Models of Carcinogenesis Flashcards
What are 3 assumptions about carcinogenesis
- Malignant transformation of a single cell is sufficient to give rise to a tumour
- Any cell in a tissue is as likely to be transformed as any other of the same type
- Once a malignant cell is generated, the mean time to tumour detection is generally constant
What are 5 different non exclusive models in which cells can become carcinogenic?
- Mutational
- Genome instability
- Non-genotoxic
- Darwinian
- Tissue organisation
What is the mutational model?
- Caused by chemical carcinogens that can mutate DNA and therefore the cancer arises due to accumulation of irreversible DNA damage.
- They act in a geneotoxic manner
What are the 4 classes of carcinogens?
- Chemical (eg nitrosamines, carbamates, azo dyes etc)
- Physical (radiation from UV/ionising and asbestos)
- Heritable (predisposition)
- Viral (Hepatitis B/Epstein Barr)
Why does smoking increase the risk of cancer?
Cigarettes contain polycyclic hydrocarbon benzo(a)pyrene (BP) as well as 81 other carcinogens. BP is able to easily enter cells
What is the Ames test?
- A test to determine the mutagenic activity of chemicals by observing whether they cause mutations in sample bacteria.
- A high number of revertants on the plates suggests the mutagen used causes mutations
How do physical carcinogens work?
They act by imparting energy into the biological material, using radiation as the primary agent
How does radiation cause cancer?
- Different types of radiation can act as physical carcinogens. Includes ionising radiation (X-rays, nuclear) and UV radiation.
- If the damage caused isn’t repaired, it can lead to translocations and mutations.
- UV is leading cause of melanoma
How do heritable carcinogens work?
- It predisposes cancer to offspring.
- Only accounts for 5% of cancers.
- Is an inherited germline mutation, allowing increased risk of cancer.
- Mostly caused by a mutation to a single gene (monogenic hereditary diseases).
- The risk is increased if a deficiency in DNA repair occurs and the damage accumulates.
Which heritable syndromes are caused through DNA repair defects?
- Ataxia telangiectasia
- Bloom’s syndrome
- Lynch type ll
- Fanconi’s anaemia
Which heritable syndromes are caused through chromosomal abnormalities?
Down’s syndrome & Klinefelter’s syndrome
What is Ataxia Telangiectasia
- Causes neuromotor dysfunction and dilation of blood vessels
- Caused by a mutation in ATM gene which disrupts cell cycle arrest, DNA repair and apoptosis
- Cancer predisposition = lymphoma, leukaemia, breast cancer
What is Bloom’s syndrome?
- Causes short stature (rarely exceed 5 feet), skin rash due to sun exposure
- Caused by a mutation in BLM gene which disrupts its ability to maintain structure and integrity of DNA
- Cancer predisposition = skin cancer, basal cell carcinoma, squamous cell carcinoma
What is Lynch type ll?
- No symptoms
- Mutations in mismatch repair (MMR) genes
- Cancer predisposition = colorectal cancer
What is Lynch type ll?
- No symptoms
- Mutations in mismatch repair (MMR) genes
- Cancer predisposition = colorectal cancer
How do viral carcinogens work?
- Usually viruses complete the lytic cycle where they multiply inside an infected cell, kill the cell and then go on to infect other cells, eg common cold
- Some complete the latent cycle where they’re able to transform cells into tumour cells
- These viruses are tumourigenic viruses
What properties do tumourigenic viruses need to function?
- Need stable association with cells through chromosomal intergration
- Must not kill cells as they require them to live and replicate
- Must evade immune surveillance of infected cells through not expressing viral antigens on cell surface
Which DNA viruses are associated with cancer?
- Burkitt’s lymphoma
- Nasopharyngeal carcinoma
- Epstein-Barr virus
- Hepatitis B/C
Which RNA retroviruses are associated with cancer?
- HTLV-l
- Adult T-cell leukaemia
- Lymphoma
What is Knudson’s hypothesis for hereditary cancers?
- Became the basis of the ‘two-hit’ hypothesis and led to the formation of the tumour suppressor gene theory
- This led to the discovery of Rb1 (TSG that causes retinoblastoma when both copies are mutated)
- He found that in inherited type, if the first mutated allele was inherited, the second mutation would lead to cancer
- In the sporadic type, both mutations had to occur to lead to cancer
- Therefore, 2 events are needed for carcinogenesis and that the cell with the first event must survive in the tissue long enough to sustain a second event
What is the non-genotoxic model of carcinogenesis?
- Characterised by an emphasis on non-genetoxic effects
- Several important modulators of cancer risk act through a functional change rather than a structural change in the DNA
- There is a group of carcinogens which induce cancer via non-genotoxic mechanisms
- These include: tumour promoters, endocrine modifiers, receptor mediators
- In high proportion of these, multiple pathways can be altered for carcinogenesis
What is the Darwinian model of carcinogenesis?
- carcinogenesis through mutation and selection-model of clonal expansion
- certain cancer cells become resistant to therapy
What is the tissue organisation model of carcinogenesis?
- Tissues are groups of cells with similar functions (epithelial, connective muscle, nervous)
- It consists of the tissue organisation field theory (TOFT)
How does the somatic mutation theory (SMT) work?
- Caused by a single catastrophic event
- Cancer is derived from a single somatic cell that has accumulated multiple DNA mutations
- these mutations damage genes which control cell proliferation and the cell cycle
- results in neoplastic lesions
How does tissue organisation field theory (TOFT) work?
- Caused by general deterioration of the tissue microenvironment due to extracellular causes
- Carcinogenesis in this case is primarily due to a problem with tissue organisation
- carcinogenic agents destroy the normal tissue leading to disruptions of cell signalling which compromises genomic integrity
