Mechanisms of oncogenesis Flashcards
What is the incidence of cancer? and mortality statistics
Ever 2 mins someone in the UK is diagnosed, 359,960 new cases of cancer in UK 2015
Mortality: every 4 minutes someone in UK dies of cancer
Survival: half of people diagnosed survive 10 years or more
How can cancer be prevented/reduced risk?
Smoking
Obesity and weight, small changes you can stick with help to lose weight
Hormones changes in our hormone levels can affect the risk of cancer
Sun and UV, UV light from sun and sunbeds cause skin cancer
Physical activity, around 3400 cases can be prevented by keeping active
Diet and healthy eating, eating healthy balanced diet reduces risk of cancer
Inherited genes, some inherited faulty genes increase your risk of cancer
Infections and HPV, some infections increase risk of cancer
Air pollution and radon, although exposure ti air pollution can be linked to cancer, the UK risk is low
Work place causes of cancer
Alcohol increases risk of cancer
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
85% of cancers occur in eptihelial cells - carcinomas
cancers in mesoderm cells (bone and muscle) - sarcomas
cancers found in glandular tissues - adenocarcinomas
What are the hallmarks of cancer?
Evading growth suppressors
Avoiding immune destruction
Enabling replicative immortality
Tumour promoting inflammation - 2011
Activating invasion and metastasis
Inducing angiogenesis
Genome instability and mutation - 2011
Resisting cell death
Deregulating cellular energetics
Sustaining proliferative signalling
Why is cancer more prevalent as lifespan increases?
Accumulation of mutations over time represents the multi-step process that underlies carcinogenesis.
accumulation occurs after cells defence mechanism of DNA repair has been evaded
the longer we live, the more time there is for DNA to accumulate mutation sthat may lead to cancer
What two types of cells do mutations affect?
In egg or sperm = germ line mutations
- Can be passed onto offspring
- increased risk of developing cancer
In somatic cells
- non-heritable
- but can be passed onto daughter cells by cell division
- constitute almost all mutations in tumour cells
- only one of cells in body need to be transformed to create tumour
What signals does cells proliferate in response to?
What counter balances this?
1.
- Messages
- Growth factors EGF and PDGF
- Cytokines, growth hormone
- Interleukins
- Hormones
- Apoptosis, programmed cell death as a result of irreparable damage.
Why do you need to regulate cell prolieration and death?
Regulation needed as mutations in DNA that alter function of normal genes involved in growth, apoptosis and differentiation affects balance of cell proliferation and apoptosis.
Can lead to tumour e.g mutations in genes regulating processes, cells continue to divide
What is an oncogene?
Normal genes regulate growth, these can be activated to be oncogenic - proto-oncogenes
Oncogene is a proto-oncogene that has been mutated in a way that leads to signals that cause uncontrolled growth ie. cancer
What are tumour suppressor genes?
Tumour suppressor genes inhibit both growth and tumour formation.
Act as braking signals during G1 of cell cycle to stop/slow cell cycle before S phase.
If tumour suppressor genes are mutated, normal brake mechanism is disabled, resulting in uncontrolled growth ie. cancer
What are the 3 assumptions about 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 mean time to tumour detection is generally constant
What is model 1 mechanism for cancer?
Model 1, Chemical carcinogens
Cancer is multi-step process, includes initiation, promotion and progression
Carcinogens can alter any of these processes to include carcinogenic effects
chemical carcinogens can induce DNA damage and act in a genotoxic manner.
What are the classes of carcinogens and examples of each of them?
Chemical: 10 groups:
- Polycyclic aromatic hydrocarbons
- Aromatic amines
- Azo dyes
- Nitrosamines
- Carbamates
- Halogenated compounds
- Alkylating agents
Physical
- Radiation – ionising, ultraviolet
- Asbestos
Heritable
- Predisposition
Viral
- Hepatitis B
- Epstein Barr
How do polycyclic aromatic hydrocarbons, aromatic amines, nitrosamines and alkylating agents exert their effects?
Adding functional groups to DNA bases, called DNA adducts.
e.g benzo[a]pyrene, polycyclic hydrocarbon, on its own isn’t carcinogenic but gets converted from pro-carcinogen to carcinogen via microsomal enzymes, causes G to T transversions
Wat is the Ames test? How is it conducted?
