Mechanisms Of Oncogenesis Flashcards
What the statistics for cancer?
Every two minutes, someone is diagnosed with cancer in the UK. Every four minutes, someone dies from cancer in the UK.
1 in 2 people in the UK born after 1960 will be diagnosed with some form of cancer during their lifetime.
42% of cancers in the UK are linked to lifestyle.
What factors can increase the risk of cancer?
- Smoking (biggest cause)
- Obesity and weight
- Hormones
- Alcohol
- Some jobs
- UV and sun
- Lack of physical activity
- Infections and HPV
- Bad diet and eating badly
- Inherited genes (faulty genes inherited)
- Air pollution and radon
Why is incidence of cancer more common in older people?
Cancer is a disease of aging and there is loss of control of cell signalling pathways.
Cancer is slightly more common in males than females.
What is cancer?
Group of diseases characterised by:
- Abnormal cell proliferation
- Tumour formation
- Invasion of neighbouring normal tissue
- Metastasis to form new tumours at distant sites
There is angiogenesis.
There are carcinomas, sarcomas and adenocarcinomas.
What are carcinomas?
Cancer in epithelial cells. Most common.
What are sarcomas?
Cancers derived from mesodermal cells (bone and muscle)
What are adenocarcinomas?
Cancers in glandular tissue
How many hallmarks of all cancers?
6
What do these hallmarks include?
- Genome instability
- Tumour inflammation
- Avoid immune destruction and reprogramming energy metabolism
What do cancer cells do?
- 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
- Sustaining proliferative signalling
- Evading growth suppressors
Explain the DNA in tumours
The DNA contains many alterations such as point mutations and deletions. The accumulation of mutations over time represents the multi-step process that underlies carcinogenesis. This accumulation only only occurs after the cells defence mechanism DNA repair have been evaded.
What happens if there is severe damage to a normal cell?
Apoptosis is induced.
Why may apoptosis not occur of damaged cells?
Although many mechanisms exist for blocking carcinogenesis, overburdening the system increases the possibility that cells will escape surveillance.
Why is cancer more prevalent in older people?
The longer we live, the more time there is for DNA to accumulate mutations that may lead to cancer
How can cancer be hereditary?
- Germline mutation - alteration in DNA (e.g mutation, deletion) in oocyte/spermatozoa
- Now offspring contains the mutation hence inheritable mutation.
This mutation increases risk of developing cancer. Rarely involved in causing cancer immediately.
What makes up most mutations in tumour cells?
Somatic mutations
Explain how a tumour forms
All cells in a primary tumour arise from a single cell. Initiation of development of cancer is clonal.
Only one of the billions of cells need to be transformed to create a tumour.
Then we get continued accumulations of mutations.
How do tumour cells evolve?
Subclonal selection allows a growth advantage and explains the heterogeneity of cells in a tumour. It is dependent on the interaction with other tumour cells and the tumour microenvironment.
How are tumours heterogenic?
Tumours accumulate changes to help them change
Explain somatic mutations
There is alteration of DNA in somatic cell (somatic mutation). These cells divide (clonal cells) to form a tumour. This is non-inheritable mutation.
How can a normal cell convert into a tumour cell?
Loss of control of proliferation = control of cell division within a tissue is important in rapidly self renewing tissues. Proliferation must balance cell loss. When this control is lost, you may get a tumour cell.
- Signals = messages such as growth factors (e.g EGF, PDGF) and cytokines (e.g growth hormone, interleukins) and hormones (e.g oestrogen) are needed for cell proliferation. (Proliferation of damaged cell can form tumour)
- Apoptosis = programmed cell death occurs as a result of irreparable damage. (If damaged cells don’t undergo apoptosis, they can proliferate and form a tumour)
So these need to be balanced to prevent tumours from forming.
What is the pathway for normal cells?
- Proliferation (division and growth)
- Differentiation to perform a specific function
- Eventually, apoptosis
This process is in balance and under tight control.
What can happen in a damaged cell (carcinogenesis)?
A cell may be damaged due to mutations in DNA that alter the function of normal genes involved in growth. This may cause uncontrolled proliferation, undifferentiation and mess up apoptosis. This would cause uncontrolled cell division to increase total cell number. This is carcinogenesis.
What are protooncogenes and tumour suppressor genes?
