Mechanisms of Oncogenesis Flashcards
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
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 adenocarcinomas
What are the hallmarks of cancer?
Sustaining proliferative signalling 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
What is the evidence for cancer being a disease of the genome?
Carcinogens cause alterations to the DNA - Mutations
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 if severe damage 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
Cancer is more prevalent as lifespan has increased
How do tumours develop?
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 1014 cells in body need to be transformed to create a tumour
Continued accumulation of mutations
Tumour cells can ‘evolve’- subclonal selection allowing a growth advantage and explain the heterogeneity of cells in a tumour
Dependent on interaction with other tumour cells and the tumour microenvironment
How does a normal cell become a tumour cell?
A cell will proliferate in response to different factors
Processes such as apoptosis will keep proliferation in check
Regulation of all those points in differentiation pathway is important
Mutations in the genes that regulate those processes means that cells will continue to divide which will give you an increase in cell number which eventually leads to a clinically detectable tumour
What is the difference between 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
What are the 3 assumptions that come with multistage 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 is the first model of carcinogenesis- ‘mutational’?
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.
What are the classes of carcinogens and some examples?
Chemical: - 10 groups: polycyclic aromatic hydrocarbons, aromatic amines, azo dyes, nitrosamines, carbamates, halogenated compounds, alkylating agents Physical: - Radiation- ionising and ultraviolet - Asbestos Heritable: - Predisposition Viral: - Hepatitis B - Epstein Barr
How can chemical carcinogens induce cancer?
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, 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
Not a carcinogen until it gets in your body where it gets converted into bezo(a)pyrene epoxide which causes G to T transversions
What is the Ames test?*
A test to determine the mutagenic activity of chemicals by observing whether they cause mutations in sample bacteria.
What are physical carcinogens? How can radiation act as a physical carcinogen?
Unlike chemical carcinogens, physical carcinogens act by imparting energy into the biological material
Energy—-> Changes in bonding of molecules——> Biological effects
Radiation is the primary physical agent
Several types of radiation can act as carcinogens:
1. Ionising radiation (X-rays, nuclear radiation), UV radiation cause damage
2. DNA breaks, Pyrimidine dimers causing failed repair
3. Translocation mutations
What is meant by heritable carcinogens?
DNA damage is a risk factor for cancer development
Accounts for 5% of all cancers
An inherited germline mutation, has an increased risk of developing certain tumours but are rarely involved in causing cancer immediately
In most known hereditary malignant syndromes the elevated cancer risk is due to a mutation of a single gene (monogenic hereditary diseases)
The affected genes concerned usually have a controlling function on the cell cycle or the repair of DNA damage
A deficiency in DNA repair would cause more DNA damages to accumulate, and increase the risk for cancer
What are some syndromes predisposing someone 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
How can ataxia-telangiectasia predispose someone to cancer?
Ataxia telangiectasia- neuromotor dysfunction, dilation of blood vessels,
telangiectasia = spider veins
- Mutation in ATM gene, codes for a serine/threonine kinase that is recruited and activated by
- dsDNA breaks leading to cell cycle arrest, DNA repair and apoptosis -cell cycle arrest
- Cancer predisposition: lymphoma, leukaemia and breast cancer
