Transcript Chemical Carcinogenesis

ENVR 430
Chemical Carcinogenesis:
Initiation, Promotion, Progression
Ivan Rusyn
Laboratory of Environmental Genomics
Department of Environmental Sciences & Engineering
[email protected]
843-2596
0031 MHRC
CANCER:
“A multicausal, multistage group of diseases the mechanisms of which are still only
partially known” (IARC Scientific Publications, 1992)
“Cancer is a group of diseases characterized by uncontrolled growth and spread of
abnormal cells […] that can result in death” (American Cancer Society, 2006)
Age adjusted Cancer Death Rates, by Site, US, 1930-2002
• Benign tissue is not cancer. Although the cell growth is
moderately increased, the cells do not invade nearby tissue
or spread to other parts of the body
• Malignant tissue is cancer. The cancer cells divide out of
control. They can invade and destroy nearby healthy
tissue. Also, cancer cells can break away from the tumor
they form and enter the bloodstream and lymphatic system
• Metastasis: the spread of cancer beyond the organ of
origin
WHAT MAY CAUSE CANCER ?
 Hereditary disorders
Chemicals
 Viruses
 Chronic inflammation
 ???
From http://www.cancersupportivecare.com/riskintro.html

History of Chemical Carcinogenesis
• Chemical carcinogenesis was first
suggested by clinicians 200 years ago
– Scrotal cancer in chimney sweeps - Potts
– Nasal cancer and snuff dipping - Hill
– Today, >50 chemicals are recognized as
human carcinogens
• First experimental studies in animals
were done ~80 years ago
History of Chemical Carcinogenesis
• Large numbers of chemicals were tested for
carcinogenic potential in the 1970-1990s
– Maximum Tolerated Doses (MTD) were used.
– 60% of rodent carcinogens were genotoxic
– 40% of rodent carcinogens were nongenotoxic
– Some chemicals were single site, single species
carcinogens
– Others were multisite, multispecies carcinogens
– Dose-response varies from <1/2 MTD to <1/1000 MTD
• Most regulations use straight mathematical
extrapolation of high dose rodent data to predict
risks
WORLD HEALTH ORGANIZATION
INTERNATIONAL AGENCY FOR RESEARCH ON CANCER
IARC Monograph Evaluations
LYON, FRANCE
Slide courtesy of V. Cogliano (IARC)
IARC:
Slide courtesy of V. Cogliano (IARC)
A tour of IARC’s classifications
Preamble, Part B, Section 6(d)
Slide courtesy of V. Cogliano (IARC)
Slide courtesy of V. Cogliano (IARC)
IARC (2007) - monographs.iarc.fr
•Carcinogenic to humans (group 1) – 100 agents to date
•Probably carcinogenic to humans (group 2A) – 68
•Possibly carcinogenic to humans (group 2B) – 246
•Not classifiable as to its carcinogenicity to humans (group 3) – 516
•Probably not carcinogenic to humans (group 4) – 1
U.S. EPA (2003)
•Carcinogenic to humans
•Likely to be carcinogenic to humans
•Suggestive evidence of carcinogenic potential
•Inadequate information to assess carcinogenic potential
•Not likely to be carcinogenic to humans
U.S. NTP (2002) (see NTP levels of evidence.pdf)
•Known to be a human carcinogen
•Reasonably anticipated to be a human carcinogen
Cal/EPA (2004)
•Known to the state to cause cancer
Cancer Cases Attributable to
Environmental Carcinogens (Worldwide, 1990)
Infections (viruses, parasites, H. pylori)
Tobacco (smoked and smokeless)
Occupation
Alcohol drinking
16%
14%
4%
3%
37%
Diet and dietary components including contaminants
Pollution
Reproductive factors
25%
2%
2%
29%
IARC Group 1 – Carcinogenic to humans
Monographs Volumes 1-84 (1972-2002): 89 Agents and Exposures
Medical drugs and treatments
Industrial processes
Infectious agents or processes
Physical agents
Industrial chemicals
Inhaled particulates
Metals and inorganic salts
