified in late stage: high recurrence and mortality rates

29 第四军医大学 Fourth Military Medical University Cancer Biomarker and Types of Cancer: statistically significant association between a particular cancer and the associated cancer marker (s) AFP = alpha fetoprotein CEA = carcinogenic embryonic antigen CA 15-3 = carbohydrate antigen 15-3 CA 19-9 = carbohydrate antigen 19-9 CA 125 = carbohydrate antigen 125 PSA = free prostate specific antigen + prostate specific antigen - alpha(1)antichymotrypsin complex PSAF = free prostate specific antigen PSAC = prostate specific antigen - alpha(1)antichymotrypsin complex PAP = prostatic acid phosphatase hTG = human thyroglobulin hCGb = human chorionic gonadotropin beta Ferr = Ferritin NSE = neuron specific enolase IL-2 = interleukin 2 IL-6 = interleukin 6 A2M = alpha 2 macroglobulin B2M = beta 2 microglobulin

30 第四军医大学 Fourth Military Medical University Problems of Cancer Biomarker  No cancer biomarker is absolutely specific  No cancer biomarker test is free of false negatives  No cancer biomarker test is free of false positives  No cancer biomarker is absolutely specific  No cancer biomarker test is free of false negatives  No cancer biomarker test is free of false positives

31 第四军医大学 Fourth Military Medical University Antibody Based Cancer Biomarkers Cancer MarkerAntibodyCancer CA125OC 125ovarian cancer CA 15-3DF3, 115D8breast cancer, ovarian cancer CA 549BC4E549, BC4N154breast cancer, ovarian cancer CA 27-29B27.29breast cancer MCAb-12breast cancer, ovarian cancer DU-PAN-2Du-PAN-2 pancreatic cancer, ovarian cancer, gastrointestinal cancers, lung cancer CA pancreatic cancer, liver cancer, gastrointestinal cancers CA pancreatic cancer, ovarian cancer, gastrointestinal cancers CA 50C50 pancreatic cancer, rectal cancer, gastrointestinal cancers CA 72-4B27.3, cc49 gastric carcinoma, pancreatic cancer, ovarian cancer CA 242C242 gastrointestinal cancers pancreatic cancer Her-2/neuHerceptinbreast cancer HAb18G/CD147HAb18 hepatocellular carcinoma, ect

32 第四军医大学 Fourth Military Medical University Antibody Based Cancer Biomarkers Human 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 secreted 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 year’s Human Genomic Plan. This has empowered more direct means of target identification, e.g. by expanding protein databases and enabling the mapping of novel cancer-associated genes (Venter et al. 2001).

33 第四军医大学 Fourth Military Medical University Antibody Based Cancer Biomarkers Complete genome sequences have provided a plethora 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 function, in large complex networks. Complete genome sequences have provided a plethora 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 function, in large complex networks. Nature, 428, , 2004.

34 第四军医大学 Fourth Military Medical University 转化医学与公众健康转化医学与公众健康

35 EA. Zerhouni , NIH 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 应用的理论、技术、方法和药物 基础研究 → 临床应用,实验室成果 → 产业化 在实验室到病房( Bench to Bedside, B2B )之间架起一条 快速通道 双向、开放: 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 “ 驱动临床研究引擎的激发器 ” 转化医学概念转化医学概念

36 第四军医大学 Fourth Military Medical University 美国已经在 38 所大学建立了转化医学研究中心,在 2012 年以前 将会达到 60 个以上, NIH 每年资助经费达 5 亿美元 英国已投入 4.5 亿英镑用于转化医学研究,并启动世界上首个转 化医学合作研究中心 欧洲共同体为转化医学计划投入 60 亿欧元 Science Translational Medicine 、 Journal of Translational Medicine 和 Translational Research 三本国际性专业杂志 转化医学发展现状转化医学发展现状

37 第四军医大学 Fourth Military Medical University 转化医学战略研讨会 2009 ,中国工程院 2010 ,中国科学院 转化医学中心 中南大学 上海交通大学 同济大学 成果转化率: 25% ,商品化: <15% 中国的转化医学中国的转化医学

