Mechanisms of Oncogenesis Flashcards
List some cancer statistics.
INCIDENCE:
- every two minutes someone in the UK is diagnosed with cancer
- 359,960 new cases of cancer in the UK in 2015, that’s 990 cases diagnosed every day
MORTALITY:
- every four minutes someone in the UK dies from cancer
RISK:
- 1 in 2 people in the UK born after 1960 will be diagnosed with some form of cancer during their lifetime
SURVIVAL:
- half (50%) of people diagnosed with cancer in England and Wales survive their disease for ten years or more (2010-11)
- cancer survival is improving and has doubled in the last 40 years in the UK
PREVENTION:
- 4 in 10 (42%) of cancer cases in the UK each year are linked to lifestyle
- these are cases that can be prevented largely through lifestyle changes
What are some factors that can be targeted to prevent and reduce the risk of cancer?
- smoking: smoking is the most important preventable cause of cancer in the world
- obesity and weight: small changes you can stick with help keep weight off for good
- hormones: changes in our hormone levels can affect the risk for cancer
- alcohol: the less you drink, the lower the risk of cancer
- workplace causes of cancer: some jobs can affect people’s risk of cancer or may have done in the past
- sun and UV: overexposure to UV light from the sun or sunbeds is the main cause of skin cancer
- physical activity: around 3400 cases of cancer in the UK each year could be prevented by keeping active
- infections and HPV: you can’t catch cancer, but some infections such as human papilloma virus can increase the risk
What is cancer?
Cancer is the name for a group of diseases characterised by:
- abnormal cell proliferation
- tumour formation
- invasion of neighbouring normal tissue
- metastasis to form new tumours at distant sites
Over 200 different types of cancer have been classified, often according to their origin:
- approximately 85% of cancer occur in epithelial cells - CARCINOMAS
- cancers derived from mesoderm cells (bone and muscle) are SARCOMAS
- cancers found in glandular tissue are called ADENOCARCENOMAS
List the hallmarks of cancer.
- evading growth suppressors
- avoiding immune destruction
- enabling replicative immortality
- tumour-promoting inflammation
- activating invasion and metastasis
- inducing angiogenesis
- genome instability and mutation
- resisting cell death
- deregulating cellular energetics
- sustained proliferative signaling
Explain how evidence suggests that cancer is a disease of the genome at the cellular level.
Carcinogens cause alterations to the DNA - mutation.
DNA from tumours has been shown to contain many alterations from point mutations to deletions.
The accumulation of mutations over time represents the multi-step process that underlies carcinogenesis.
This accumulation occurs only after the cells defence mechanism of DNA repair have been evaded.
In cases of severe damage cell apoptosis is induced; however, 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.
That’s why cancer is more prevalent as lifespan has increased.
Describe tumour cells.
Somatic mutations constitute almost all mutations in tumour cells.
All cells in a primary tumour arise from a single cell: initiation of the
development of cancer is clonal .
Only one of the 10^14 cells in the body need to be transformed to create a tumour.
It is the continued accumulation of mutations.
Tumour cells can ‘evolve’- sub clonal selection allows a growth advantage and explains the heterogeneity of cells in a tumour.
It’s dependent on interaction with other tumour cells and the tumour microenvironment.
Describe oncogenes and tumour suppressor genes.
Normal genes regulate growth
Normal genes that can be activated to be oncogenic are called proto-oncogenes.
An oncogene is a proto-oncogene that has been mutated in a way that leads to signals that cause uncontrolled growth- i.e., cancer.
This is like pushing down on the gas pedal.
Tumour suppressor genes inhibit both growth and tumour formation.
They act as braking signals during phase G1 of the cell cycle, to stop or slow the cell cycle before S phase.
If tumour-suppressor genes are mutated, the normal brake mechanism will be disabled, resulting in uncontrolled growth, i.e. cancer.
With the scheme of multi-stage carcinogenesis, what are the three assumptions made?
- 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 the 5 models of cancer?
Model 1: mutational
Model 2: genome instability
Model 3: non-genotoxic
Model 4: Darwinian
Model 5: tissue organisation
Describe the first model of cancer.
CHEMICAL CARCINOGENS
Cancer is a multi step process that includes initiation, promotion and progression.
Chemical carcinogens can alter any of these process to induce their carcinogenic effects.
The presence of multiple mutations in critical genes is a distinctive feature of cancer cells and supports that cancer arises through the accumulation of irreversible DNA damage.
In the majority of instances, chemical carcinogens can induce this DNA damage and act in a genotoxic manner.
List the several classes of carcinogens.
CHEMICAL: 10 groups:
- polycyclic aromatic hydrocarbons
- aromatic amines
- azo dyes
- nitrosamines
- carbamates
- halogenated compounds
- alkylating agents
PHYSICAL:
- radiation (ionising and UV)
- asbestos
HERITABLE: predisposition
VIRAL:
Hep B, Epstein Barr
How do some chemical carcinogens (such as aromatic hydrocarbons) exert their effects?
Four of the major groups polycyclic aromatic hydrocarbons, aromatic amines, nitrosamines and alkylating agents exert their effects by adding functional groups to DNA bases called DNA adducts.
One example is coal tar, which contains benzo[a]pyrene BP), a polycyclic hydrocarbon.
Benzo[a]pyrene is commonly found in cigarette smoke (together with 81 other carcinogens)!
BP ranks high in the measure of how easy it enters into cells.
What is the Ames test?
A test to determine the mutagenic activity of chemicals by observing whether they cause mutations in sample bacteria.
AMES TEST:
You take rat liver extract, you mush it up and you combine it with a Salmonella strain that will only grow in the presence of histidine.
If you plate on that onto an agar plate that lacks histidine, following overnight incubation, you should have very few colonies on that plate. If you get one or two, it’s due to natural reversion.
If you add the chemical in question to that, and then plate it, and then you get lots of colonies, it suggest that there is now a change in the bacteria, and it can now grow in the absence of histidine. This confirms that the compound you’re testing is in fact carcinogenic.
How do physical carcinogens act?
Unlike chemical carcinogens physical carcinogens act by imparting energy into the biological material.
List some syndrome predisposing to cancer.
DNA REPAIR DEFECTS: - Ataxia Telangiectasia - Bloom’s syndrome - Fanconi’s anaemia - Li-Fraumeni syndrome - Lynch type II xeroderma pigmentosum
CHROMOSOMAL ABNORMALITIES:
- Down’s syndrome
- Klinefelter’s syndrome