Lifestyle factors (incl. herbal remedies)
Other
24
13
10
10
7
5
5
7
8
Exposures to Chemicals in the Workplace
Agent
Industries and Trades with
Proved Excess Cancers and
Exposure
Primary Affected Site
p-Aminodiphenyl
Chemical manufacturing
Urinary bladder
Asbestos
Construction, asbestos mining and
milling, production of friction products
and cement
Copper mining and smelting
Pleura, peritoneum,
bronchus
Skin, bronchus, liver
Chemical manufacturing
Bronchus
Chemical and rubber manufacturing,
petroleum refining
Bone marrow
Benzidine, -naphthylamine, and
derived dyes
Dye and textile production
Urinary bladder
Chromium and chromates
Tanning, pigment making
Nasal sinus, bronchus
Isopropyl alcohol manufacture
Chemical manufacturing
Nickel
Polynuclear aromatic hydrocarbons
from coke, coal tar, shale, mineral oils,
and creosote
Vinyl chloride monomer
Nickel refining
Steel making, roofing, chimney
cleaning
Cancer of paranasal
sinuses
Nasal sinus, bronchus
Skin, scrotum, bronchus
Chemical manufacturing
Liver
Wood dust
Cabinetmaking, carpentry
Nasal sinus
Arsenic
Alkylating agents (mechloroethamine
hydrochloride and
bis[chloromethyl]ether)
Benzene
Modified from Cullen et al. (1990).
Carcinogenic Risks of Chemical Agents Associated
with Medical Therapy and Diagnosis
Chemical or Drug
Associated Neoplasms
Evidence for Carcinogenicity
Alkylating agents
(cyclophosphamide,
melphalan)
Inorganic arsenicals
Bladder, leukemia
Sufficient
Skin, liver
Sufficient
Azathioprine (an
immunosuppressive drug)
Lymphoma, reticulum
cell sarcoma, skin,
Karposi’s sarcoma (?)
Bladder
Sufficient
Leukemia
Vagina (clear cell
carcinoma)
Limited
Sufficient
Liver cell adenoma
Endometrium
Skin
Sufficient
Limited
Sufficient
Liver
Renal pelvis (carcinoma)
Limited
Sufficient
Lymphoma,
neuroblastoma
Liver (angiosarcoma)
Limited
Chlornaphazine
Chloramphenicol
Diethylstibesterol
Estrogens
Premenopausal
Postmenopausal
Methoxypsoralen with
ultaviolet light
Oxymetholone
Phenacetin
Phenytoin
(diphenyhydantoin)
Thorotrast
Sufficient
Sufficient
Carcinogenic Factors Associated with Lifestyle
Chemical, Physiological
Condition or Natural
Process
Alcoholic beverages
Associated Neoplasm
Evidence for
Carcinogenicity
Esophagus, liver,
oropharynx, larynx
Sufficient
Aflatoxins
Liver
Sufficient
Betel chewing
Mouth
Sufficient
Dietary intake (fat, protein,
calories)
Reproductive history
Late age at first pregnancy
Zeo or low parity
Tobacco smoking
Breast, colon,
Sufficient
endometrium, gallbladder
Breast
Ovary
Mouth, pharynx, laryns,
lung, esophagus, bladder
Sufficient
Sufficent
Sufficient
Modified from Pitot (1986) and Vainio et al. (1991)
Chemical Carcinogenesis
in the 21st Century
New perceptions of previously known carcinogens:
Combined effects of multiple exposures
Examples:
o Alcohol drinking and aflatoxins
o Alcohol drinking and HBV/HBC
o Alcohol drinking and tobacco smoking
o Alcohol drinking and asbestos/arsenic/radon
Stages of Carcinogenesis
Initiation
Initiating
Event
Cell Proliferation
(clonal expansion)
Promotion
Cell Proliferation
Progression
Cell Proliferation
Malignancy
Cellular and Molecular Mechanisms in Multistage
Carcinogenesis: INITIATION
“Simple”
genetic
changes
From http://newscenter.cancer.gov/sciencebehind/
Initiating event involves cellular genome – MUTATIONS
Target genes:
- oncogenes/tumor suppressor genes
- signal transduction
- cell cycle/apoptosis regulators
SOURCES OF MUTATIONS
ENDOGENOUS DNA DAMAGE
EXOGENOUS DNA DAMAGE
Free Polymerase
Environmental Life
Radicals Errors
Depurination Agents
Styles
DNA REPAIR
CELL REPLICATION
MUTATION
Chemical Exposure (air, water, food, etc.)
