Mechanisms of oncogenesis Flashcards
What is cancer?
= group of diseases characterised by:
- Abnormal cell proliferation
- Tumour formation
- Invasion of neighbouring normal tissue
- Metastasis to form new tumours at distant sites
What are the different type of cancers?
Carcinomas = cancer occurring in epithelial cells
Sarcomas = cancer derived from mesoderm cells
Adenocarcinomas = cancers found in glandular tissue
What are the hallmarks of cancer?
What are the major functional changes in cancer?
- Increased growth
- Failure to undergo programmed cell death (apoptosis)
- Loss of differentation
- Failure to repair DNA damage
How do mutations lead to cancer?
Carcinogens cause alterations to the DNA - mutations
The accumulation of mutations represents the multi-step process that underlies carcinogenesis and it occurs after the cells defence mechanism has been evaded
- If cases are severe then cell apoptosis is induced
Many mechanisms exist for blocking carcinogenesis but over burdening the system increases the possibility that cells will escape surveillance
The longer we live, the more time there is for DNA to accumulate mutations that may lead to cancer
What are the different types of mutations?
How is proliferation under tight control?
**mutations in DNA that alter the function of normal genes involved in growth apoptosis and differentiation can affect the balance
- So the total cell number will continually increase leading to carcinogenesis
What are oncogenes?
= proto-oncogene that has been mutated to lead signals that cause uncontrolled growth ie. Cancer
- Proto-oncogenes = normal genes that can be activated to be oncogenic
What are tumour suppresor genes?
= inhibit both growth and tumour formation
- Act as braking signals during G1 of the cell cycle to stop or slow the cell cycle before S phase
- If they are mutated - it will lead to cancer
What is model 1 of carciogenesis?
Chemical carcinogens can affect any point in the multi-stage process of cancer (initiation, promotion or progression)
- Work by altering the structure of DNA, and if not repaired, a accumulation of irreversible DNA damage
Carcinogens = cancer causing chemicals
- Chemical - organic compounds - add groups to DNA called DNA adducts to cause DNA damage
- Physical - radiation and asbestos - act by imparting energy into the biological material which changes bonding of molecules
- Heritable - genetic predisposition - most common is due to a mutation of a single gene. Ataxia telangiectasia - spider eyes - mutation in ATM gene - cancer predisposition including lymphoma and breast cancer
- Viral - Hep B - has to be stable with cells, must not kill cells and most evade immune surveillance of infected cells
How do you find if something is carcinogenic?
Ames Test - to determine the mutagenic activity of chemicals by observing whether they cause mutations in sample bacteria
What is model 2 of carciogenesis?
Genome instability
High frequency of mutations of genome
Study of Knudson
- You can have either inherited retinoblastoma or sporadic retinoblastoma
- He found patients that had the sporadic form often developed the tumour much later on in life compared to those who had the inherited form
- At least 2 events are necessary for carcinogenesis and that the cell with the first event must survive in the tissue long enough to sustain a second event
What is model 3 of carcinogensis?
- non-genotoxic
- Several important modulators of cancer risk (diet, obesity, hormones) do not seem to act through a structural change in DNA but rather through functional changes including epigenetic events
- However there is a group of carcinogens that induce cancer via non-genotoxic mechanisms
What is model 4 of carcinogensis?
- Darwinian
- As the tumour grows, more mutations and accumulated and more evolving of the mutations
- This model is natural selection of those that will have a growth advantage
What is model 5 of carcinogensis?
Tissue organisation - different theorys to understand the forces driving carcinogensis:
Somatic mutation theory:
- neoplastic lesions are the results of DNA-level events
- Single castratophic event tirggering carcinogenesis
Tissue organization field theory:
- DNA mutations are random, and the effect (not the cause) of tissue-level events
- general deterioration of the tissue microenviroment due to extraceullar causes
