Mechanisms of Oncogenesis Flashcards
What are some risk factors of cancer?
Smoking Obesity and weight Alcohol Workplace Sun and UV Physical activity Hormones Infections and HPV Inherited genes Air pollution and radon Diet and healthy eating
Define Cancer and what hallmarks characterises it ?
Abnormal cell proliferation
Tumour formation
Invasion of neighbouring normal tissue
Metastasis to form new tumours at distant sites
What are some different types of cancers ?
85% Cancer in epithelial cells =Carcinomas
Cancers from mesoderm (bone /muscle ) cells =Sarcomas
Cancers in glandular tissue =Adenocarcinomas
What are the Hallmarks of cancer ?
- Deregulating cellular energetics
- Sustaining proliferative signalling
- Evading growth suppressors
- Avoiding immune destruction
- Enable replicative immortality
- Tumour-promoting inflammation
- Activating invasion and metastasis
- Inducing angiogenesis
- Genome instability and mutation
- Resisting cell death
What are some characteristics of the cancer DNA ?
DNA from tumours has been shown to contain many alterations from point mutations to deletions
The accumulation of mutations over time represents multi-step process that underlies carcinogenesis
What are the two types of mutations which can happen in cancer?
- Egg/Sperm Cell mutations -Germ line mutation
These are inheritable mutations and can increase risk of developing cancer
2.Somatic cell mutation
Outline Somatic cell mutations and what they can cause
Somatic cell has alteration in DNA , cell division - Clonal cells.
All cells in a primary tumour arise from a single cell , initiation of developmental of cancer is clonal.
Continued accumulation of mutations
10^14 cells in body
Tumour cells can evolve allowing a growth advantage and explain and heterogeneity of cells in a tumour.
Tumours can interact with the tumour micro environment
Describe the process through which a normal cell can become a tumour cell
The control of cell division within a tissue is important in self renewing when proliferation must balance cell loss.
There are signals which induce proliferation for e.g. Growth factors :EGF,PDGF Cytokines: Growth hormones ,interleukins Hormones: Oestrogen
Process is controlled however and balanced with Apoptosis
Programmed cell death as a result of irreparable damage
What is the typical cell life cycle ?
Normal cells
Proliferation (growth + division)
Differentiation
Perform function
Apoptosis
(Programmed cell death )
What problems can arise ?
Regulation of the cell life cycle processes is vital and if mutations are acquired in the genes that regulate this means :
Cells are not balanced between cell death and dividing
They will continue dividing and this will increase cell number which leads to tumours
Carcinogenesis
What are the genes which regulate the processes relating to cell growth ?What can go wrong with them
Normal genes that can be activated to be oncogenic are called proto-oncogenes
An oncogene is a pro-oncogene that has been mutated in a way which leads to signals that cause uncontrollable growth
Mutation 1:Accelerated cell division
Tumour suppressor genes inhibit both growth and tumour formation. They act as braking signals during phase G1 of the cell cycle to stop/slow the cell cycle before the S phase.
If tumour suppressor genes are mutated the normal brake mechanism will be disabled . This causes cancer
Mutation 1=Susceptible to cancer
Mutation 2= Leads to cancer
What are three assumptions which are made when it comes to cancer ?
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 five models of carcinogenesis ?
- Mutational -Chemical carcinogens
- Genome instability
- Non-genotoxic
- Darwinian
- Tissue organisation
These models overlap
Outline Model 1-Chemical carcinogens and how it can cause cancer
Cancer is a multi step process which includes :
Initiation , promotion and progression
Chemical carcinogens can alter any of these three processes to induce 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.
Chemical carcinogens can induce DNA damage and act in a genotoxic (damage to genetic information within a cell ) manner
What are the four groups of Carcinogens ?Provide examples for each
1.Chemical
polycyclic aromatic hydrocarbons ,aromatic amines,azo dyes,nitrosamines,carbamates,halogenated compounds ,alkylating agents
2.Physical
RAdiation-Ioninsing /Ultraviolet
Asbestos
3.Heritable
Predisposition
4.Viral
Hepatitis B
Epstein Barr
What are chemical carcinogens ?
Four of the major groups are polycyclic aromatic hydrocarbons , aromatic amines, nitrosamines and alkylating agents exert their effects by adding functional grous to DNA bases called DNA adducts
Example -Coal Tar Benzo(a)pyrene , polycyclic hydrocarbon
Found in cigarrete smoke
What are pro-carcinogens ?
These are any substance which is transformed into carcinogens through metabolism.
They are converted into carcinogens through microsomal enzymes
How do we know if a chemical is actually a carcinogen ?
By doing an Ames test which is a test to determine the mutagenic activity of chemicals by observing whether they cause mutations in sample bacteria.
A rat liver extract is taken and combined with a salmonella strain which only grows in Histidine.
This mixture is then plated and grown in an agar media which lacks histidine.
There should be very little colonies however following addition of the chemical, if the bacteria does grow this suggests that there may have been mutations
What are physical carcinogens ?
These impart energy into the biological material altering the bonding.
