1. Cancer Biology & Translation Medicine
肿瘤生物学与转化医学
Cancer Biology & Translation Medicine
陈志南
Zhi-Nan Chen

2. Global Action Against Cancer1
Lung
Global (Year) 7
Esopha-
geal 2
Breast
7.6 million
Deaths
Cancer
10.9 million
New Cases 6
Cervical 3
Colon 5
Liver 4
Gastric
Update Edition 2005

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

4. The third time investigation of death causes:
与排名第一的脑血管病仅有0.13%的差距，属于世界较高水平，而且呈持续增长的趋势，与70年代中期相比，死亡率增加了83.1%，与90年代初期相比，也增加了22.5%。其中食管癌、胃癌、宫颈癌、鼻咽癌死亡率及其构成呈明显下降趋势，宫颈癌下降幅度最大；而与环境、生活方式有关的肺癌、肝癌、结直肠癌、乳腺癌、膀胱癌死亡率及其构成呈明显上升趋势，以肺癌和乳腺癌上升幅度最大，过去30年分别上升了46.5%和96%]。原发性肝癌（primary liver cancer）所致的死亡率在世界范围内居于第三位，而在我国一直高居首位，尽管2008年我国死亡原因调查显示，肺癌已代替肝癌成为我国首位恶性肿瘤死亡原因（占全部恶性肿瘤死亡的22.7%），但肝癌的死亡率依然呈上升趋势。另据WHO估计，到2030年，我国因恶性肿瘤所致死亡率将由2005年的20.2%上升至23.6%[57]。可见，不管是在世界范围内，还是在我国，恶性肿瘤依然是威胁人类健康和生命的重大疾病，对其发病机制、早期诊断方法及有效治疗措施的研究仍是全球生物医学研究领域的重中之重。
The third time investigation of death causes:
cancer ranks second with a mortality rate of 22.32%.
——Ministry of Health, April 2008

5. Multiple Carcinogen Cancer: Three Characteristics Cancer Etiology 增生异常
Cancer Etiology
Inherited susceptibility
Chemical carcinogens
Radiation
Infectious agents
DNA repair system
General health (diet, stress, etc)
Immune system
Cancer Cell: Contributing Factors
Cancer: Three Characteristics
Multiple Carcinogen

6. Multiple Stages Tumor Cell Dysplasia Initiation Development Invasion
Carcinoma
in situ
Cell
Primary cancer
Metastasis
(2nd Cancer)
genomic DNA
transcription
translation
post-transcription
post translation
Tumor
Initiation
Development
Invasion
Metastasis
Multiple Stages

7. Multiple Gene Mutation
Loss of genomic integrity and imbalance of molecules are mechanism for the cancer incidence
Multiple Gene Mutation
EMBO reports 1, 2, , 2000

8. Cancer Initiation & Invasion
Four Mechanisms

9. removing errors, normal variants
Cancer Genome Atlas
Mining the cancer genome
Sequencing: 13,023 genes
removing errors, normal variants
Breast cancer 11 Samples
Colon cancer 11 Samples
Cancer Molecular
Balance & Mutation
1149 mutation genes
(Individual tumors: average 90)
(Significant frequency: 189 genes)
(Significant frequency: average 11 per tumor)
but that only a subset of these contribute to the neoplastic process. Using stringent criteria to delineate this subset,
, vast majority unknown and predicted to affect a wide range of cellular functions, including transcription, adhesion, and invasion
provide new targets for diagnostic and therapeutic intervention, and open fertile avenues for basic research in tumor biology
Tobias Sjoblom, et al. Science 314: , 2006

10. Cancer Genome Atlas
Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution
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
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.
but that only a subset of these contribute to the neoplastic process. Using stringent criteria to delineate this subset,
, vast majority unknown and predicted to affect a wide range of cellular functions, including transcription, adhesion, and invasion
provide new targets for diagnostic and therapeutic intervention, and open fertile avenues for basic research in tumor biology
Sohrab P. Shah, et al. Nature 461: , 2009

