Download - 肿瘤生物学与转化医学 Cancer Biology & Translation Medicine 第四军医大学 [email protected] 陈志南 Zhi-Nan Chen
第四军医大学 Fourth Military Medical University
Global Action Against Cancer
Update Edition 2005
Global (Year)
7.6 millionDeaths
10.9 millionNew Cases
5Liver
1Lung
7Esopha-
geal
3Colon
2Breast
4Gastric
6Cervical
Cancer
第四军医大学 Fourth Military Medical University
Disease Control Division,Ministry of Health of PRC, 2008
Cancer
6Cervical
5Colon
8Nasopharyn-
geal
1Lung
2Liver
7Breast
3Gastric
4Esopha-
geal
City 24.41 (2nd)
Incidence 2,000,000Mortality 1,500,000
Cancer
Countryside 26.93 (1st)
Liver CancerMortality/100,000
Against Cancer in China
第四军医大学 Fourth Military Medical University
The third time investigation of death causes: 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 2008Ministry of Health, April 2008
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 EtiologyCancer Etiology
Multiple CarcinogenMultiple Carcinogen
Cancer: Three CharacteristicsCancer: Three Characteristics
第四军医大学 Fourth Military Medical University
TumorTumor
InitiationInitiation
DevelopmentDevelopment
InvasionInvasion
MetastasisMetastasis
TumorTumor
InitiationInitiation
DevelopmentDevelopment
InvasionInvasion
MetastasisMetastasis
Dysplasia
Carcinomain situ
Cell
Primary cancer
Metastasis(2nd Cancer)
genomic DNA
transcription
translation
post-transcription
post translation
Multiple StagesMultiple Stages
第四军医大学 Fourth Military Medical University
EMBO reports 1, 2, 115-119, 2000
Loss of genomic integrity and imbalance of Loss of genomic integrity and imbalance of molecules are mechanism for the cancer incidencemolecules are mechanism for the cancer incidenceLoss of genomic integrity and imbalance of Loss of genomic integrity and imbalance of molecules are mechanism for the cancer incidencemolecules are mechanism for the cancer incidence
Multiple Gene MutationMultiple Gene Mutation
第四军医大学 Fourth Military Medical University
Cancer Initiation & Invasion
Four Mechanisms
Cancer Initiation & Invasion
Four Mechanisms
第四军医大学 Fourth Military Medical University
Mining the cancer genome
Tobias Sjoblom, et al. Science 314: 268-274, 2006
Cancer Genome AtlasCancer Genome Atlas
Sequencing: 13,023 genes
removing errors, normal variants
Breast cancer 11 Samples Colon cancer 11 Samples
1149 mutation genes
(Individual tumors: average 90)
(Significant frequency: 189 genes)
(Significant frequency: average 11 per tumor)
Cancer MolecularBalance & Mutation
第四军医大学 Fourth Military Medical University
Sohrab P. Shah, et al. Nature 461: 809-813, 2009
Mutational evolution in a lobular breast tumour profiled at single nucleotide resolutionMutational 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.
