Cancer Biology

1
?????????? Cancer Biology Translation Medicine
??? Zhi-Nan Chen
??????znchen_at_fmmu.edu.cn
2
Global Action Against Cancer
1 Lung
Global (Year)
7 Esopha- geal
2 Breast
7.6 million Deaths
10.9 million New Cases
Cancer
3 Colon
6 Cervical
5 Liver
4 Gastric
Update Edition 2005
3
Cancer
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 26.93 (1st)
7 Breast
3 Gastric
City 24.41 (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
cancer ranks second with a mortality rate of
22.32. Ministry of Health, April 2008
5
Cancer Etiology
Cancer Three Characteristics
Multiple Carcinogen
6
Tumor Initiation Development Invasion Metastasis
Multiple Stages
7
Loss of genomic integrity and imbalance of
molecules are mechanism for the cancer incidence
Multiple Gene Mutation
EMBO reports 1, 2, 115-119, 2000
8
Cancer Initiation Invasion Four Mechanisms
9
Cancer Genome Atlas
Mining the cancer genome
Cancer Molecular Balance Mutation
1149 mutation genes (Individual tumors average
90) (Significant frequency 189
genes) (Significant frequency average 11 per
tumor)
Tobias Sjoblom, et al. Science 314 268-274, 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 (113), 19 were not
detected in the primary tumour, and two were
undetermined.
Sohrab P. Shah, et al. Nature 461 809-813, 2009
11
Invasion Metastasis Main Death Causes
12
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. 2008 Oct 31 135 (3) 510-523
13
Control of cell cycle
G1 DNA pre-synthesis S DNA synthesis G2 DNA
post- synthesis M Cell division GO
Oncogenes STOP Tumor superessor
G1?S?G2?M
14
Matrix Degradation MMPs
Matrix degradation Structural base of tumor
invasion metastasis
Epithelial lining cells
Transformed epithelial 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

• Tumorgt2-3mm Need vessels
• Key Molecular MMPs, VEGF, bFGF, PDGF
• Tumor vessels density is a marker for early
  diagnosis and prognosis

Nature Rev Cancer, 4, 2004
16
Cancer Wounds that fail to heal
The Chain of Inflammation Cancer Tumor
Development
Nature, 420, 2002
17
Strong association inflammation and cancer
18
Oxidative Stress????
Chronic inflammation
ROS ???
RNS ???
Oxidized DNA nucleosides ???????
Peroxynitrite ?????
Aldehydes?
DNA damage
DNA mutation
19
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
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
Blood vessel
Cytokines
Chemokines
Macrophage
CypA
CD147
ROS
Hypoxia
CypA
PI3K
Erk1/2
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
Tumor Metabolism
Cancer Cell. 13 472-482, 2008
22
Intratumoral hypoxia and metabolic symbiosis
Anaerobic glycolysis
or Aerobic stromal cell
J Clin Invest. 118 (12) 3835-3837, 2008
23
Molecular Mechanisms of Cancer-Specific Metabolic
Reprogramming
?????
????
????
???????
????
????
24
Cancer Biomarker -- A Systems Approach

• ???? Risk assessment
• ???? Noninvasive screening for early-stage
  disease
• ???? Detection and localization
• ???? Disease stratification and prognosis
• ???? Response to therapy
• ???? 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)

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), 544-546, 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
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 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 cancers pancreatic cancer
Her-2/neu Herceptin breast cancer
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 years Human Genomic Plan.

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, 225-231, 2004.
34
?????????
35
??????

• EA. Zerhouni,NIH?????(NIH Roadmap),2003
• ????????????????????????????????????????
• ?????????,?????????
• ???????(Bench to Bedside, B2B)??????????
• ?????
• ?????????????
• ????????????????????
• ????????????

36
????????

• ?????38??????????????,?2012???????60???,NIH???????
  5???
• ?????4.5???????????,??????????????????
• ??????????????60???
• Science Translational Medicine?Journal of
  Translational Medicine?Translational
  Research?????????

37
???????

• ?????????
• 2009,?????
• 2010,?????
• ??????
• ????
• ??????
• ????
• ?????25,???lt15

38
?????4P??
Predictive Medicine ???? Preventive Medicine
???? Personalized Medicine ????? Participate
Medicine ????
39
Personalized Prevention Early Detection
40
Personalized Medicine ?????

• 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 ?????
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
43
Xiao-Ling Yu, Zhi-Nan Chen, J Biol Chem, 283
(26), 2008 National patent 200710018514.X PCT
patent PCT/CN2007/003034 PDB ID 3B5H
44
(No Transcript)
45
(No Transcript)
46
Case Positive Positive Rate () P
Fetal 67 1 1.49 lt0.0001
Normal 196 16 8.16 lt0.0001
Cancer 1565 1040 66.45
Shao-Hui Hu, Zhi-Nan Chen, et al. Proteomics, 7
(13), 2007
47
???? ??? ??? ??? (????) ??? (????)
? ? 147? 77.66 77.66 100
??????? 44? 0.00 77.66 100
? ? 186? 95.04 95.04 98
????? 100? 2.00 95.04 98
??? 200? 65.35 65.35 91
?????? 100? 9.00 65.35 91
??? 199? 86.22 86.22 97.5
?????? 80? 2.77 86.22 97.5
??? 101? 76.23 76.23 83.67
?????? 52? 16.33 76.23 83.67
?? 193? 76.68 76.68 83.37
????? 98? 16.63 76.68 83.37
??? 120? 71.84 71.84 88.46
?????? 55? 11.54 71.84 88.46
??? 195? 77.68 77.68 93.93
?????? 100? 6.07 77.68 93.93
? ? ? ? ? ? ? ? ? 78.75 91.73
Yu Li, Zhi-Nan Chen, et al. Histopathology, 2009
48
Cancer Biol Ther 5 (7), 2006
49
Anti-recurrence Treatment after Liver
Transplantation
Hepatology, 45 (2) 269-276, 2007
50
(No Transcript)
51
????,????