Test to determine the mutagenic activity of chemicals by observing whether they cause mutations in sample bacteria
Take bacteria, e.g rat liver extract mushed up with salmonella strain that only grows in presence of histidine
Plate mixture on an agar plate lacking histidine
Overnight incubation
Should have very few colonies on the plate, only due to natural reversion you may get some
If you add chemical in question to it
plate it and you get lots of colonies suggests there has been change in bacteria and they can now grow in the absence of histidine
Confirms compound is carcinogenic
How do physical carcinogens work?
By imparting energy into biological material, altering bonding of molecules.
e.g radiation causes DNA breaks and pyrimidine dimers, but can be repaired.
but if you have mutations in DNA damage repair mechanisms there is failure to repair, leading onto more changes - translocations and mutations
What syndromes predispose to cancer?
Cancer 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
What is ataxia telangiesctasia? What cancers does it predispose to?
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 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 structure and integrity of DNA
Cancer predisposition: skin cancer, basal cell carcinoma and squamous cell carcinoma
What is lynch type?
Doesn’t cause symptoms, first sign a person has LS is when symptoms of bowels and womb cancer develop
mutations in DNA mismatch (MMR) genes, notably MLH1, MSH2, MSH6 and PMS2
cancer predispostion: colorectal cancer
What properties do tumorigenic viruses require?
Stable associated with cells
- Chromosomal integration
- Episome
Must not kill cells, hence often that viruses hijack machinery in host cell for its benefit
- Non-permissive host (virus cannot replicate)
- Suppression of vital lytic cycle
- Viral release by budding
Must evade immune surveillance of infected cells
- Immune suppression, shouldn’t be picked up by immune system. Hence you find in latent phase allow virus to survive within host being undetected by immune system
- Viral antigens not expressed at cell surface
Examples of viruses associated with human cancer
DNA viruses
- Epstein-Barr virus (doesn’t give symptoms) – Burkitt’s lymphoma, nasopharyngeal carcinoma
- Papilloma viruses – cervical carcinoma, warts
- Hepatitis B and C – hepatoma
RNA retroviruses
- HTLV-I -adult T-cell leukaemia, lymphoma
Explain model 2, genome instability
Knudson performed statistical analysis on cases of retinoblastoma of two types, inheritedand sporadic type
Suggested that multiple hits were required to cause cancer
e.g if the first mutated allele was inherited, the second mutation would lead to cancer.
In sporadic forms of the tumour both mutations had to take place and hence sporadic form tumour developed later in life than inherited
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 model 3, non genotoxic
Non-genotoxic characterised by an emphasis on 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 epigenetic events
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 (17B-estradiol)
- Receptor-mediators (2,3,7,8-tetrachlorodibenzo-p-dioxin)
- Immunosuppressants (cyclosporine) or
- Induces 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 high proportion of them, multiple pathways need to be altered for cancer induction
Explain model 4, Darwinian
Carcinogenesis by mutation and selection model of clonal expansion
the role of the environment in selecting cells that have some accquired advantage
cells acquire mutations due to carcinogens
cells will have mutations in mechanisms driving cell growth
leads to transformation
single tumour cell continually evolving
eventually end up with more tumour cells
can also apply selection e.g patients undergoing chemotherapy, patients end up resistant to treatment due to selecting cells that can outgrow chemotherapy
Explain model 5, tissue organisation
SMT theory
Tissues are groups of cells with similar function: epithelial, connective muscle and nervous
Somatic mutation theory SMT
- Cancer is derived from single somatic cell that has successively accumulated multiple DNA mutations
- mutations damage genes which control cell proliferation and cell cycle
- thus according to SMT neoplastic lesions are the result of DNA-level events
Explain tissue organisation field theory TOFT (model 5)
Carcinogenesis is primarily a problem of tissue organisation
Carcinogenic agents destroy the normal tissue architecture, disrupting cell-to-cell signalling and compromising genomic integrity
DNA mutations are random and the effect, not the cause, of the tissue-level events
Carcinogenesis as general deterioration of the tissue microenvironment due to extracellular causes
How does the immune system respond to cancer?
- Protect from virus-induced tumours
- Eliminate pathogens
- Identify and eliminate tumour cells
Immune surveillance.
What is cancer immunoediting?
Despite immune surveillance tumours can still arise.
Normal cells exposed to carcinogens and transformed, have tumour antigens on surface, immune system picks these up.
Elimination
- immune system eradicates developing tumours but is not 100% and some cells may enter equilibrium
Equilibrium
- When incomplete removal is present tumour cells remain dormant and enter equilibrium. immune system exerts 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
- expanding tumour populations become clinically detectable, here you have cancer progression
