Mechanism of Oncogenesis Flashcards
Describe the incidence of cancer in the UK
Incidence - Every two minutes someone in the UK is diagnosed with cancer
359,960 new cases of cancer in the UK in 2015, that’s 990 cases diagnosed every day
Outline the mortality rate of cancer in the UK
Mortality - Every four minutes someone in the UK dies from cancer
What is the cancer risk of the UK population?
1 in 2 people in the UK born after 1960 will be diagnosed with some form of cancer during their lifetime
What are the chances of cancer survival in the UK?
Cancer survival - Half (50%) of people diagnosed with cancer in England and Wales survive their disease for ten years or more (2010-11)
Cancer survival is improving and has doubled in the last 40 years in the UK
How can cancer be prevented?
4 in 10 (42%) of cancer cases in the UK each year are linked to lifestyle
These are cases that can be prevented largely through lifestyle changes
What are the lifestyle factors contributing to cancer onset?
- smoking
- obesity + weight
- hormones
- sun + UV
- Workplace causes
- alcohol
- physical activity
- infections + HPV
- diet
- inheritance
- air pollution and radion
Describe the age range in prevalence of cancer
Adults aged 50-74 account for more than half (53%)
of all new cancer cases, and elderly people aged 75+
account for more than a third (36%), with slightly
more cases in males than females in both age groups.
Why are there more 50-74 y/o in the population with cancer than any other age range?
There are more people aged 50-74 than aged 75+
in the population overall, hence the number of
cancer cases is higher in 50-74s, but incidence
rates are higher in 75+s.
What is cancer?
Cancer is the name for a group of diseases
What are the group of diseases responsible for cancer?
Cancer is 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 many types of cancer are there?
Over 200 different types of cancer have been classified, often according to their origin
Where are the common occurrences of cancer?
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 defined by Hanahan and Weinberg?
- sustaining proliferative signalling
- evading growth suppressors
- avoiding immune destruction
- enabling replicative immortality
- tumour-promoting inflammation
- activating invasion + metastasis
- inducing angiogenesis
- genome instability + mutation
- resisting cell death
- deregulating cellular energetics
What is the consequence of carcinogens?
Carcinogens cause alterations to the DNA - Mutations
DNA from tumours has been shown to contain many alterations from point mutations to deletions
How does carcinogenesis occur?
The accumulation of mutations over time represents the multi-step process that underlies carcinogenesis
When does carcinogenesis occur?
This accumulation occurs only after the cells defence mechanism of DNA repair have been evaded
When is apoptosis induced during cancer?
In cases of severe damage cell apoptosis is induced
What mechanisms are available in the body to fight cancer?
Many mechanisms exist for blocking carcinogenesis but over burdening the system increases the possibility that cells will escape surveillance
Why does age play a major factor in cancer development?
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 do germ line mutations lead to cancer?
Alterations in egg/sperm DNA (point mutations / deletions)
inheritable; make up ~5% of all cancers
Majority of cell mutations affect somatic cells instead
Explain how somatic mutations cause cancer?
> non-inheritable mutation
All cells in a primary tumour arise from a single cell, initiation of the development of cancer is clonal
Dependent on interaction with other tumour cells and the tumour microenvironment
Why are somatic mutations such a common cause of cancer?
Only one of the 10^14 cells in body need to be transformed to create a tumour
Continued accumulation of mutations
Why is cancer hard to cure?
Tumour cells can ‘evolve’- sub clonal selection allowing a growth advantage and explain and heterogeneity of cells in a tumour
When are normal cells converted to cancerous tumour cells?
If the balance between the process by which cells proliferate and apoptosis occurs is lost normal healthy cells can convert into tumour cells
It is a delicate balance.
How do cells proliferate?
Cells respond to growth factors and signals allowing proliferation
How does apoptosis occur?
Damage and irreversible DNA damage acts as a balance enabling cell loss via apoptosis
Which processes regulate cell number?
Growth, Apoptosis and Differentiation
What is the cell growth and apoptosis pathway regulated by?
This pathway is regulated by a number of different genes:
- Oncogenes
- Tumour suppressor genes
Acquiring a mutation in one of those genes will cause a loss in regulation
What is the consequence in mutations of cell number regulation pathways?
Mutation usually causes an increase in cell no. to the point where you have a clinically detectable tumour
What are proto-oncogenes?
Normal genes that can be activated to be oncogenic
What is an oncogene?
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
What is the role of 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.
