Download Objectives

Carcinogenesis
Where does cancer come from and how can we avoid it?
Darrell Davidson, MD, PhD
Department of Pathology and
Laboratory Medicine
Learning Objectives
1. Direct Acting vs Procarcinogen
2. Initiator vs Promoter
3. Two types of Radiation,
Which organs
4. Two types of Virus,
Mechanistic differences
5. Examples of Virus related malignancy
6. 3 Avoidable Cancer Causes
Carcinogenesis Outline
• Chemical Carcinogenesis
– Procarcinogen
– Initiator, Promoter
• Radiation Carcinogenesis
– UV radiation
– Ionizing rdiation
• Viral Carcinogenesis
– RNA virus
– DNA virus
So who cares?
• Magnitude of the problem
• You're the expert
• Future developments
Multistep Carcinogenesis
Carcinogenesis Outline
• Chemical Carcinogenesis
– Procarcinogen
– Initiator, Promoter
• Radiation Carcinogenesis
– UV radiation
– Ionizing radiation
• Viral Carcinogenesis
– RNA virus
– DNA virus
•
Royal Museum of
Surgeons, London
Scrotal Carcinoma in
Chimney Sweeps
Squamous Cell
Carcinoma of
Scrotum
Royal College
of Surgeons
Museum,
London
Chemical Carcinogen
Metabolic Alteration
• Electrophiles
• Direct acting
– Weak carcinogens
– Cytotoxic cancer chemotherapy
• Indirect acting
– Procarcinogen —> Proximate Carcinogen —>
Ultimate Carcinogen —> Metabolites
– Strong carcinogens
– Mixed function oxidase (P450) activates
– CYP1A1 increases lung CA risk 2.4 x
Screening and Testing
•
•
•
•
•
•
Ames test (10-30%"false negative")
Cell culture
Chromosome studies
DNA transcription and repair
Animal exposure studies
Epidemiologic (IARC)
Initiator-Promoter Experiments
Initiator Properties
•
•
•
•
•
•
Chemicals that damage genes, mutagenic
Single application effective, irreversible
Additive effect of multiple doses
No threshold or maximum
Replication to "fix" initiation
Electrophilic attack, covalent binding
Promoter Properties
• Enhance growth (not mutagenic)
• Multiple applications necessary,
Reversible effect
• Time-dependent, Non-additive
• Threshold and Maximum effect seen
• Alter expression of genetic message
• No covalent binding
Chemical Carcinogenesis Diagram (Robbins fig
8-42)
Progression
•
•
•
•
•
Neoplastic evolution toward autonomy
Higher mutation rate (10-100,000x)
Random and spontaneous variant cells
Selection for viability and proliferation
Therapy itself a selective pressure
Chemical Carcinogens
and ras Gene
• Mutations
•
repaired Unless
p53, Rb or other
key regulator
genes also
damaged
• RAS mutations
occur in 15-20%
of human tumors
• Most common
oncogene
Each chemical carcinogen
causes a set pattern of
base substitutions at
specific codons
– Methylnitrosurea
GA codon 12
– 7,12Dimethylbenz[a]anthracene
A T codon 61
Ras mutation effect (Robbins fig 8-25)
Carcinogenesis Outline
• Chemical Carcinogenesis
– Procarcinogen
– Initiator, Promoter
• Radiation Carcinogenesis
– UV radiation
– Ionizing radiation
• Viral Carcinogenesis
– RNA virus
– DNA virus
Radiation
Carcinogenesis
• Ultraviolet
– skin tumors
– UVA (315-400 nm)
– UVB (280-315 nm)
– UVC (100-280 nm)
Asymmetry
Border
Color
Diameter
• Ionizing
– therapeutic
– occupational
– nuclear weapons
Trinity
7/16/45
Radiation
Carcinogenesis
Mechanism
• Long latency
• Direct damage (free-radicals)
– not only DNA, but also RNA & enzymes
• Causes immunodeficiency
• Latent oncogenes or virus
• Promoter effect of regeneration
Carcinogenesis Outline
• Chemical Carcinogenesis
– Procarcinogen
– Initiator, Promoter
• Radiation Carcinogenesis
– UV radiation
– Ionizing radiation
• Viral Carcinogenesis
– RNA virus
– DNA virus
Microbial
Carcinogenesis
• RNA virus (retrovirus)
– HTLV-1
– HCV
• DNA virus
– HPV
– EBV
– HBV
– HSV-8
• Helicobacter pylori (?)