38 第四军医大学 Fourth Military Medical University 转化医学与 4P 医学 Predictive Medicine – 预测医学 Preventive Medicine – 预防医学 Personalized Medicine – 个体化医学 Participate Medicine – 参与医学

39 第四军医大学 Fourth Military Medical University Personalized Prevention & Early Detection Lifestyle changes Screening Chemoprevention Prophylactic Surgery Average ModerateHighVery High RISK

40 第四军医大学 Fourth Military Medical University Personalized Medicine – 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 Phamacogenetics is essential for individualized therapy

41 第四军医大学 Fourth Military Medical University Herceptin, 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

42 第四军医大学 Fourth Military Medical University Our Study Molecular Docking HAb18G & Its Antibodies HAb18G/CD147 & HAb18, 6H8, 5A12 Antibodies HAb18G/CD147 I Set

43 第四军医大学 Fourth Military Medical University Our Study Crystal Structure of HAb18G/CD147 C2 I Xiao-Ling Yu, Zhi-Nan Chen, J Biol Chem, 283 (26), 2008 National patent: X PCT patent: PCT/CN2007/ PDB ID: 3B5H

44 HAb18G/CD147 Our Study Tissue Atlas - HAb18G/CD147

45 HAb18G/CD147 Our Study Tissue Atlas - HAb18G/CD147

46 第四军医大学 Fourth Military Medical University Our Study Tissue Atlas - HAb18G/CD147 Shao-Hui Hu, Zhi-Nan Chen, et al. Proteomics, 7 (13), 2007 Lung Liver FetalNormalCancer CasePositive Positive Rate (%) P Fetal < Normal < Cancer

47 第四军医大学 Fourth Military Medical University Yu Li, Zhi-Nan Chen, et al. Histopathology, 2009 Our Study Tissue Atlas - HAb18G/CD147 组织类型病例数阳性率 灵敏度 (真阳性率) 特异度 (真阴性率) 肝 癌 147 例 77.66% 100% 良性病变肝组织 44 例 0.00% 肺 癌肺 癌 186 例 95.04% 98% 良性肺疾病 100 例 2.00% 乳腺癌 200 例 65.35% 91% 良性乳腺疾病 100 例 9.00% 食管癌 199 例 86.22% 97.5% 良性食管疾病 80 例 2.77% 卵巢癌 101 例 76.23% 83.67% 良性卵巢疾病 52 例 16.33% 胃癌 193 例 76.68% 83.37% 良性胃疾病 98 例 16.63% 宫颈癌 120 例 71.84% 88.46% 良性宫颈疾病 55 例 11.54% 直肠癌 195 例 77.68% 93.93% 良性直肠疾病 100 例 6.07% 平 均 值 78.75%91.73%

48 第四军医大学 Fourth Military Medical University Cancer Biol Ther 5 (7), 2006 Our Study Iodine ( 131 I) Metuximab Injection (LICARTIN TM )

49 第四军医大学 Fourth Military Medical University Anti-recurrence Treatment after Liver Transplantation recurrence rate 30.42↓ survival rate 20.62↑ AFP 44.08% 57.09% 26.67% 82.50% 61.88% P= P= P= Control group Treatment group 60 cases HCC (III, IV stage) 87.82% Our Study Iodine ( 131 I) Metuximab Injection (LICARTIN TM ) Hepatology, 45 (2): , 2007

50 第四军医大学 Fourth Military Medical University Our Study Iodine ( 131 I) Metuximab Injection (LICARTIN TM ) 四期临床(截至 年 4 月累计使用 1500 支) 北京利卡汀治疗基地,原子能研究院 401 医院 上海利卡汀临床研究中心,东方肝胆医院 广州利卡汀治疗基地,广州军区 458 医院 北京佑安医院 解放军总医院 武警总医院 北大肿瘤医院 上海中山医院 上海东方肝胆医院 中山大学肿瘤医院 浙江大学一院、二院 浙江省肿瘤医院 四川大学华西医院 华中附属协和医院 湖南省医院 中南大学湘雅医院 福建医大第一医院 四军大唐都医院 郑州大学一附院 河南省医院 中国医大一附院、二附院 福建医大协和医院

51 第四军医大学 Fourth Military Medical University


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