5. Carcinogenesis Flashcards
What proportion of cancers are related to smoking and alcohol?
1 in 9 cancers - smoking (1 in 5 deaths)
3% - alcohol
Do we know the cause of most cancers?
Nope, most causes are unknown
How are carcinogens identified?
Human studies
Animal Studies
Lab Studies
What carcinogens are there?
Viruses
Radiation
Inherited familial syndromes
Diet
What is a tumor initiator?
Something that causes transformation of normal cells into tumor cells
What are some examples of tumour initiators?
X-rays
UV light
DNA alkylating agents
What is a tumor promoter?
A proliferation inducer
What are some examples of tumor promoters?
Phorbol Esters (croton oil)
Inflammation (Hepatitis)
Estrogens + Androgens
EBV
What types of oncogenic radiation are there?
Ultraviolet X-ray Radioisotopes Nuclear fallout Background radiation
How does radiation impact oncogenesis?
Direct effect on DNA
Activation of cellular oncogenes
Why do Australians have the highest incidence rate for skin cancers globally?
- Attitude
- Genes - inherited - mutated
- Geological Circumstance = unlikely
How does UV radiation damage DNA?
Induce covalent bonds between pyrimidines
Bends helix
Polymerase can no longer read DNA template
What cancer is UVB light the principle cause of?
Squamous cell carcinoma
Basal cell carcinoma
Malignant melanoma
What type of UV light is the principle cause of cancer?
UVB SPF sunscreens block
Can UV light penetrate deeper than the skin?
No
UVA = acellular dermis
UVB = basal layer of epidermis
UVC = superficial skin
What did early use of X-rays cause?
Skin cancer
Leukemia
Papillary thyroid cancer
How long is radiation induced malignancy lag?
10-30 yrs
What increased risk is associated with diagnostic X-rays, if any?
Not much at all
Except in abdominal x-rays and fetal exposure - increased incidence of leukemia
When was the first link between radiotherapy and cancer established?
Around 1965 when paper released showed link between Ankylosing Spondylitis and Leukaemia
What cancer type is commonly associated with radiotherapy?
Sarcomas
What type of cancer is common among workers using radium-containing paints?
Osteosarcoma
Radioactive mineral mining is associated with…
Lung cancer
Thorium increases risk of?
Hepatocellular
Angiosarcoma
Cholangiocarcinoa
What are some potential radioactive isotopes that cause cancer?
Radioactive iodine (I131) = thyroid cancer
Radioactive phosphorous (P32) = AML
Where is radioactive iodine (I 131) found?
Nuclear energy
Medical diagnostics
Natural Gas production
Nuclear fission
When does cancer typically develop after exposure to radioactive iodine (I 131)?
15 - 25 years later (Chernobyl)
What risk did a 1.0 GY exposure to radiation result in?
50% increase cancer risk
What was the first cancer associated with atomic bomb radiation (within 5 yrs)?
Leukaemia
What co-factor is a key activator of carcinogens?
Cytochrome P450
What accounts for individual differences in responses to carcinogens?
Genetic polymorphisms
How does tumour initiation occur via chemical carcinogens?
DNA-adduct derived mutations in cancer susceptibility genes
Benzo[a]pyrene binds DNA
Induces base pair / frame shift mutation
Nucleotide Excision repair (NER) inhibition
How does tumor promotion occur via chemical carcinogens?
Arylhydrocarbon receptor (AhR) mediated signal transduction
Describe the process of tumor promotion in terms of benzo[a]pyrene and aryl-hydrocarbon receptor (AhR)
Benzo[a]pyrene binds arylhydrocarbon receptor and translocates to nucleus
AhR heterodimerises with AhR nuclear translocator (ARNT)
Complex binds xenobiotic responsive elements (XREs)
This induces expression of genes involved in carcinogen metabolism
Changes expression of cellular growth and differentiation factors
What are the mode of actions Chemical carcinogens take in cancer formation?
Induce change in DNA Base alkylation, deletion, breakage, cross-linkage Epigenetic mechanisms Synergistic action with viruses Promoter for other carcinogens Potency: varies with carcinogen
Why is it difficult to identify a specific carcinogen?
Many carcinogens in low levels everywhere
Exposed to large numbers of chemicals in lifetime
Long lag phase
What cancer is Benzidine associated with?
Bladder Cancer in dye industry
What is an example of a polycyclic Aromatic Hydrocarbon and what type of cancer does it cause?
Benzo[a]pyrene, gardeners and chimney sweeps
Enough S’nuff - Sot weed factor
Coal Tar
What is Benzo[a]pyrene found in?
Coal tar
Cigarette smoke
Well-cooked meat
“Pro-carcinogen” - metabolites mutagenic
How does benzo[a]pyrene damage DNA?
Intercalates DNA
Disrupts DNA copying
Specifically targets p53 gene
What % of cancers does smoking cause?
20-30%
How many cancers p/a in australia?
12,000
How many carcinogenic chemicals in cigarettes?
> 60
What is asbestos?
Naturally occuring fibrous material
What does asbestos induce?
Mutagenicity
Chromosomal alterations
Aneuploidy
What cancer is asbestos associated with?
Lung cancer and mesothelioma
What are Aflatoxins?
Naturally occuring mycotoxins
Produced by Aspergillus flavus and aspergillus parasiticus
What is the most toxic form of aflaoxin?
B1 - liver carcinogen
What do aflatoxins reside in?
Food Peanuts Corn Grain Pistachios
How do they cause cancer?
Absorbed into GI tract
Transported by portal vein to liver - Oxidized by cytochrome P450
Results in error in DNA replication, G-T mutation in p53
Inactivation of tumor supressor genes = Hepatocellular carcinoma
What types of cancer does Vinyl chloride cause?
Liver angiosarcoma
How much evidence is there linking Diet to carcinogenesis?
Barely any
Small associations with low-fiber diet and colonic carcinoma
Fatty diet = breast cancer
What possible protective agents are there?
Beta-carotene
Vitamin C, D, E
Selenium
Can lack of nutrients enhance risk of Ca?
Yes, folate deficiency related to colorectal carcinoma
What cancer risks are associated with obesity?
Colon, breast kidney, pancreas
Tumorogenic: Increased tumor promoting cytokines and insulin
What portion of alcohol metabolism causes cancer?
Acetylaldehyde
What cancers are associated with alcohol?
Oesophageal Pharyngeal Stomach Liver Breast
Are endogenous hormones typically initiators or promoters of cancer?
Typically initiators
What are some hormone-related cancers?
Breast Endometrium Prostate Testis Thyroid
What are the two mechanisms associated with Hormone carcinogenesis?
Induction of neoplasia by hormones
Hormonal dependence of neoplasms
What type of cancer does Diethylstilbestrol cause?
Vaginal and uterine carcinomas
What cancers do steroid hormones cause?
Hepatic neoplasms
What does hormonal dependence mean?
Some cancers rely on hormonal stimulation
What hormone is breast cancer associated with?
Oestrogen
How does Oestrogen cause breast cancer?
- Error in DNA replication
- Oestrogen promoting rapid prolif
- no time for DNA repair = errors
- Oestrogen metabolites are genotoxic
- Oestradiol induces DNA mutations
- Increased susceptibility with BRCA mutations
- Oestradiol induces DNA mutations
What genetic aberrations can contribute to cancer?
Somatic mutations occur often
Inherited germline mutations occur in rare familial cancers
Aneuploidy occurs often
What are the phases of the multi-step hypothesis?
Initiation = First event
Promotion = Subsequent events
Multiple hits occur, producing change in genome
Lag period
