3 - MECHANISM OF ONCOGENESIS Flashcards
What are some factors that can be targeted to prevent and reduce the risk of cancer 8
- 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 4
Cancer is a group of diseases characterised by specific hallmarks.
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
Define Carcinoma 1
Carcinoma is a category of types of cancer that develop from epithelial cells.
Specifically, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that arises from cells originating in the endodermal, mesodermal or ectodermal germ layer during embryogenesis.
Approximately 85% of cancer occur in epithelial cells
Define Sarcomers 1
A sarcoma is a cancer that arises from transformed cells of mesenchymal (connective tissue) origin.
Connective tissue is a broad term that includes bone, cartilage, fat, vascular, or hematopoietic tissues, and sarcomas can arise in any of these types of tissues.
Cancers derived from mesoderm cells (bone and muscle)
Define Adenocarcinomas 1
A malignant tumour formed from glandular structures in epithelial tissue.
Cancers found in glandular tissue are called adenocarcinomas
How do cancers provide themselves with nutrients 1
Provide themselves with nutrients as a result of angiogenesis
What are the hallmarks of cancer 10
- evading growth suppressors
- enabling replicative immortality
- activating invasion and metastasis
- inducing angiogenesis
- resisting cell death
- deregulating cellular energetics
- sustained proliferative signalling
- avoiding immune destruction
- genome instability and mutation
- tumour-promoting inflammation
Two enabling characteristics: genome instability and tumour inflammation
Two emerging hallmarks: avoiding immune destruction and reprogramming energy metabolism
Evidence Suggest that Cancer is a Disease of the Genome at the Cellular Level 6
- Carcinogens cause mutations to the DNA. DNA from tumours show that many alterations (from point mutations to deletions) take place.
- 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
- 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 can an accumulation of mutations occur in DNA 1
This accumulation occurs only after the cells defence mechanism of DNA repair have been evaded
Germline mutations 2
- Germline mutation can be passed onto offspring
- IN risk of developing cancer
Somatic mutations and tumour cells 9
- 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
What can help convert a Normal Cell to a Tumour Cell 3
A cell proliferates in response to lots of different signals
GF, hormones, interleukins, cytokines
There are processes in the body that will counteract them though e.g. apoptosis
Growth, Apoptosis and Differentiation Regulate Cell Numbers
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Oncogenes 3
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.
Oncogenes are normal genes within your cells that regulate cell growth –> compared to racing cars –> the accelerator pedal and so a mutation will put your foot down on the pedal and eventually hit a brick wall which is cancer
Tumour Suppressor Genes 4
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.
Tumour suppressor genes need 2 mutations to stop their function like taking away the brakes of a car. You lose the ability to stop the car
What do Tumour Suppressor Genes do in the cell cycle 2
They act as braking signals during phase G1 of the cell cycle, to stop or slow the cell cycle before S phase.
3 assumptions of multistage carcinogenesis 3
- 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 meantime to tumour detection is generally constant
Molecular Mechanisms of Cancer - Five models of carcinogenesis 5
Molecular Mechanisms of Cancer - Five models of carcinogenesis 5
Model 1: Mutational
Model 2: Genome instability
Model 3: Non-genotoxic
Model 4: Darwinian
Model 5: Tissue organisation
MGDTN - My Giant D To Night
Model 1 Chemical Carcinogens - overview 3
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 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
Model 1 Chemical Carcinogens:
Specific carcinogenic agents implicated in the causation of certain cancer - table
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Model 1 Chemical Carcinogens
Types/Classes of carcinogens 4
- Chemical
- Physical
- Heritable
- Vital
Model 1 Chemical Carcinogens
Types/Classes of carcinogens - Example of Chemical 10
- polycyclic aromatic hydrocarbons
- aromatic amines
- azo dyes
- nitrosamines
- carbamates
- halogenated compounds
- alkylating agents
Model 1 Chemical Carcinogens
Types/Classes of carcinogens - Example of Physical 2
- radiation (ionising and UV)
- asbestos
Model 1 Chemical Carcinogens
Types/Classes of carcinogens - Example of Heritable 1
- predisposition
Model 1 Chemical Carcinogens
Types/Classes of carcinogens - Example of Viral 2
- Hepatitis B
- Epstein Barr
Model 1 Chemical Carcinogens
Other uses of cancer-causing chemicals in tobaccos and cigarette smoke
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Model 1 Chemical Carcinogens
Chemical carcinogens - Example, coal tar 6
- 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
- Benzopyrene goes to benzopyrene epoxide
Model 1 Chemical Carcinogens
Ames Test 5
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
Model 1 Chemical Carcinogens
What does radiation do as a primary physical agent 6
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
Model 1 Chemical Carcinogens
DNA Repair Defects - Ataxia telangiectasia
What is it? Where does the mutation occur? Cancer predisposition? 3
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
Model 1 Chemical Carcinogens
DNA Repair Defects - Bloom’s syndrome
What is it? Where does the mutation occur? Cancer predisposition? 3
Bloom’s 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.
Model 1 Chemical Carcinogens
DNA Repair Defects - Lynch type
What is it? Where does the mutation occur? Cancer predisposition? 3
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
Model 1 Chemical Carcinogens
Heritable carcinogens - Syndromes Predisposing to Cancer 7
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.
These mutations affect genes that regulate cell cycle, apoptosis and DNA damage repair
If you have this mutation you have a predisposition to that type of cancer due to the inability to repair DNA
Model 1 Chemical Carcinogens
Identifying Infectious Agents as Carcinogens - Viral infection process 5
- Most harm caused when viruses multiply inside the infected cell, kill the cell and release progeny to further infect other cells
- Viral infections when they infect, will be very proliferative –> they will exhibit a lytic cycle –> cell will lyse, releasing more viruses
- Viruses can switch from a lytic to a latent pathway, and they could allow transformation of cells into tumor cells.
- Most of the damage is done as part of their lytic cycle
- Viruses can be associated with cancer in rare cases and is shown usually later on.
Model 1 Chemical Carcinogens
Viral carcinogenesis 5
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Model 4 Darwinian 6
How? 1 Considerations? 2 Process? 4
- This is carcinogenesis by Mutation and Selection-Model of Clonal Expansion
- Always takes into account that there is a selective pressure - natural selection and artificial selection
- It is based on the role of the environment in selecting cells that have some acquired advantage.
- There is the sequential accumulation of mutations due to exposure to carcinogens.
- The tumour cells will be selected for ability to grow and invade
- Selection will include resistance to therapy.
- Some mutations may be deleterious for tumour.
- Chemotherapy is artificial selection, can lead to production of resistant cell types
- Accumulation of mutations
- The cells don’t acquire the same mutations
- You have natural selection for the cells that will have a growth advantage
Model 5 Tissue Organisation 2
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 does cancer immunoediting consist of? 3,3
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.
- When normal cells are exposed to carcinogens, they could become transformed –> these cells will have tumour antigens on their surface.
- The immune system will pick up the tumour antigens
- Cancer immunoediting is very important
Cancer immunoediting - Elimination 1
The immune system is able to eradicate developing tumours.
Cancer immunoediting - Equilibrium 3
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).
Cancer immunoediting - Escape 1
The expanding tumour populations becomes clinically detectable.
