Transcript Carcinogenesis

Carcinogenesis
Tee L. Guidotti
Dept. of Environmental and
Occupational Health
GWUMC
Characteristics of Toxicological
Mechanisms
Carcinog.
Genome
Target
? No
ThresThreshold
hold
Outcome Stereotyp
Response Stochastic
Latency Long
Immune
Immune
Recognition
Stereotyp
Nonstoch.
Short
Toxicity
Receptor
Threshold,
dose-dep.
Multiple
Dose-dep.
Variable
Characteristics of a Cancer
• Uncontrolled growth
– beyond normal hyperplasia in vivo
– loss of cell-cell inhibition in vitro
– anaplasia (highly variable)
– apoptosis (normal cell death) defective
• Tendency to invade surrounding tissue
• Tendency to travel beyond site of origin
– metastasis may occur late
Early Theories of Carcinogenesis
• Surfeit of black bile (Hippocrates)
• Omnis cellula ex cellula (Bichat,
Pasteur)
• Irritation hypothesis (Virchow)
– medicolegal issues
– persists as lay theory
• Embryonic hypothesis (teratomas, etc.)
• Parasitic hypothesis
Recent Theories of
Carcinogenesis
• Chemical carcinogenesis
– derived from observations by Pott, 1775
– major line of mechanistic oncology every
since
• Viral theory of carcinogenesis
• Two-stage mechanism of Ca.genesis
– two processes: initiation, promotion
– followed by progression
Steps in Chemical
Carcinogenesis
1.
2.
3.
4.
5.
6.
7.
Biotransformation
Initiation: Covalent binding to DNA
Fixation: Mutation stabilized by mitosis
Gene expression, transformation
Neoplastic growth, proliferation
Progression, local effects
Metastasis
Initiation - 1
• Biotransformation:
– procarcinogenultimate carcinogen
• Interaction with macromolecules
– silent binding to other receptors
• covalent binding to critical DNA sites
– repairnormal cell + DNA adducts
– cytotoxicity
– fixationinitiation
Initiation - 2
• Induced transcription errors
• DNA polymerase
• Binding to oncogenes
– regions of genome that code for cell
growth and differentiation
– may result in cell transformation
• Binding to tumour suppressor genes
– apoptosis
Oncogenes - 1
• Oncogenes are activated, unregulated
versions of protooncogenes
• Protooncogenes normal genes encoding
for protein kinase and other growth
signals
• Their gene products stimulate cell
growth
• Viral oncogenes are altered copies of
protooncogenes
• 20% of human tumours show oncogenes
Oncogenes - 2
• Single copies of oncogenes are
sufficient to result in malignant
transformation
• Oncogene products are convenient
biomarkers of effect
• Thought by some to be underlying
mechanism (distinct from cause) of
all Ca
Tumour Suppressor Genes
• Genes that block neoplastic growth,
e.g. p53
• Functional opposites of oncogenes, hence
originally named anti-oncogenes
• Very difficult to identify and characterize
• Characteristic double allelic activity:
– both alleles must be damaged for malignant
activity
– retinoblastoma follows “two hit” model
InitiationPromotion - 1
• Cell affected by Ca.gen must replicate
for Ca to occur
• Cell division fixes the mutation in
daughter cells
• Promoters induce rapid tissue growth
– irritation or necrosis
– hyperplasia and stimulate growth
• Fixation occurs when mutation is
passed on
InitiationPromotion - 2
• Initiator = Carcinogen
• Cocarcinogen interacts with
initiator, may be an initiator itself
• Promoter acts at same time or after
initiator, is not (usually) initiator
alone at dosage at which it
promotes
Initiation by Physical Means
• Ionizing radiation
– h + O2free radicalsDNA damage
• Nonionizing radiation
– UV between 280 - 320 nmpyrimidine
dimers?
• Epigenetic Ca.gens: Asbestos, silica,
foreign bodies
Initiation by Biological Agents
• Human viral pathogens
– oncogenic retroviruses (HIV)
– DNA viruses (Epstein-Barr, HSV-2,
papilloma, HBV)
• Bacteria, biotransformation
• Endoparasites (Schistomsoma spp.)
Promotion - 1
• “Incomplete” carcinogen requires a
promoter
• “Complete” carcinogen both initiates
and promotes
• Stimulation of cell division for fixation
• Not genotoxic
• Dose-dependent, may have threshold
Promotion - 2
• Promoters induce small foci of
“preneoplastic” proliferation where
transformed cells reside in tissues
• Selection pressure favours more
rapidly proliferating foci
• At high concentrations, cytotoxic
promoters may inhibit
carcinogenesis by negative selection
pressure on susceptible cells
Promoters - 3
• Promoters are mitogens, may be
endogenous as well as exogenous
– hormones (estrogen, prolactin, thyroxin)
• Exogenous promoters
– phorbol esters (experimental)
– phenobarbital
– foreign bodies
– aromatic hydrocarbons (also initiators)
– dioxin (most potent in animal studies)
Progression
• Proliferation of successful clone
• Adaptive growth
• Dormancy period in many cases,
ends for many reasons (hormonal,
nutritional, lymphokines,
immunodeficiency etc.)
• Tumour vascularization,
angiogenesis
• Develops into detectable tumour
Predisposing Factors - Genetic
• Metabolism, biotransformation
• Rare AuD cancers
– familial polyposis straight AuD)
– retinoblastoma (two hit model)
• Predisposition to initiation
• Inaccurate repair mechanisms
• Immunodeficiency
Predisposing Factors - Dietary
•
•
•
•
•
Caloric intake
Protein deficiency, high fat
Carotenes and retinoids - deficiency
Tocopherols - deficiency
Selenium (glutathione peroxidase) deficiency
• Zinc deficiency
• Flavanoids (enzyme inhibition) deficiency