MoD session 10: carcinogenesis Flashcards
Describe intrinsic and extrinsic causes of neoplasia
Intrinsic: hereditary, age, gender (especially women’s hormonal influences)
Extrinsic: environmental and behaviour. About 30% of all cancers are due to: high BMI, low fruit an veg intake, physical inactivity, tobacco and excess alcohol use
What were the lessons learned from the industrial chemical that caused factory workers to develop bladder cancer?
- There can be a long delay between carcinogen exposure and malignant neoplasm onset
- Risk of cancer depends on carcinogen dosage
- Some carcinogens show organ specificity
What types of substance can be mutagenic carcinogens (initiators)?
Polycyclic aromatic hydrocarbons Aromatic amines N-nitroso compounds Alkylating agents Natural products e.g. aflatoxin, asbestos
What is a pro-carcinogen?
A chemical that is only converted to a carcinogen by cytochrome P450 enzymes in the liver
This is why need liver in Ames test to test if mutagen is a carcinogen
What is a complete carcinogen?
A chemical carcinogen that acts as both an initiator and a promoter
Give an example of a complete carcinogen
Cigarette smoking: the chemicals it contains plus the hot smoke causing bronchial metaplasia both contribute to carcinogenesis
Why do younger age groups tend to develop germ line cancers?
The mutations bypass the step in carcinogenesis that takes years
Describe the sequence in which carcinogens are administered
Initiators must be given first, followed by a second class of carcinogens called promoters Ames test shows initiators are mutagens whilst promoters are not (they cause prolong proliferation in targets) Monoclonal expansion of mutation cells then become fully malignant by progression
Which types of radiation can cause cancer?
UV light: exposed daily so increased risk of skin cancer, especially from UVB. Doesn’t penetrate deeper than skin
Ionising radiation: strips electrons from atoms as very high energy. Includes X-rays, nuclear radiation and natural background radiation from radon seeping from the earth’s crust (dangerous as broken down to polonium then inhaled, so people living in areas with high activity need well-ventilated homes)
How does radiation damage cells?
Directly by altering bases or causing single or double stranded breaks
Indirectly by generation of free radicals
How can infection cause cancer?
Directly: affecting genes that control cell growth
Indirectly: causing chronic tissue injury where resulting regeneration acts as a promoter for pre-existing mutation or causes new mutations from errors of DNA replication
Role of Human Papilloma Virus and cervical cancer
A direct carcinogen
It expresses proteins E6 (inhibits p53: tumour suppressor gene, so inhibited activates telomerase) and E7 (inhibits pRB so cells speed through G1S checkpoint), thus causing abnormal cell proliferation
Mutations in epithelial cells occur
Role of hepatitis B and C viruses in liver cancer
Indirect carcinogens
Cause chronic liver cell injury and regeneration: repeatedly damage hepatocytes, hepatocytes respond by cell division and so increase chances of mutations occur
Role of HIV in cancer
Indirect carcinogen
Lowers immunity and allows for other potentially-carcinogenic infections to occur
Role of helicobacter pylori in stomach cancer
Indirect
Chronic gastric inflammation increases risk of gastric carcinomas
Role of parasitic flukes in cancer
Indirect
Chronic inflammation in bile ducts and bladder mucosa increases risk of cholangio- and bladder carcinomas
Describe the observations that were made when studying retinoblastoma
Can be sporadic or dominantly-inherited. Two-hit hypothesis explains the differences:
- Familial: first hit in gremline affecting all cells, second hit a somatic mutation in one of the retinal cells (RBI gene). Usually bilateral
- Sporadic: no gremlin mutation so both hits are somatic and occur in the same cell, so usually unilateral
RB gene normally restrains cell proliferation by inhibiting passage past the restriction point in the cell cycle, so inactivation of both RB alleles allows unrestrained passage and therefore proliferation.
What are tumour suppressor genes?
Genes which inhibit neoplastic growth by acting like brakes on tumour development. Need 2 hits to be inactivated: 1 for each allele
What are oncogenes?
Genes that enhance neoplastic growth. They abnormally-activated versions of normal genes (proto-oncogenes). Only need 1 allele of each porto-oncogene activated to favour neoplastic growth
RAS
The first human oncogene discovered, which is mutated in about 1/3 of all cancers. The RAS porto-oncogene encodes a small G protein which relays signals into the cell and pushes cells past the cell cycle restriction point.
Mutant RAS encodes a protein that is always active, producing a constant signal to pass through the restriction point (phosphorylates)
What can proto-oncogenes and tumour suppressor genes encode? Give an example for each
Growth factors e.g. PDGF Growth factor receptors e.g. HER2 Plasma membrane signal transducers e.g. RAS Intracellular kinases e.g. BRAF Transcription factors e.g. MYC Cell cycle regulators e.g. CYCLIN D1 Apoptosis regulators e.g. BCL2
TSGs encode proteins in the same pathways but with antigrowth effects, e.g. TP53
Xeroderma pigmentosum
Autosomal recessive condition due to mutation in genes for nucleotide excision repair
Patients very sensitive to UV damage and develop skin cancer at a young age
Hereditary non-polyposis colon cancer
Autosomal dominant. Germline mutations in genes for DNA mismatch repairs, causing micro satellite instability
APC gene is responsible
BRCA1 and BRCA2
Used for repair of ds DNA breaks, so mutated versions predispose to breast, ovarian, fallopian tube and peritoneal cancers