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
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 AtlasCancer Genome Atlas
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
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 onprotease
Myosin strongContraction
A little circle cell
Rac/WAVE2 signal
Rho/ROCK signal
Cell. 2008 Oct 31; 135 (3): 510-523
Adhesion MovementAdhesion Movement
第四军医大学 Fourth Military Medical University
G1→S→G2→MR
Control of cell cycleControl of cell cycle
G1: DNA pre-synthesis
S: DNA synthesis
G2: DNA post- synthesis
M: Cell division
GO: Oncogenes
STOP: Tumor superessor
第四军医大学 Fourth Military Medical University
Epithelial lining cellsTransformed epithelial cells
Tumor fbTissueMartrixTransformed Transformed
epithelial cellsepithelial cellsMMP-7, 13MMP-7, 13 (9)(9)
Epithelial cells ofEpithelial cells oftumor angiogenesistumor angiogenesis
MMP-1, 2, 14MMP-1, 2, 14
Tumor fbTumor fbMMP-MMP-1, 2, 3, 11, 141, 2, 3, 11, 14
Matrix degradation: Matrix degradation: Structural base of tumor invasion & metastasisStructural base of tumor invasion & metastasisMatrix degradation: Matrix degradation: Structural base of tumor invasion & metastasisStructural base of tumor invasion & metastasis
Matrix Degradation —— MMPsMatrix Degradation —— MMPs
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
AngiogenesisAngiogenesis
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
第四军医大学 Fourth Military Medical University
CancerCancerChronic inflammation
Chronic inflammation
BacterialH pylori幽门螺杆菌
BacterialH pylori幽门螺杆菌
VirusEB, HCV
VirusEB, HCV
Parasiteflukes, schistosomes
吸虫,血吸虫
Parasiteflukes, schistosomes
吸虫,血吸虫
Chemial irritisPMA 佛波酯
Chemial irritisPMA 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
Strong association: inflammation and cancer
第四军医大学 Fourth Military Medical University
Oxidative Stress 氧化应激 Oxidative Stress 氧化应激
Aldehydes 醛 Aldehydes 醛 Oxidized DNA nucleosides
氧化脱氧核苷酸
Oxidized DNA nucleosides
氧化脱氧核苷酸
DNA mutation DNA mutation
Peroxynitrite过氧亚硝基
Peroxynitrite过氧亚硝基
ROS活性氧ROS
活性氧
DNA damage DNA damage
P53 、 Rb P53 、 Rb
DNA repair DNA repair
RNS活性氮RNS
活性氮
Chronic inflammationChronic inflammation
第四军医大学 Fourth Military Medical University
Inflammatory cytokines & OncogenesInflammatory cytokines & Oncogenes
OncogenesInflammatory
cytokines
RASIL-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
EGFR CXCL8
proto-oncogene Tpl2 NF-kB
OncomiRs, miR-155
Inflammatory mediators in macrophages and in monocytesCancer Letters, 267, 2008
Tumor inflammation environment
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ROS
HIF
Blood vessel
Cancer cell
Macrophage
Cytokines Chemokines
CD147
CypA
Erk1/2 P38Proliferation
Anti-apoptosis
Angiogenesis
CypA
Hypoxia
Our study
Not confirmed
Reported
PI3K
Signal TransductionSignal Transduction
The Seven Hallmarks of Cancer and Their Links to Tumor Metabolism
Cancer Cell. 13: 472-482, 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
第四军医大学 Fourth Military Medical University
J Clin Invest. 118 (12): 3835-3837, 2008
Intratumoral hypoxia and metabolic symbiosis
or Aerobic stromal cell
Anaerobic glycolysisAnaerobic glycolysisAnaerobic glycolysisAnaerobic glycolysis
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
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 ApproachCancer Biomarker -- A Systems Approach
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?How Identified Cancer Biomarker?
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), 544-546, 2005
Amplichip Cyp 450 TestAmplichip Cyp 450 TestGlobal SNP ArraysGlobal SNP Arrays
MicroarrayMicroarraySAGESAGE
MALDI-MS/MSMALDI-MS/MS2D Gels- MS2D Gels- MS
NMRNMRGC-MSGC-MSLC-MSLC-MSFT-IRFT-IR
第四军医大学 Fourth Military Medical University
What is an Ideal Cancer Biomarker?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
第四军医大学 Fourth Military Medical University
Application of Cancer BiomarkerApplication 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
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
第四军医大学 Fourth Military Medical University
Problems of Cancer BiomarkerProblems 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
第四军医大学 Fourth Military Medical University
Antibody Based Cancer BiomarkersAntibody Based Cancer Biomarkers
Cancer Marker Antibody Cancer
CA125 OC 125 ovarian cancer
CA 15-3 DF3, 115D8 breast cancer, ovarian cancer
CA 549 BC4E549, BC4N154 breast cancer, ovarian cancer
CA 27-29 B27.29 breast cancer
MCA b-12 breast cancer, ovarian cancer
DU-PAN-2 Du-PAN-2 pancreatic cancer, ovarian cancer,gastrointestinal cancers, lung cancer
CA 19-9 19-9 pancreatic cancer, liver cancer,gastrointestinal cancers
CA 19-5 19-5 pancreatic cancer, ovarian cancer,gastrointestinal cancers
CA 50 C50 pancreatic cancer, rectal cancer,gastrointestinal cancers
CA 72-4 B27.3, cc49 gastric carcinoma, pancreatic cancer,ovarian cancer
CA 242 C242 gastrointestinal cancerspancreatic cancer
Her-2/neu Herceptin breast cancer
HAb18G/CD147HAb18G/CD147 HAb18HAb18 hepatocellularhepatocellular carcinoma, ectcarcinoma, ect
第四军医大学 Fourth Military Medical University
Antibody Based Cancer BiomarkersAntibody 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).
