Mechanisms of oncogenesis Flashcards
What are the risk factors of cancer?
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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?
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- 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?
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Look at the flow diagram of apoptosis, growth and differentiation
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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
How to physical carcinogens act?
- Unlike chemical carcinogens physical carcinogens act by imparting energy into the biological material.
- Radiation is the primary physical agent
- Several types of radiation can act as carcinogens
- Energy alters molecules and bonding
- Exposure to sun is one of the biggest risks for melanoma (skin cancer)
- If the pyrimidine dimers/DNA breaks aren’t repaired, it will lead to permanent mutations
- UV radiation and Ionizing radiation
- UV doesn’t penetrate lower than your skin
How can cancer be inherited?
- 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 is 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
What is blood syndrome?
short stature, rarely exceed 5 feet tall, skin rash that develops
after exposure to the sun
Mutation in BLM gene that provides instructions for coding a member of the RecQ helicase family
that help maintain the structure and integrity of DNA
Cancer predisposition: skin cancer. basal cell carcinoma and squamous cell carcinoma.
What is Lynch type?
Lynch type- LS doesn’t cause any symptoms.
Sometimes the first sign that a person has LS is when the symptoms of bowel and womb cancer develop.
Mutations in DNA mismatch repair (MMR) genes, notably MLH1, MSH2, MSH6 and PMS2.
Cancer predisposition: colorectal cancer
Can viruses transform into tumour cells?
Yes
What properties do tumourigenic viruses have?
Stable association with cells
• chromosomal integration
• episome
Must not kill cells
• non-permissive host (virus cannot replicate)
• 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
Describe model 2 of cancer - genome instability
Knudson’s Hypothesis for Hereditary Cancers
• First proposed by Carl Nordling in 1953 and then formulated by Knudson in 1971
• Developed by Knudson for retinoblastoma, which became the basis of the ‘two-hit’ hypothesis
• and led to the formulation of the theory of ‘tumour suppressor genes’(TSGs) and then to the
• discovery of Rb1, the TSG that causes retinoblastoma when both copies are mutated
• Knudson performed statistical analysis on cases of retinoblastoma of which there are two types the inherited type and the sporadic type
• Knudson suggested that multiple hits were required to cause cancer. So for example if the first mutated allele was inherited the second mutation would lead to cancer. In the sporadic forms of the tumour both mutations had to take place and hence this could explain the difference of age at diagnosis
At least two 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.
Describe model 3 of cancer - non-genotoxic
Non-genotoxic is characterized by an emphasis on non-genotoxic effects
Several important modulators of cancer risk (diet, obesity, hormones and insulin resistance) do not seem to act through a structural change in DNA but rather through functional changes including epigenetic events.
There is, however, a group of carcinogens that induce cancer via non-genotoxic mechanisms. Non-genotoxic carcinogens have been shown to act as:
• tumour promoters (1,4-dichlorobenzene),
• endocrine-modifiers (17β-estradiol),
• receptor-mediators (2,3,7,8-tetrachlorodibenzo-p-dioxin),
• immunosuppressants (cyclosporine) or
• inducers of tissue-specific toxicity and inflammatory responses (metals such as arsenic and beryllium)
Although little is known about this group of carcinogens it is known that in a high proportion of them, multiple pathways need to be altered for cancer induction
Describe model 4 of cancer - darwinian
- Carcinogenesis by Mutation and Selection-Model of Clonal Expansion
- the role of the environment in selecting cells that have some acquired advantage
Describe model 5 of cancer - tissue organisation
- To understand the changes that occur during cancer it is important to understand the principles of cell and tissue organisation and mechanisms that control growth and structure.
- Tissues - Groups of cells with similar function are known as tissues: epithelial, connective muscle and nervous
What is the somatic mutation theory and tissues organisation theory?
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What is the immune response to cancer?
The immune system will: • Protect from virus-induced tumours • Eliminate pathogens • Identify and eliminate tumour cells LEADS TO Immune surveillance LEADING TO Despite this tumours can still arise-Concept of cancer immunoediting
3 E’s of cancer imminoediting
The Three Es Elimination The immune system is able to eradicate developing tumours Equilibrium When incomplete removal is present tumour cells remain dormant and enter equilibrium. The immune system exerts a potent and relentless pressure that contains the tumour. During this phase some of the tumour may mutate or give rise to genetic variants that survive, grow and enter the next phase(Longest of the phases, around 20 years) Escape The expanding tumour populations becomes clinically detectable