E.g. UV radiation
Ionizing radiation
DNA breaks which forms pyrimidine dimers however failed repair following this can cause translocation mutations
What are heritable carcinogens and what effects do they have ?
DNA damage is a risk factor for cancer development
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 hereditary malignancy syndromes , the elevated cancer risk is due to a mutation of a single gene = monogenic hereditary diseases
The affected genes usually have a controlling function on the cell cycle or the repair of DNA damage.
A deficiency in DNA repair would cause more DNA damage to accumulate and increase the risk of cancer
What are some DNA repair defects due to ?
Ataxia telangiectasia Bloom's syndrome Fanconi's anaemia Li-Fraumeni syndrome Lynch type 2 xeroderma pigmentosum
What are some chromosomal abnormalities ?
Down’s syndrome
Klinefelter syndrome
What is Ataxia telangiectasia and how can it lead to Cancer ?
This is a neuromotor dysfunction causing dilating of blood vessels
Telangiectasia = spider veins
Mutation in ATM gene which codes for serine /threonine kinase (Phosphorylation of CHECK 1 , CHECK 2 and activation ofp53 and DNA repair ) that is recruited and activated by dsDNA breaks leading to cell cycle arrest , DNA repair and apoptosis .
Cancer predisposition : Leukaemia and breast cancer
Outline Blooms Syndrome and how it may lead to cancer
Short stature , rarely exceeds 5 feet tall, skin rash that develops follwing sun exposure.
Mutation in the BLM gene that provides instructions for coding a member of the RecQ helicase family that helps maintain the structure and integrity of DNA
Cancer predisposition: Skin cancer , basal cell carcinoma and squamous cell carcinoma
Outline Lynch Type and how it can lead to cancer
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
Identify how infectious agents can be carcinogens
Viruses capable of causing a wide range of human disease from small pox to the common cold.
Most harm is caused when viruses multiply inside the infected cell , which kills the cell and releases progeny ( descendant ) to further infect other cells
During latent phase of infection , restricticted pattern of gene expression and these can include oncogenes.
What properties does a virus need to have to be a tumourigenic virus ?
Must have stable association with cells:
-Chromosomal integration
Episome
Must not kill cells :
Non-permissive host (virus cannot replicate )
Suppresion of viral lytic cycle
Viral release by budding
Must evade immune surveillance of infected cells:
During latent phase very few genes are expressed
Immune suppression
Viral antigens not expressed at cell surface
Describe viral carcinogenesis
Viral gene products act as transcription factors
Virus carries mutated cellular gene ( oncogene )
Viral integration into the cellular genome distrupts cellular genes
Viral gene products inactivate cell cycle regulatory proteins
Viral infection results in immunodeficiency
What viruses are associated with human cancer?
DNA viruses: Epstein -Barr Virus Papilloma viruses Hepatitis B and C Burkitts's lymphoma Nasopharyngeal carcinoma Cervical carcinoma Warts Hepatoma
RNA retroviruses :
HTLV-I
Adult T- cell leukaemia
Lymphoma
Outline Model 3 - Non genotoxic
Non-genotoxic is characterised by an emphasis on non-genotoxic effects
Important modulators of cancer risk (diet, obesity , hormones and insulin resistance ) do not seem to act through DNA structural changes but through functional changes (epigenetics )
Carcinogens that induce cancer via non-genotoxic mechansism:
tumour promoters
endocrine modifiers
receptor modifi
Outline Model 3 - Non genotoxic
Non-genotoxic is characterised by an emphasis on non-genotoxic effects
Important modulators of cancer risk (diet, obesity , hormones and insulin resistance ) do not seem to act through DNA structural changes but through functional changes (epigenetics )
Carcinogens that induce cancer via non-genotoxic mechanism:
tumour promoters
endocrine modifiers
receptor mediators
Immunosuppressants
Inducers of tissue specific toxicity and inflammatory responses
Outline Model 4 - Darwinian
(NATURAL SELECTION)
Carcinogenesis by Mutation and Selection model of clonal expansion
The role of the environment in selecting cells that have some acquired advantage
Sequential accumulation of mutations due to exposure to carcinogens
Tumour cells will be selected for ability to grow/invade
Selection will include resistance to therapy
Some mutations may be deleterious for tumour
What are tissues
Groups of cells with similar function are known as tissues: epithelial connective and nervous
What is the somatic mutation theory (SMT)?
Single catastrophic event triggering carcinogenesis
Cancer is derived from a single somatic cell that has successively accumulated multiple DNA mutations
These mutations damage genes which control cell proliferation and cell cycle
According to SMT , neoplastic lesions are the results of DNA -level events
What is the tissue organisation field theory ?
Carcinogenesis as general deterioration of the tissue microenvironment due to extracellular causes
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
How does the immune system respond to cancer ?
The immune system will :
- Protect from virus induced tumours
- Eliminate pathogens
- Identify and eliminate tumour cells
Immune surveillance
Despite this tumours can still arise -Cancer immunoediting
Outline the three E’s and Cancer immunoediting
Elimination:
The immune system is able to eradictae 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
Escape
The expanding tumour populations becomes clinically detectable
