Cellular pathology: Mechanisms of Oncogenesis Flashcards
What civilisation does the earliest decriptions of cancer come from?
Ancient Egypt
What civilisation was the first to identify canacer as a distinct illness?
Ancient Greeks
Describe the origins of the word “cancer”
- Hippocrates first referred to several types of cancer as the Greek word carcinos (meaning crab or crayfish)
- Celsos later translated the word to the latin word cancer (also means cancer)
Describe some historical treatments of cancer
- In Ancient Greece treatment of cancer was was based on the humor theory of four bodily fluids (black and yellow bile, blood, and phlegm)
- Treatment consisted of diet, blood-letting, and/or laxatives.
- Surgery was undertaken to remove tumours followed by the cauterization of the surrounding vessels to stop excessive haemorrhage.
What is cancer?
- Cancer is the name of a group of diseases characterised by distinct hallmarks which include:
- Abnormal cell proliferation
- Tumour formation
- Invasion of neighbouring normal tissue
- Metastasis to form new tumours at distant sites
What are cancers that originate in epithelial cells called?
Carcinomas
What are cancers that originate in mesoderm cells (bone and muscle) cells called?
Sarcomas
What are cancers that originate in glandular tissue called?
Adenocarcinomas
What are the two enabling hallmarks of cancer and the two emerging hallmarks?
- Enabling hallmarks: Genome instability and tumour inflammation
- Emerging hallmarks: Avoiding immune destruction and reprogramming energy metabolism
Cancer is caused by the accumulation of mutations within DNA. What is the name for something that causes mutations within DNA?
Carcinogen
What is Carcinogenesis?
A multi-step process that leads to the accumulation of mutations over time which leads to cancer formation
How is Carcinogenesis allowed to occur to the point of a cell becoming cancerous?
- Cells have a defence mechanism of DNA repair against caricnogenesis
- Over burdening this system increases the possibility that cells will escape surveillance and will be allowed to accumulate muations unrestricted
- This may eventually lead to a cell accumulating enogh mutations to become cancerous
How do germline mutations contribute to development of cancer?
- They Increase risk of developing cancer - as they are inheritable and so can be passed onto offspring
- Rarely involved in causing cancer immediately
How do somatic mutations contribute to the development of cancer?
- Somatic mutation occurs in one normal cell to covert that cell into a tumour cell
- Initial tumour cell divides and so starts to create a clonal population of tumour cells (all have initial mutation).
Why are tumour cells said to be heterogeneous?
- As tumour cells grow they accumulate mutations which allow them to continue to grow and gain an advantage
- Different tumour cells will accumulate different mutations so they will be heterogeneous
What is the accumulation of mutations in different tumour cells depenedent on?
- Interaction with other tumour cells
- Tumour microenvironment
Mutations in what types of gene leads to the development of a tumour cell?
- Proto-oncogene
- Tumour suppressor gene
What is a proto-oncogene?
- A normal gene that helps regulate cell growth/differentiation that becomes an oncogene when mutated
What is an oncogene?
- A proto-oncogene that has been mutated in a way that leads to signals that cause uncontrolled growth
What is a tumour suppressor gene?
- Genes that 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 are the 3 assumptions made about the models of 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 time taken for that malignant cell to become a tumour detection is generally constant
Give the names of the five models of carcinogenesis
- Mutational model (model 1)
- Genome instability model (model 2)
- Non-genotoxic model (model 3)
- Darwinian model (model 4)
- Tissue organisation model (model 5)
Explain the mutational model (model 1) of carcinogenesis
- States that cancer is a multi-step process which includes initiation, promotion and progression
- These 3 processes can be altered by carcinogens
- Carcinogens alter these processes by causing DNA damage
- If carcinogens cause enough DNA damage for it to become irreversible then cancer can arise
What are the different types of carcinogen?
- Chemical
- Physical - Radiation and Asbestos
- Heritable
- Viral - Hepatitis B
Name some of the 10 groups of chemical carcinogen
- Polycyclic aromatic hydrocarbons
- Aromatic amines
- Nitrosamines
- Alkylating agents
How do chemical carcinogens exert their effects on DNA?
- Chemical carcinogens exert their effects by adding functional groups called DNA adducts to DNA
Benzo[a]pyrene, a polycyclic hydrocarbon, is refered to as a pro-carcinogen. Explain how Benzo[a]pyrene is converted from a pro-carcinogen into a carcinogen?
- Benzo[a]pyrene is converted into benzo[a]pyrene epoxide by microsomal enzymes
- Benzo[a]pyrene epoxide is the carcinogen
What specific effect does Benzo[a]pyrene epoxide have on DNA?
- It converts Guanine nucleotides into thymine nucleotides
Describe a test used to see whether a particular chemical is a carcinogen
- You add a strain of Salmonella to a test tube (Salmonella requires histidine to grow)
- You then add liver extract (contains enzymes) and also add the suspected carcinogen
- You then grow the Salmonella bacteria on a plate containing minimal histidine
- If the suspected carcinogen isn’t a carcinogen then Salmonella won’t be able to grow on the plate
- If the suspected carcinogen is indeed one then there will be Slamonella growth on the plate
- This is because the carcinogen has mutated the DNA of Salmonella to allow it to grow in absence of histidine
- This test is called the Ames test
How do physical carcinogens exert their effects on DNA?
- Physical carcinogens, e.g. radiation, impart energy into DNA
- This leads to the DNA becoming damaged as addition of energy to DNA leads to DNA breaks or pyrimidne dimers to form
- If these types of DNA damage aren’t repaired then eventually mutations will form in the DNA
What is a heritable carcinogen and how can it increase the risk of developing cancer?