第四军医大学 Fourth Military Medical University
Antibody Based Cancer BiomarkersAntibody 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, 225-231, 2004.
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转化医学与公众健康转化医学与公众健康
第四军医大学 Fourth Military Medical University
• 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转化医学概念转化医学概念
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转化医学发展现状转化医学发展现状
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中国的转化医学中国的转化医学
第四军医大学 Fourth Military Medical University
转化医学与转化医学与 4P4P 医学医学转化医学与转化医学与 4P4P 医学医学
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
第四军医大学 Fourth Military Medical University
Personalized Prevention & Early Detection Personalized Prevention & Early Detection
Lifestyle changes
Screening
Chemoprevention
Prophylactic Surgery
Average Moderate High Very High
RISK
第四军医大学 Fourth Military Medical University
Personalized Medicine – 个体化治疗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
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Personalized Medicine – 个体化治疗
第四军医大学 Fourth Military Medical University
Our StudyMolecular Docking
HAb18G & Its Antibodies
HAb18G/CD147 & HAb18, 6H8, 5A12 Antibodies
HAb18G/CD147 I Set
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), 2008National patent: 200710018514.X
PCT patent: PCT/CN2007/003034 PDB ID: 3B5H
HA
b18G
/C
D147
Our Study Tissue Atlas - HAb18G/CD147
HA
b18G
/C
D147
Our Study Tissue Atlas - HAb18G/CD147
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
Fetal Normal Cancer
Case Positive Positive Rate(%) P
Fetal 67 1 1.49 <0.0001
Normal 196 16 8.16 <0.0001
Cancer 1565 1040 66.4566.45
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%77.66% 100%良性病变肝组织 44 例 0.00%
肺 癌 186 例 95.04%95.04% 98%良性肺疾病 100 例 2.00%
乳腺癌 200 例 65.35%65.35% 91%良性乳腺疾病 100 例 9.00%
食管癌 199 例 86.22%86.22% 97.5%良性食管疾病 80 例 2.77%
卵巢癌 101 例 76.23%76.23% 83.67%良性卵巢疾病 52 例 16.33%
胃癌 193例 76.68%76.68% 83.37%良性胃疾病 98例 16.63%
宫颈癌 120例 71.84%71.84% 88.46%良性宫颈疾病 55例 11.54%
直肠癌 195 例 77.68%77.68% 93.93%良性直肠疾病 100 例 6.07%
平 均 值 78.75% 91.73%
第四军医大学 Fourth Military Medical UniversityCancer Biol Ther 5 (7), 2006
Our Study Iodine (131I) Metuximab Injection(LICARTINTM)
第四军医大学 Fourth Military Medical University
Anti-recurrence Treatment after Liver Transplantation
recurrence rate30.42↓ survival rate
20.62↑
AFP44.08%
57.09%
26.67%
82.50%
61.88%
P=0.0174 P=0.0289
P=0.0016
Control groupTreatment group
60 cases HCC (III, IV stage)
87.82%
Our Study Iodine (131I) Metuximab Injection(LICARTINTM)
Hepatology, 45 (2): 269-276, 2007
第四军医大学 Fourth Military Medical University
Our Study Iodine (131I) Metuximab Injection(LICARTINTM)
• 四期临床(截至 21010 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
第四军医大学 Fourth Military Medical University