Mechanisms of Oncogenesis Flashcards
What is cancer and what is it characterised by?
• 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
What are carcinomas?
Cancer which occur in epithelial cells
What are sarcomas?
Cancers derived from mesoderm cells(Bone and muscle)
What are adenocarcinomas?
Cancers found in glandular tissues are called adenocarcinomas
How many hallmarks of cancer are their?
6
What are the 2 enabling characteristics in the hallmarks of cancer?
- Genome instability
- Tumour inflammation
What are 2 emerging hallmarks?
- Avoiding immune destruction
- Reprogramming energy metabolism
What do carcinogens cause at a genome level?
• Carcinogens cause DNA mutations
-Point mutations to deletions
What does the accumulation of mutations over time represent?
The accumulation of mutations over time represents the multi-step process that underlies carcinogenesis
When does the accumulation of mutations occur?
This accumulation occurs only after the cells defence mechanism of DNA repair have been evaded
What happens in case of severe damage to the cell?
In cases of severe damage, cell apoptosis is induced
Why is cancer more prevalent?
Cancer more prevalent as lifespan has increased
What are germline mutations?
• Germline mutations: mutations in the egg and sperm that can be passed onto offspring
What do somatic mutations constitute?
Somatic mutations constitute almost all mutation in tumour cells
What are the majority type of mutation?
Somatic mutation
Inheritability of somatic mutations
Non- inheritable so cannot be passed onto offspring but can be passed onto daughter cells as a result of cell division
What do all cells in a primary tumour arise from and hence what is initial development of cancer known as?
• As all cells in a primary tumour arise from a single cell, initiation of the development of cancer is known as clonal
How do tumour cells evolve?
• Initially tumorigenesis is clonal but as more mutations are acquired, they become heterogenous
What interactions are tumour cells dependent on?
• Dependent on interaction with other tumour cells and the tumour microenvironment
What do cells proliferate as a result of?
• Cells will proliferate as a result of many different things
e.g. hormones, interleukins, cytokines, growth factors
What does DNA damage result in and if doesn’t happen, then what does this lead to?
DNA damage results in DNA repair and if this doesn’t happen, leads to apoptosis
What pathways regulate cell numbers?
- Growth
- Apoptosis
- Differentiation
What does mutations in the genes that regulate growth, apoptosis and differentiation result in?
Rather than a balance between cell growth and cell death, there will be continual division
- Results in increased cell number
- Results in clinically detectable tumour
What do cells with mutations in the genes that regulate growth, apoptosis and differentiation express?
Express oncogenes and tumour suppressor genes
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.
What do tumour suppressor genes inhibit?
Tumour suppressor genes inhibit both growth and tumour formation
What do tumour suppressor genes act as?
They act as braking signals during G1 phase of the cell cycle to stop or slow the cell cycle before S phase
What do tumour suppressor genes have to acquire to knock outs its function?
• These have to acquire two individual mutations to knock out it’s function – lose the ability to stop uncontrolled cell growth
What happens if tumour suppressor genes are mutated?
• 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?
a. Malignant transformation of a single cell is sufficient to give rise to a tumour
b. Any cell in a tissue is as likely to be transformed as any other of the same type
c. Once a malignant cell is generated the mean time to tumour detection is generally constant
What is model 1 of carcinogens?
Chemical carcinogens
What is cancer?
• Cancer is a multi-step process that includes initiation, promotion and progression
What can chemical carcinogens alter?
○ Chemical carcinogens can alter initiation, promotion and progression to induce their carcinogenic effects
How do carcinogens work?
Work by altering structure of DNA
What is a distinctive feature of cancer cells and hence what hypothesis does this supports?
• 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 do chemical carcinogens induce in the majority of instances?
• In the majority of instances chemical carcinogens can induce this DNA damage and act in a genotoxic manner
What are the classes of carcinogens?
- Chemical
- Physical
- Heritable
- Viral
What are the 4 major groups of chemical carcinogens and how do they exert their effects?
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
What group does coal tar contain?
Polycyclic hydrocarbon
How does coal tar become carcinogenic?
Is not carcinogenic by itself but gets converted in the bodyby microsomal enzymes
What is the AMES test used to determine?
• A test to determine the mutagenic activity of chemicals by observing whether they cause mutations in sample bacteria
Steps involved in AMES test
• Add chemical and then plate it to get many colonies: suggests there’s mutations in the bacteria so they are carcinogenic
1. Take rat liver extract and combine with salmonella strain that only grows in presence of histidine
2. Plate mixture onto agar plate that lacks histidine
3. Overnight incubation
4. If many colonies formed, suggests there has been a change in the bacteria and they can now grow in the absence of histidine
- Confirms chemical is carcinogenic
How do physical carcinogens act?