11. Invasion & Metastasis — Main Death Causes
Travel
Intravasation
Primary tumor
(Cell escape)
Invasion
Invasion & Metastasis
— Main Death Causes
Extravasation
Transport
Growth
(2nd tumor)
Migration

12. Mesenchymal cell-like movement
Adhesion Movement
A little long cell
Need protease
Mesenchymal cell-like movement
Form of pseudopodium
Rho/ROCK signal
A little circle cell
A little rely on
protease
Amoeba-like movement
Myosin strong
Contraction
Rac/WAVE2 signal
Cell Oct 31; 135 (3):

13. Control of cell cycle G1→S→G2→M G1: DNA pre-synthesis S: DNA synthesis
G2: DNA post- synthesis
M: Cell division
GO: Oncogenes
STOP: Tumor superessor 13

14. Matrix Degradation —— MMPs
Structural base of tumor invasion & metastasis
Transformed epithelial cells
Epithelial lining cells
Tumor fb
MMP-1, 2, 3, 11, 14
Tissue
Martrix
Tumor fb
Transformed epithelial cells
MMP-7, 13 (9)
Epithelial cells of
tumor angiogenesis
MMP-1, 2, 14

15. Angiogenesis Tumor>2-3mm: Need vessels
Key Molecular: MMPs, VEGF, bFGF, PDGF
Tumor vessels density is a marker for early diagnosis and prognosis
Tumor capillary basement membrane is often flawed. It is of importance to tumor metastasis
肿瘤新生毛细血管基底膜往往存在缺陷，对肿瘤转移的发生具有重要意义
Nature Rev Cancer, 4, 2004

16. The Chain of Inflammation & Cancer
Cancer: Wounds that fail to heal
The Chain of Inflammation & Cancer
Tumor Development
Nature, 420, 2002

17. Strong association: inflammation and cancer
Bacterial
H pylori
幽门螺杆菌
Virus
EB, HCV
Parasite
flukes, schistosomes
吸虫，血吸虫
Chemial irritis
PMA 佛波酯
Nondigestible Particles
asbestos, silica
石棉纤维，矽
Cancer
Chronic inflammation

18. Oxidized DNA nucleosides
Oxidative Stress氧化应激
Chronic inflammation
ROS
活性氧
RNS
活性氮
Oxidized DNA nucleosides
氧化脱氧核苷酸
Peroxynitrite
过氧亚硝基
Aldehydes醛
DNA mutation
DNA damage
P53、Rb
DNA repair

19. Inflammatory cytokines & Oncogenes Tumor inflammation environment
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
EGFR
CXCL8
proto-oncogene Tpl2
NF-kB
OncomiRs, miR-155
Inflammatory mediators in macrophages and in monocytes
Tumor inflammation environment
Cancer Letters, 267, 2008

20. Signal Transduction Cancer cell Blood vessel Cytokines Chemokines
Macrophage
CypA
CD147
Hypoxia
ROS
CypA
Erk1/2
PI3K
P38
HIF
Proliferation
Anti-apoptosis
Angiogenesis
Reported
Cancer cell
Our study
Not confirmed

21. The Seven Hallmarks of Cancer and Their Links to Tumor Metabolism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
Cancer Cell. 13: , 2008

22. Anaerobic glycolysis Intratumoral hypoxia and metabolic symbiosis
or Aerobic stromal cell
J Clin Invest. 118 (12): , 2008

23. 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. Cancer Biomarker -- A Systems Approach 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
Leland H. Hartwell, et al. Nat Biotech, 24 (8), 2006

25. How Identified Cancer Biomarker?
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

26. System Biology Approaches “-omic” Technologies
(Preclinical or Clinical Utilization)
MALDI-MS/MS
2D Gels- MS
NMR
GC-MS
LC-MS
FT-IR
Microarray
SAGE
Amplichip Cyp 450 Test
Global SNP Arrays
Trends Biotechnol. 23 (11), , 2005

