5. Carcinogenesis Flashcards by Alex Martin

What proportion of cancers are related to smoking and alcohol?

1 in 9 cancers - smoking (1 in 5 deaths)

3% - alcohol

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Do we know the cause of most cancers?

Nope, most causes are unknown

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How are carcinogens identified?

Human studies
Animal Studies
Lab Studies

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What carcinogens are there?

Viruses
Radiation
Inherited familial syndromes
Diet

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What is a tumor initiator?

Something that causes transformation of normal cells into tumor cells

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What are some examples of tumour initiators?

X-rays
UV light
DNA alkylating agents

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What is a tumor promoter?

A proliferation inducer

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What are some examples of tumor promoters?

Phorbol Esters (croton oil)

Inflammation (Hepatitis)
Estrogens + Androgens
EBV

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What types of oncogenic radiation are there?

Ultraviolet
X-ray
Radioisotopes 
Nuclear fallout
Background radiation

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How does radiation impact oncogenesis?

Direct effect on DNA

Activation of cellular oncogenes

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Why do Australians have the highest incidence rate for skin cancers globally?

Attitude
Genes - inherited - mutated
Geological Circumstance = unlikely

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How does UV radiation damage DNA?

Induce covalent bonds between pyrimidines
Bends helix
Polymerase can no longer read DNA template

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What cancer is UVB light the principle cause of?

Squamous cell carcinoma
Basal cell carcinoma
Malignant melanoma

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What type of UV light is the principle cause of cancer?

UVB SPF sunscreens block

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Can UV light penetrate deeper than the skin?

No
UVA = acellular dermis
UVB = basal layer of epidermis
UVC = superficial skin

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What did early use of X-rays cause?

Skin cancer
Leukemia
Papillary thyroid cancer

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How long is radiation induced malignancy lag?

10-30 yrs

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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

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When was the first link between radiotherapy and cancer established?

Around 1965 when paper released showed link between Ankylosing Spondylitis and Leukaemia

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What cancer type is commonly associated with radiotherapy?

Sarcomas

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What type of cancer is common among workers using radium-containing paints?

Osteosarcoma

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Radioactive mineral mining is associated with…

Lung cancer

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Thorium increases risk of?

Hepatocellular
Angiosarcoma
Cholangiocarcinoa

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What are some potential radioactive isotopes that cause cancer?

Radioactive iodine (I131) = thyroid cancer

Radioactive phosphorous (P32) = AML

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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?

1. Error in DNA replication - Oestrogen promoting rapid prolif - no time for DNA repair = errors 2. Oestrogen metabolites are genotoxic - Oestradiol induces DNA mutations - Increased susceptibility with BRCA 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

5. Carcinogenesis Flashcards

(66 cards)