These are normal genes that control growth.
Protooncogenes are important to regulate cell growth.
Tumour suppressor genes inhibit growth and tumour formation.
How do tumour suppressor genes work?
They act as braking signals during G1 of the cell cycle to stop or slow the cell cycle before the S phase.
What happens when there’s a mutation in a tumour suppressor gene?
The normal brake mechanism will be disabled resulting in uncontrolled growth - cancer.
What happens when a protooncogene is mutated?
It forms an oncogene. It leads to signals that cause uncontrolled growth like cancer.
What 3 assumptions do we make for 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 are the 5 models for carcinogenesis?
- Mutational
- Genome instability
- Non-genotoxic
- Darwanian
- Tissue organisation
Explain ‘mutational’
The main focus is chemical carcinogens. Can be viruses, tobacco and lung HPV, DNA adducts. Mathematical model using Armitage-doll.
Cancer is multi-step process that includes initiation, promotion and progression. Chemical carcinogens can alter any of these processes 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 cancer causing chemicals called?
Carcinogens
What are the classes of carcinogens?
- Chemical e.g aromatic hydrocarbons, aromatic amines, azodyes, nitroasmines, halogenated compounds, alkylating agents
- Physical e.g radiation (ionizing and ultraviolet), asbestos
- Heritable e.g predisposition
- Viral e.g hep B, Epstein Barr
What are the cancer causing chemicals in tobacco and cigarettes?
- Benzene
- Arsenic
- Cadmium and lead
- Formaldehyde
- Polonium 210
- Chromium
- 1,3 butadiene
- Nickel
- Vinyl chloride
- Beryllium
- Ethylene oxide
- Polycyclic aromatic hydrocarbons
- Orthotoluidine
- 4-aminobiphenyl
What do chemical carcinogens do?
Four of the major groups polycyclic aromatic hydrocarbons, aromatic amines, nitrosamines have their effects by adding functional groups to DNA bases called DNA adducts.
E.g coal tar which contains benzoapyrene, a polycyclic hydrocarbon. Found in cigarette smoke. It can enter cells really easily.
How does benzoapyrene work?
It is a procarcinogen. Microsomal enzymes in our body converts it to a carcinogen (benzoapyrene expoxide). It converts guanine to thymine by altering functional groups.
What is the ames test?
It used to see the mutagenic activity of chemicals by seeing whether they cause mutations in sample bacteria.
When you add the possible mutagen to agar plate and incubate it, a high number of revertants (his- to his+) suggests the mutagen causes mutations
Explain physical carcinogens
These impart energy into biological material.
Energy —> changes in bonding of molecules —> biological effects
Several types of radiation can act as carcinogens.
How does ionizing radiation act as carcinogen (X-rays, nuclear radiation, UV radiation)?
Damages DNA by breaking Pyrimidine dimers —> failed repair leads to translocations mutations
How do heritable carcinogens work?
They predispose you to cancer. They account for 5% of all cancers.
An inherited germline mutation has an increased risk of developing certain tumours but rarely immediately cause cancer.
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.
What happens in deficiency in DNA repair?
It would cause more DNA damages to accumulate and increase the risk of cancer.
Give some syndromes predisposing to cancer?
DNA repair defects:
- Ataxia telangiectasia
- Bloom’s syndrome
- Fanconi’s syndrome
- Li- Fraumeni’s syndrome
- Lynch Type II
- Xeroderma pigmentosum
Chromosomal abnormalities:
- Down’s syndrome
- Klinefelter’s syndrome
Explain ataxia telangiectasia
Neuromotor dysfunction, dilation of blood vessels, spider veins.
Mutation in the ATM gene. Codes for serine/threonine kinase that’s recruited and activated by double stranded DNA breakage that should lead to cell cycle arrest, DNA repair and apoptosis. It’s role is to phosphorylate tumour suppressor genes such as p53 directly and indirectly.
Cancer predisposition = lymphoma, leukaemia and breast cancer.
Explain Bloom’s Syndrome
It is caused by a mutation in the BLM gene. BLM provides instructions for coding a member of the RecQ helicase family to help maintain the structure and integrity of DNA.