27. 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. 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

29. 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
Cancer Biomarker and Types of Cancer: statistically significant association between a particular cancer and the associated cancer marker (s)

30. 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. Antibody 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
CA 27-29
B27.29
breast cancer
MCA
b-12
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
CA 50
C50
pancreatic cancer, rectal cancer,
CA 72-4
B27.3, cc49
gastric carcinoma, pancreatic cancer,
CA 242
C242
pancreatic cancer
Her-2/neu
Herceptin
HAb18G/CD147
HAb18
hepatocellular carcinoma, ect

32. 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. 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.
Nature, 428, , 2004.

34. 转化医学与公众健康

35. 转化医学概念 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”

36. 转化医学发展现状 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

37. 中国的转化医学 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%

38. 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. Personalized Prevention & Early Detection
Lifestyle changes
Screening
Chemoprevention
Prophylactic Surgery
Average Moderate High Very High
RISK

40. 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. Personalized Medicine – 个体化治疗
Herceptin, the first marketed personalized medicine, was approved using a coordinated drug/diagnostic approval process that will become more common.

42. HAb18G/CD147 & HAb18, 6H8, 5A12 Antibodies
Our Study
Molecular Docking
HAb18G & Its Antibodies
HAb18G/CD147 I Set
经过上述抗原抗体分子对接，证明三个抗体结合表位是在该分子胞外段的不同部位
HAb18G/CD147 & HAb18, 6H8, 5A12 Antibodies

43. Crystal Structure of HAb18G/CD147
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. Our Study
Tissue Atlas - HAb18G/CD147
HAb18G/CD147

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

46. Our Study Tissue Atlas - HAb18G/CD147 66.45 Fetal Normal Cancer Case
Lung
Liver
Fetal
Normal
Cancer
Case
Positive
Positive Rate
(%) P
Fetal 67 1
1.49
<0.0001
Normal
196 16
8.16
Cancer
1565
1040
66.45
Shao-Hui Hu, Zhi-Nan Chen, et al. Proteomics, 7 (13), 2007

47. 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
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
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
6.07%
平 均 值
78.75%
91.73%
Yu Li, Zhi-Nan Chen, et al. Histopathology, 2009

48. Iodine (131I) Metuximab Injection
Our Study
Iodine (131I) Metuximab Injection
(LICARTINTM)
Panel A, a defect in the upper region of the right lobe of the liver (arrow) in 99mTc-sodium phytate-colloid scan.
Panel B, the hot region of HCC (arrow) in SPECT 7 days after LICARTIN treatment.
Panel C, the CT scans of one patient (PR ).
Panel D, the CT scans of one patient (CR ).
Cancer Biol Ther 5 (7), 2006

49. Iodine (131I) Metuximab Injection
Our Study
Iodine (131I) Metuximab Injection
(LICARTINTM)
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=0.0174
P=0.0289
P=0.0016
Control group
Treatment group
60 cases HCC (III, IV stage)
87.82%
Then the anti-metastasis and recurrence effect of LICARTIN was determined in the post-orthotopic liver transplantation (OLT) HCC patients. Our initial results showed that LICARTIN significantly decreased recurrence rate and increased survival rate of HCC patients, compared with untreated control group. So LICARTIN is a promising new anti-metastasis and recurrence agent for treating HCC.
Hepatology, 45 (2): , 2007

50. Iodine (131I) Metuximab Injection
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
Then the anti-metastasis and recurrence effect of LICARTIN was determined in the post-orthotopic liver transplantation (OLT) HCC patients. Our initial results showed that LICARTIN significantly decreased recurrence rate and increased survival rate of HCC patients, compared with untreated control group. So LICARTIN is a promising new anti-metastasis and recurrence agent for treating HCC.

51. 千里之行，始于足下