Retrovirus
• Infectious homologue (v-onc) of
Cellular oncogenes (c-onc)
• Reverse transcriptase*
vRNA *—> dsDNA "provirus" —> integration
—> mRNA—>
viral core proteins (gag)
reverse transcriptase(pol)
coat glycoproteins(env)
• Permissive or NonPermissive host cells
• Protein Kinase regulator or paracrine
Growth Factor release
Retrovirus Examples
• avian leukosis virus
– heritable provirus
(myc )
• murine leuk/sarc
– heritable only (abl )
• other leuk/sarc
– feline by saliva only
(sis )
• HTLV I
– Japan, Caribbean
– tax gene
proliferation
• HCV
– blood transfusion
– cirrhosis in 17%
hepatoma in 50%
of those
HTLV-1 Transformation (Robbins fig
8-44)
DNA Virus
• Animal tumors
• Transformation incompatible with
viral replication
• Tumor-Specific Antigens (TSA)
– Membrane bound
– Protein kinase
DNA Virus Examples
• Human Papillomavirus (HPV)
– 6,11 vs 16, 18, 31, 33, 35, 51
– E6 binds p53, E7 binds Rb product
• Epstein-Barr Virus (EBV)
– Herpesvirus 4
– t(8;14) cmyc to chr 2, 14, 22
– Burkitt’s lymphoma, Hodgkin’s, Nasopharyngeal CA
• Hepatitis B Virus (HBV)
– HBx binds p53 and activates growth promoter genes
• Herpesvirus 8 (KSHV)
– Kaposi’s sarcoma (endothelial cells)
HPV Carcinogenesis
EBV and Burkitt’s
Unavoidable Factors
Virus
5%
Reproductive
4%
Pollution
2%
Radiation
2%
Medical Dx & Rx
1%
Total
14%
Preventable Factors
Trichopoulos, et al, What Caueses Cancer, Sci Amer, Sept, 1996
Tobacco
30 %
Diet
30 %
Occupational
5%
Sedentary
lifestyle
Alcohol
3%
Salt
3%
3%
Total
74%
5000
100
4500
90
4000
80
3500
3000
70
Per capita cigarette
consumption
60
2500
50
Male lung cancer
death rate
2000
40
1500
30
1000
20
500
Female lung cancer
death rate
10
0
1900
1905
1910
1915
1920
1925
1930
1935
1940
1945
1950
1955
1960
1965
1970
1975
1980
1985
1990
1995
2000
0
Age-Adjusted Lung Cancer Death
Rates*
Per Capita Cigarette Consumption
Tobacco Use in the US
1900-2003
Year
*Age-adjusted to 2000 US standard population.
Source: Death rates: US Mortality Public Use Tapes, 1960-2003, US Mortality Volumes, 1930-1959, National
Center for Health Statistics, Centers for Disease Control and Prevention, 2005. Cigarette consumption: US
Department of Agriculture, 1900-2003.
Trends in Obesity* Prevalence
Adults Aged 20 to 74 1960-2004†
45
40
33
Prevalence (%)
35
31
30
23
25
20
15
13
15
15
10
5
0
Both sexes
1960-62
1971-74
1976-80
1988-94
1999-2002
2003-2004
*Obesity is defined as a body mass index of 30 kg/m2 or greater. † Age adjusted to the 2000 US standard population. Source:
National Health Examination Survey 1960-1962, National Health and Nutrition Examination Survey, 1971-1974, 1976-1980,
1988-1994, 1999-2002, National Center for Health Statistics, Centers for Disease Control and Prevention, 2002, 2004. 20032004: National Health and Nutrition Examination Survey Public Use Data Files, 2003-2004, National Center for Health
Statistics, Centers for Disease Control and Prevention, 2006.
Trends in Overweight* Prevalence (%)
Adults 18+ 1997-2006
1992
1995
‘97
‘00
1998
2005
‘05
‘06
Less than 50%
50 to 55%
More than 55%
State did not participate in survey
*Body mass index of 25.0 kg/m2or greater. Source: Behavioral Risk Factor Surveillance System, CD-ROM (1984-1995,
1998) and Public Use Data Tape (2004, 2005), National Center for Chronic Disease Prevention and Health Promotion,
Centers for Disease Control and Prevention, 1997, 2000, 2005, 2006.
Learning Objectives
1. Direct acting vs Procarcinogen
2. Initiator vs Promoter
3. Two types of radiation,
Which organs
4. Two types of virus,
Mechanistic differences
5. Examples of RNA & DNA virus
related malignancy
6. 3 avoidable cancer causes
Answers to Objectives 1
1. Direct (weak) alkylating agents
Procarcinogen (strong) metabolic activation
2. I: irreversible, mutation-like, additive,
no threshold, early S phase
P: decays, enhance growth, not cumulative,
definite threshold, milieu sensitive
Both: replication to “fix” initiation
3. UV: skin
Ionizing: leukemia, thyroid, lung, breast
Answers to Objectives 2
4. RNA dsDNA provirus integrates
DNA episomal genes integrate
5. HTLV-1: T-cell leukemia (tax),
HCV: HCCA (cirrhosis 17%).
HPV (E6/p53, E7/Rb),
EBV (EBNA-1 product),
HBV (HBx product/p53),
HSV-8 (endothelial).
6. Tobacco, Diet, Occupational
Sunset over Cape Cod