What is the effect of mutations in tumour suppressor genes?
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
What are the 5 molecular mechanisms of cancer?
- Mutational
- Genome Instability
- Non-genotoxic
- Darwinian
- Tissue organisation
Describe the formation of cancer formation
Cancer is a multi-step process that includes initiation, promotion and progression.
What is the effect of chemical carcinogens on the multistage process of cancer?
Chemical carcinogens can alter any of these process to induce their carcinogenic effects
What evidence supports the idea cancer is due to DNA damage?
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.
What is the major consequence of chemical carcinogens?
In the majority of instances chemical carcinogens can induce this DNA damage and act in a genotoxic manner.
> specific chemicals can induce cancer
What are the different classes of carcinogens?
- chemicals
- physical
- heritable
- viral
- environmental
What are the different types of chemical carcinogens?
10 groups:
- polycyclic aromatic
- hydrocarbons
- aromatic amines
- azo dyes
- nitrosamines
- carbamates
- halogenated compounds
- alkylating agents
Give examples of physical carcinogens
Asbestos, Radiation - ionizing & UV
What is the effect of heritable carcinogens?
Patients have a predisposition to cancer
Name some viral carcinogens
Hepatitis B, Epstein Barr
How do chemical carcinogens lead to cancer?
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
Give an example of a DNA adduct caused added due to chemical carcinogens
One example is coal tar, which contains benzo[a]pyrene, a polycyclic hydrocarbon
Benzo[a]pyrene is commonly found in cigarette smoke (together with 81 other carcinogens)
Outline how Benzo[a]pyrene can become carcinogenic
On its own it’s a procarcinogen, and becomes a carcinogen when taken in and in contact with microsomal enzymes (Benzo[a]pyrene epoxide) changes G to T
What is the purpose of the Ames test?
A test to determine the mutagenic activity of chemicals by observing whether they cause mutations in sample bacteria
Outline how an Ames test is carried out
Ames test uses salmonella (strain of bacteria that requires histidine) mixed with liver extract and plated on a plate with minimal histidine - this produces no growth as in absence of histidine
Introducing a carcinogen will produce colonies if the compound is mutagenic
How do physical carcinogens lead to cancer?
Unlike chemical carcinogens physical carcinogens act by imparting energy into the biological material (not changing DNA)
What is the most common physical cancerous agent?
Several types of radiation can act as carcinogens
How does UV radiation lead to skin cancer?
- skin exposed to ionising / UV radiation
- Causes DNA breaks and pyrimidine dimers form (DNA damage)
- Failed repair
- Translocation mutations occur
What are heritable carcinogens?
syndromes predisposing to cancer
What is the major heritable carcinogen?
DNA damage is a risk factor for cancer development
Accounts for 5% of all cancers
Describe the effect of germline mutations in cancer
An inherited germline mutation, has an increased risk of developing certain tumours but are rarely involved in causing cancer immediately
Are heritable cancers due to a single or multiple gene mutations?
In most known hereditary malignant syndromes the elevated cancer risk is due to a mutation of a single gene (monogenic hereditary diseases)
What is a common factor among cancerous genes?
The affected genes concerned usually have a controlling function on the cell cycle or the repair of DNA damage
How does failed DNA repair increase cancer risk?
A deficiency in DNA repair would cause more DNA damages to accumulate, and increase the risk for cancer
Which DNA repair defects cause syndromes predisposing to cancer?
DNA Repair Defects
- Ataxia telangiectasia
- Bloom’s syndrome
- Fanconi’s anaemia
- Li-Fraumeni syndrome
- Lynch type II
- xeroderma pigmentosum
What chromosomal abnormalities lead to syndromes predisposing to cancer?
Chromosomal Abnormalities
- Down’s syndrome
- Kleinefelter’s Syndrome
What is ataxia telangiectasia?
A neuromotor dysfunction, dilation of blood vessels, telangiectasia = spider veins
How does a DNA defect cause ataxia telangiectasia?
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
Which cancers are predisposed by ataxia telangiectasia?
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
Describe the DNA defect that causes Bloom’s syndrome
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
What are the cancers predisposed by blooms syndrome?
skin cancer. basal cell carcinoma and squamous cell carcinoma.
What is Lynch type?
Mutations in DNA mismatch repair (MMR) genes, notably MLH1, MSH2, MSH6 and PMS2.
Describe the signs of 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.
What cancer can Lynch type lead to?
Cancer predisposition: colorectal cancer
What diseases are viruses responsible for?
