Models of carcinogenesis Flashcards
Describe the pathogenesis of cancer
- multi-step process that involves the accumulation of mutations over times
- occurs when cells defense mechanism of DNA repair has been evaded
What are the 3 assumptions made in regards to carcinogenesis
- malignant transformation of a single cells 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 tumour detection is generally constant
What are the 5 models of carcinogenesis?
- mutational
- genome instability
- non-genotoxic
- darwinian
- tissue organisation
Model 1 - chemical carcinogens
- cancer is a multi-step process, initiation, promotion and progression
- presence of multiple mutations supports the feature that cancer arises through the accumulation of irreversible DNA damage
Specific chemicals which induce cancer
chimney smoke = scrotal carcinoma
benzene = acute leukemias
radium = osteosarcoma
arsenic = skin carcinoma
What are the 4 classes of carcinogens?
- chemical - polycyclic aromatic hydrocarbons, aromatic amines, alkylating agents
- physical = radiation (ionising, UV) asbestos
- heritable = predisposition
- viral - hep B, epstein barr
What are the 4 major groups in chemical carcinogens?
- aromatic hydrocarbons
- aromatic amines
- nitrosamines
- alkylating agents
they exert their effects by adding functional groups to DNA bases called DNA adducts
What is the Ames test?
a test to determine the mutagenic activity of chemicals by observing whether they cause mutations in sample bacteria
How do physical carcinogens act?
- impart energy into biological material
- radiation is the primary physical agent
- ionising (x-ray)
- UV
How do heritable carcinogens act?
- 5% of all cancers
- inherited germ-line mutation has an increased risk of developing certain tumour but are rarely involved in causing cancer immediately
- usually due to mutation of a single gene
- affected gene is often involved in controlling the cell cycle or the repair of DNA damage
What are some syndromes caused by DNA repair defects
- ataxia telangiectasia
- blooms syndrome
- fanconis anaemia
- li-fraumeni syndrome
What are some syndromes caused by chromosomal abnormalities
- downs syndrome
- klinefelters syndrome
Describe ataxia telangiectasia
- neuromotor dysfunction, dilation of blood vessels
- mutation in ATM gene, codes for serine/threonine kinase that is recruited and activated by dsDNA breaks leading to cell cycle arrest, DNA repair ad apoptosis - cell cycle arrest
cancer predisposition - lymphoma, leukaemia
Describe blooms syndrome
- short stature, rarely exceed 5ft, skin rash that develops after exposure to sun
- mutation in BLM gene that provides instructions for coding member of the RecQ helicase family that helps maintain the structure and integrity of DNA
- cancer predisposition - skin cancer, basal cell carcinoma
Describe lynch syndrome
- doesn’t cause any symptoms
- first sign is that person has bowel or womb cancer
- mutations in DNA mismatch repair genes, MLH1, MSH2, MSH6, PMS2
cancer predisposition - colorectal cancer
What are the properties required of tumourigenic viruses?
- stable association with cells : chromosomal integration
- must not kill cells : non-permissive host, suppression of viral lytic cycle, viral release by budding
- must evade immune surveillance of infected cells : immune suppression, viral antigens not expressed at cell surface
Viruses associated with human cancer
DNA viruses - EBV, papiloma virus, hep b, burkitts lymphoma
RNA retroviruses - HTLV-1
Describe model 2 - genome instability
- two hit hypothesis - multiple hits are required to cause cancer
- if first mutated allele was inherited the second mutation would lead to cancer
at least two events are required, and first event must survive in tissue long enough to sustain a second event
Describe model 3 - non- genotoxic
- tumour promoters - 1,4 dichlorobenzene
- endocrine modifiers
- receptor ediators
- immunosuppressants - cyclosporine
Describe model 4 - darwinian
carcinogenesis by mutation and selection model of clonal expansion
- role of the environment in selecting cells that have some acquired advantage
- sequential accumulation of mutations due to exposure to carcinogens
- tumour cells will be selected for ability to grow and invade
- selection will include resistance to therapy
- some mutations may be deleterious for tumour
What are the two forms of model 5 - tissue organisation?
- somatic mutation theory (SMT)
- tissue organisation field theory (TOFT)
Describe SMT
- somatic mutation theory (SMT) - cancer is derived from a single somatic cells that has successively accumulated multiple DNA mutations
- those mutations damage the genes which control cell proliferation and cell cycle
- lesions are a result of DNA-level events
- single catastrophic event triggering carcinogenesis
Describe TOFT
- tissue organisation field theory (TOFT)
- carcinogenesis is primarily a problem of tissue organisation
- carcinogenic agents destroy the normal tissue architecture thus disrupting cell-to-cell signalling and compromising genomic integrity
- the DNA mutations are random and the effect, not the cause, of the tissue-level events
- carcinogenesis as general deterioration of the tissue microenvironment due to extracellular causes