Internal Exposure
Metabolic Activation
Macromolecular Binding
DNA
RNA
Detoxication
Protein
(Biomarker)
Biologically Effective Dose
X
Efficiency of Mispairing
X
Cell Proliferation
Initiation
Williams J.A., Carcinogenesis 22:209-14 (2001)
Accumulation of mutations during tumor progression
Loeb L.A. Cancer Res. 61:3230-9 (2001)
EPIGENETICS
Epigenetic alterations – changes induced in cells that alter the
expression of the information on transcriptional, translational, or posttranslational levels without changes in DNA sequence
Methylation of
DNA
DNMT1
DNMT3a
DNMT3b
Modifications of
histones
P
Me
U
SAM SAH
A
A - acetylation
Me- methylation
P- phosphorylation
U - ubiquitination
RNA-mediated
modifications
• RNA-directed DNA
methylation
• RNA-mediated chromatin
remodeling
• RNAi, siRNA, miRNA …
ACQUISITION OF ADDITIONAL
RANDOM MUTATIONS
Clonal selection and
expression of initiated cells
Mutator
phenotype cells
Cancer cells
Environmental
Normal cells
ALTERATIONS IN
CELLULAR EPIGENOME
Epigenetically
reprogrammed cells
Mutator
phenotype cells
Cancer cells
Endogenous
Normal cells
Endogenous
Environmental
GENETIC AND EPIGENETIC MODELS OF THE CANCER INITIATION
Cellular and Molecular Mechanisms in Multistage
Carcinogenesis: PROMOTION
From http://newscenter.cancer.gov/sciencebehind/
Reversible enhancement/repression of gene expression:
- increased cell proliferation
- inhibition of apoptosis
No direct structural alteration in DNA by agent or its metabolites
Role of Increased Cell Proliferation in
Carcinogenesis
• Decreases time available for DNA repair
• Converts repairable DNA damage into nonrepairable
mutations (not DNA damage anymore!)
• Necessary for chromosomal aberrations, insertions,
deletions and gene amplification
• Clonally expands existing cell populations with
mutations
1.
X
No Tumors
2.
X
Tumors
3.
X
Tumors
4.
X
5.
No Tumors
No Tumors
Time
X = Application of Initiator
= Application of Promoter
Basophilic Focus
N
Adenoma
M1
Carcinoma
MN
Promotion
Regression
Progression
No Tumors
Tumors
= Application of Promoter
Adapted from: Marsman and Popp. Carcinogenesis 15:111-117 (1994)
Cellular and Molecular Mechanisms in Multistage
Carcinogenesis: PROGRESSION
• Irreversible enhancement/repression of gene expression
• Complex genetic alterations (chromosomal translocations,
deletions, gene amplifications, recombinations, etc.)
“Complex”
genetic
changes
From http://newscenter.cancer.gov/sciencebehind/
• Selection of neoplastic cells for optimal growth genotype/
phenotype in response to the cellular environment
Phenotypic characteristics of cancer cells:
• Immortalization
• Transformation
• Loss of contact growth inhibition
• Autonomy of proliferation
• Avoidance of apoptosis
• Aberrant differentiation
• Induction of angiogenesis
Human Tumors and Stages of Carcinogenesis
Hussain et al., Oncogene, 2007