Viruses capable of causing a wide range of human disease from smallpox to common cold
When are viruses most dangerous?
Most harm caused when viruses multiply inside the infected cell, kill the cell and release progeny to further infect other cells
When do cells become very proliferative?
Most viruses are very proliferative when they infect a cell, exhibiting a lytic cycle: express all the genes found in their genome
They aim to produce lots of viral capsids that can be released for further infection
How do viruses become cancerous?
In rare circumstances, viruses switch from lytic to latent cycle, which is a restrictive pattern of gene expression and some viruses can become tumorigenic; allow transformation of cells
What are the 3 required properties of tumorigenic viruses?
- Stable association with cells
- Must not kill cells
- Must evade immune surveillance of infected cells
How do tumorigenic viruses form stable associations with cells?
- chromosomal integration
- episomes
How do tumorigenic vuiruses avoid killing cells?
Via:
- non-permissive host (virus cannot replicate)
- suppression of viral lytic cycle
- viral release by budding
How do tumorigenic viruses evade immune surveillance of infected cells?
- immune suppression
- viral antigens not expressed at cell surface
What are the DNA viruses associated with human cancer?
Epstein-Barr virus Burkitt’s lymphoma nasopharyngeal carcinoma papilloma viruses cervical carcinoma warts hepatitis B and C hepatoma
What are the RNA retroviruses associated with human cancers?
HTLV-I
Adult T-cell leukaemia, lymphoma
What is the theory behind genome instability causing cancer?
> Knudson’s Hypothesis for Hereditary Cancers based on discovery of Rb1, the TSG that causes retinoblastoma when both copies are mutated
How did knudson identify genome instability as a model of cancer?
Knudson performed statistical analysis on cases of retinoblastoma of which there are two types the inherited type and the sporadic type
What were the results of knudsons’ analysis?
He suggested multiple hits were required to cause cancer
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
What is the non-genotoxic model of cancer?
Non-genotoxic is characterized by an emphasis on non-genotoxic effects
How do non-genotoxic effectors lead to cancer?
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
What are the effects of non-genotoxic carcinogens?
carcinogens that induce cancer via non-genotoxic mechanisms 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)
How do non-genotoxic carcinogens cause cancer?
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 the darwinian model of cancer
Carcinogenesis by Mutation and Selection-Model of Clonal Expansion
The role of the environment in selecting cells that have some acquired advantage
What is the significance of tissue organisation in cancer?
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
What are tissues?
Groups of cells with similar function are known as tissues: epithelial, connective muscle and nervous
What are the 2 theories describing the forces driving carcinogenesis?
Two drastically different approaches to understanding the forces driving carcinogenesis have crystallized through years of research.
- Somatic mutation theory (SMT)
- Tissue organization field theory (TOFT)
What is the somatic mutation theory?
> Single catastrophic event triggering carcinogenesis
What is the Tissue Organisation Field theory?
Carcinogenesis as general deterioration of the tissue microenvironment due to extracellular causes
Outline the tissue organisation field theory
- Carcinogenesis is primarily a problem of tissue organisation
- carcinogenic agents destroy the normal tissue architecture thus disrupting cell-to-cell signalling and compromising genomic integrity
- The DNA mutations are random and the effect, not the cause, of the tissue-level events
Outline the somatic mutation theory of cancer
- cancer is derived from a single somatic cell that has successively accumulated multiple DNA mutations
- those mutations damage the genes which control cell proliferation and cell cycle
- Thus, according to SMT, neoplastic lesions are the results of DNA-level events
How does the immune system respond to cancer?
- Protect from virus-induced tumours
- Eliminate pathogens
- Identify and eliminate tumour cells
↓ - Immune surveillance
↓ - Despite this tumours can still arise-
- Concept of cancer immunoediting
What are the 3 ‘E’s’ of cacer immunoediting?
Elimination
Equilibrium
Escape
Describe how the immune system tries to eliminate cancer
The immune system is able to eradicate developing tumours
What is equilibrium in cancer immunoediting?
When incomplete removal is present tumour cells remain dormant and enter equilibrium
Describe what occurs during equilibrium phase of cancer immunoediting
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
How long does the equilibrium phase of cancer immunoediting last?
(Longest of the phases, around 20 years)
How can cancer risk be reduced?
Some risk factors for cancer are easier to avoid than others
But everyone can avoid some of them.
There are also positive things that we can all do to reduce the cancer risk.
The choice is ours