- Unlike chemical carcinogens physical carcinogens act by imparting energy into the biological material
- Energy –> Changes bonding in molecules –>Biological effects
What is a risk factor for cancer development?
DNA damage is a risk factor for cancer development
What is the elevated cancer risk in most hereditary malignant syndromes due to?
• In most known hereditary malignant syndromes the elevated cancer risk is due to a mutation of a single gene (monogenic hereditary diseases)
What is usually the affected genes function in hereditary malignant syndromes?
• The affected genes concerned usually have a controlling function on the cell cycle or the repair of DNA damage
What does a deficiency in DNA repair cause?
• A deficiency in DNA repair would cause more DNA damages to accumulate, and increase the risk for cancer
Example of DNA repair defects
- Ataxia telangiectasia
- Bloom’s syndrome
- Lynch type
What are the symptoms of ataxia telangiectasia?
- Neuromuscular dysfunction
- Dilation of blood vessels
- Telangiectasia
What gene mutation occurs in ataxia telangiectasia?
Mutation in ATM gene
What does the ATM gene code for?
Codes for a serine/threonine kinase that is recruited and activated by dsDNA breaks leading to cell cycle arrest, DNA repair and apoptosis
What does the ATM gene activate?
Activates p53 when mutation isn’t present
What is the cancer predisposition of ataxia telangiectasia?
- Lymphoma
- Leukaemia
- Breast cancer
What are the symptoms in blooms syndrome?
short stature, rarely exceed 5 feet tall, skin rash that develops after exposure to the sun
What mutation occurs in blooms syndrome?
Mutation in BLM gene
What is the BLM gene involved in?
provides instructions for coding a member of the RecQ helicase family that help maintain the structure and integrity of DNA
What is the cancer predisposition of blooms syndrome?
○ Cancer predisposition: skin cancer. basal cell carcinoma and squamous cell carcinoma
Symptoms of lynch type
Doesn’t cause any symptoms
When do you find out if you have lynch?
Don’t know you have lynch until you have cancer
What mutations cause lynch type?
○ Mutations in DNA mismatch repair (MMR) genes, notably MLH1, MSH2, MSH6 and PMS2
What is the cancer predisposition of lynch type?
○ Cancer predisposition: colorectal cancer
When can viruses cause cancer and during what phase?
• On rare occasions, viruses can cause cancer
○ Usually during latent phase of infection
-Latent phase shows very restrictive pattern of gene expression and these can include oncogenes
What are the properties required of tumourigenic viruses?
- stable association with cells
- Must not kill cells
- Must evade immune surveillance of infected cells
What does model 2 of carcinogenesis address?
Model 2 addresses the high frequency of mutations that happen
What did knudson suggest?
Knudson suggested that multiple hits were required to cause cancer
○ 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.
What is model 3 of carcinogenesis?
Non-genotoxic
What is non-genotoxic characterized by?
• Non-genotoxic is characterized by an emphasis on non-genotoxic effects
How to non-genotoxic carcinogens 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
Inflammatory responses (metals such as arsenic and beryllium)
What is model 4 of carcinogenesis?
Darwinian
What is the darwinian model of carciogenesis?
• Carcinogenesis by mutation and selection model of clonal expansion
The role of the environment in selecting cells that have some acquired advantage
What does the darwinian model rely on?
• This model relies on natural selection
§ Can also apply artificial selection i.e. chemotherapy (can select for cells that are dividing uncontrollably)
What is model 5 of carcinogenesis?
Tissue organisation
What are the 2 driving forces of carcinogenesis?
• These are the somatic mutation theory (SMT) and the tissue organization field theory (TOFT)
What is the somatic mutation theory?
○ 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
Single catastrophic event triggering carcinogenesis
What is the tissue organisation field theory?
○ Carcinogenesis is primarily a problem of tissue organization
○ Tissue structure is altering the way cells communicate with each other
○ Deterioration of tissue micro-environment due to extra-cellular causes
○ Carcinogenic agents destroy the normal tissue architecture thus disrupting cell-to-cell signaling and compromising genomic integrity
○ The 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
What is the immune response to cancer?
• The immune system: ○ 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 in cancer immunoediting?
- Elimination
- Equilibrium
- Escape
What happens in elimination?
• The immune system is able to eradicate developing tumours
Plethora of immune cells that hone in on the tumour and eradicate it
• is not 100% - 1 or 2 cells will enter the second phase of equilibrium/cancer persistence
What happens in 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)
What happens in escape?
• The expanding tumour populations becomes clinically detectable
There is a pressure from the immune system to keep these cells suppressed but as in model 4 the cells are constantly acquiring mutations that can overcome this suppression
Prevention and reducing risks for carinogenesis
• Alcohol • Obesity and weight • Diet and healthy eating • Physical activity • Smoking • Sun and UV • Hormones • 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.
