Mechanisms of oncogenesis Flashcards
What are the risk factors of cancer?
On image
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
How are cancers classified?
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 adenocarcinomas
What are the hallmarks of cancer?
On image
- In 2000, Hanahan and Weinberg defines six hallmarks of most if not all cancers
- In 2011, this had been modified to include:
- Two enabling characteristics: genome instability and tumour inflammation
- Two emerging hallmarks: avoiding immune destruction and reprogramming energy metabolism
How is cancer a disease of the Genome at the Cellular Level?
• 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
Germline mutation can be passed onto offspring
Mutations can be germline and passed on to offspring
Majority of mutations are in somatic cells and can be passed on to daughter cells as a result of cell division
It only takes one cell
How to tumour cells arise from somatic 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 1014 cells in body need to be transformed to create a tumour
- Continued accumulation of mutations
- Tumour cells can ‘evolve’- sub clonal selection allowing a growth advantage and explain and heterogeneity of cells in a tumour
- Dependent on interaction with other tumour cells and the tumour microenvironment
- Somatic mutations can be passed on/inherited
- Takes 1 cell to undergo transformation to initiate the process
- Tumour cells can interact with the cells around them
How is a normal cell converted to a tumour cell?
On diagram
Look at the flow diagram of apoptosis, growth and differentiation
On image
What are normal genes, proto-oncogenes and oncogenes?
- 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.
What are tumour-suppressor genes?
- 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 of 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
Describe model 1 of cancer
- Cancer is s 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.
- Carcinogens alter the structure of DNA If this damage is not repaired, you will get an accumulation of the damage
- Cancer arises through irreversible DNA damage
What are the 4 main types of carcinogens?
Four main types: • Chemical • Physical • Heritable • Vital
How is benzopyrene converted into a carcinogen in our bodies?
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, it’s a pro carcinogen.
Taken into our body and comes into contact with enzymes, then it becomes carcinogenic via G to T conversions
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.
Benzo[a]pyrene is only harmful if it is inside your body it is converted to a carcinogen due to G-T transversions
DNA adduct a semgnet of DNA bound to a cancer causing chemical
Benzopyrene goes to benzopyrene epoxide
What is ames test?
- A test to determine the mutagenic activity of chemicals by observing whether they cause mutations in sample bacteria.
- Uses bacteria
- Take rat liver extract and combine it with salmonella strain that will only grow in the presence of histidine. If you plate that mixture onto an agar plate that lacks histidine, following overnight incubation, you should have very few colonies on the plate.
- If you get some colonies, it is due to natural reversion.
- If you get lots of colonies, it shows that there is a change in the bacteria and so it can now grow in the absence of histidine