- Short stature (rarely exceed 5 feet tall)
- Skin rash after sun exposure
Cancer predisposition: skin cancer, basal cell carcinoma and squamous cell carcinoma
Explain Lynch type
It is caused by mutations in DNA mismatch repair (MMR) genes, notably MLH1, MSH2, MSH6, PMS2.
Doesn’t have symptoms but sometimes the first sign is when symptoms of bowel and womb cancer develop.
Cancer predisposition: colorectal cancer
How do viruses cause harm?
Most viruses multiply inside the cell and express majority of their genes. They kill the cell and release progeny e.g capsids to further infect other cells.
Sometimes viruses switch from lytic cycle to latent cycle which can allow transformation into tumour cell.
What are the properties required of tumourigenic viruses?
- Stable association with cells = e.g chromosomal integration, episome
- Must not kill cell = non permissive host, 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
What happens in viral carcinogenesis?
- Viral gene products inactivate cycle regulatory proteins (p53, rb)
- Viral integration into cellular genome disrupts cellular genes
- Virus carries mutated cellular gene (oncogene)
- Viral gene products act as transcription factors
- Viral infection results in immunodeficiency
What DNA viruses are associated with human cancers?
Epstein-Barr virus = Burkitt’s lymphoma, nasopharyngeal carcinoma
Papilloma viruses = cervical carcinoma, warts
Hepatitis B and C = hepatoma
What RNA viruses are associated with human cancers?
HTLV -1 = adult T cell leukaemia, lymphoma
Explain ‘genome instability’
Two hit hypothesis developed for retinoblastoma. Found out that it is caused when both Rb genes are mutated.
There are two types of retinoblastoma = inherited and sporadic
Multiple hits rare required to cause cancer. E.g if the first mutated allele was inherited, the second would lead to cancer.
In sporadic forms of the tumour, both mutations had to take place hence this could explain the differences 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.
Explain ‘non genotoxic’
This is emphasis on non-genotoxic effects. Cause cancer via non-genotoxic effects.
Several important modulators of cancer risk (diet, obesity, hormones and insulin resistance) don’t act through structural change in DNA but through functional changes including epigenetics.
What do non genotoxic carcinogens act as?
- Tumour promoters (1,4 dichlorobenzene)
- Endocrine modifiers (17B-estradiol)
- Receptor-mediators (2,3,7,8- tetrachlorodibenzo-p-dioxin)
- Immunosuppressants (cyclospirone)
- Inducers of tissue specific toxicity and inflammatory responses (metals such as arsenic)
Multiple pathways need to be altered for cancer induction.
Explain ‘Darwinian’
This is the role of the environment in selecting cells that have acquired advantage. Selective pressure. Gives rise to heterogeneity
Explain clonal expansion model
- Sequential accumulation of mutations due to exposure to carcinogens
- Tumour cells will be selected for ability to grow and invade
- Selection will include resistance to therapy (artificial selection)
- Some mutations may be deleterious for tumour
Explain ‘tissue organisation’
Physical changes causing genomic changes.
What is a tissue?
Groups of cells with similar function. E.g epithelial tissue, connective tissue, muscle tissue
What are the two driving forces for carcinogenesis?
- Somatic mutation theory (STT)
2. Tissue organisation field theory (TOFT)
Explain the somatic mutation theory
Cancer is derived from a single somatic cell that’s accumulated multiple DNA mutations. These mutations damage the genes which control cell proliferation and cell cycle.
So single catastrophic event triggering carcinogenesis
According to SMT, neoplastic lesions are the results of DNA-level events.
Explain the tissue organisation theory
Carcinogenesis is primarily a problem of tissue organisation.
Carcinogenic agents destroy normal tissue architecture thus disrupting cell-to-cell signalling and compromising genomic integrity.
The DNA mutations are random and effect, not the cause, of the tissue level events.
So carcinogenesis occurs as general deterioration of the tissue microenvironment due to extracellular causes
What is the immune response in cancer?
The immune system will:
- Protect from virus induced tumours
- Eliminate pathogens
- Identify and eliminate tumour cells by immune surveillance
Despite all this, tumours can still arise = concept of immunoediting
What is cancer immunoediting?
Elimination, equilibrium and escape.
Elimination = immune system can eradicate developing tumours
Equilibrium = when incomplete removal is present, tumour cells remain dormant and enter equilibrium. 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 phase)
Escape = The expanding tumour populations become clinically detectable