- A heritable carcinogen is an inherited germline mutation that increases risk of a person developing cancer
- This is because the germline mutation is incorporated into all cells of the person who inherits it
- Genes that are uusually mutated have a function in the cell cycle or repair of DNA damage
- Mutatiuons in genes involved in DNA repair means more mutations are allowed to accumulate which increases cancer risk
What are some of the chromosomal abnormalities that increase a person’s risk of developing cancer?
- Down’s syndrome
- Klinefelter’s syndrome
What are some of the DNA repair defects that increase a person’s risk of developing cancer?
- Ataxia telangiectasia
- Bloom’s syndrome
- Lynch syndrome (type II)
What are some of the symptoms of Ataxia telangiectasia?
- Neuromotor dysfunction
- Dilation of blood vessels in the eyes
What gene is mutated in ataxia telangiectasia and what occurs as a result of this mutation in this gene?
- Mutation in the ATM gene
- Normally ATM gene codes for a serine/threonine kinase which is activated in response to double stranded DNA breaks and phisphorylates the tumour suppressor p53
- This leads to cell cycle arrest, DNA repair and apoptosis
- Mutation of this gene means that double stranded DNA breaks are unable to be repaired so mutations are able to accumulate within the DNA
What types of cancer does Ataxia telangiectasia increase the risk of developing?
- Lymphoma
- Leukaemia
- Breast cancer
What are some of the symptoms of Bloom’s syndrome?
- Short stature, rarely exceed 5 feet tall,
- Skin rash that develops after exposure to the sun
What gene is mutated in Bloom’s syndrome and what occurs as a result of this mutation?
- Mutation in BLM gene
- Normal BLM gene codes for a member of the RecQ helicase family which help maintain the structure and integrity of DNA
- A mutation in BLM gene means that particular RecQ helicase protein is unable to be produced so strucyure and integrity of DNA affeceted
What types of cancers does Bloom’s syndrome increase the risk of developing?
- Skin cancer
- Basal cell carcinoma
- Squamous cell carcinoma
What are the symptoms of lynch syndrome type II?
- Lynch type II doesn’t cause any symptoms
- First sign that a person has Lynch type II can be when the symptoms of bowel and womb cancer develop
What genes are mutated in lynch syndrom type II and what occurs as a result of these mutations?
- DNA mismatch repair (MMR) genes are mutated notably MLH1, MSH2, MSH6 and PMS2
- As a result of these mutations Mismatched bases in DNA are unable to be corrected
What cancers does Lynch syndrome type II increase the risk of developing?
- Colorectal cancer
Explain how a virus infecting a cell can lead that cell to become tumourigenic
- Normally when a virus infects a host cell it will go through a lytic cycle which results in the destruction of the host cell and its membrane
- Sometimes a virus can switch from a lytic cycle to a latent cycle, where they only express specific viral genes.
- This can result in the virus becoming tumourigenic allowing for the host cell to become a tumour cell
What are the properties required of tumourigenic viruses?
- They have to have a stable association with cells - can intergrate into host chromosome or are episomes
- Must not kill cells - virus cannot replicate and they suppress viral lytic cycle
- Must evade immune surveillance of infected cells - they’re able to suppress immune system and viral antigens not expressed at cell surface
What are some of the DNA viruses associated with cancer? For each one name the type of cancer they’re associated with
- Epstein-Barr virus - burkitt’s lymphoma, nasopharyngeal carcinoma
- Papilloma viruses - cervical carcinoma
- Hepatitis B and C - hepatoma
What are some of the RNA retroviruses associated with cancer? For each one name the type of cancer they’re associated with
- HTLV-I - Adult T-cell leukaemia, lymphoma
Explain the genome instability model (model 2) of carcinogenesis using Knudson’s hypothesis for Hereditary Cancers
- When studying retinoblastoma patients Knudson noted that there were 2 groups:
- patients that developed it at an early age
- patients that developed it much later
- Knudson also noted that there were 2 types of retinoblastoma:
- Inhertited type
- Sporadic type
- Knudson suggested that multiple hits were required to cause cancer, e.g. you need 2 different mutations in order for a cell to become cancerous
- Patients with inherited type of retinoblastoma inherited first type of mutation and so second mutation could happen very early in life
- Patients with sporadic type needed both mutations to occur which took longer and so they presented with retinoblastoma at a later age
- Knudoson’s hypothesis example of genome instability model as it shows that 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.
Model 3 of carcinogenesis states that non-genotoxic agents can induce carcinogenesis. What are some of the non-genotoxic agents that can lead to carcinogenesis?
- Diet
- Obesity
- Hormones
- Insulin resistance
How do non-genotoxic agents induce their effects on DNA?
- They don’t seem to act through a structural change in DNA but rather through functional changes including epigenetic events
There are a group of non-genotoxic carcinogens that can also induce cancer. Give some examples of how these non-genotxic carcinogens can act to induce cancer
They can act as:
- Tumour promoters (1,4-dichlorobenzene),
- Endocrine-modifiers (17β-estradiol),
- Receptor-mediators (2,3,7,8-tetrachlorodibenzo-p-dioxin),
- Immunosuppressants (cyclosporine)
- Inducers of tissue-specific toxicity and inflammatory responses (arsenic and beryllium)
Explain the Darwinian model (model 4) of carcinogenesis
- States that a tumour cell can develop due to accumulation of mutations in response to exposure to carcinogens
- That tumour cell will then be exposed to natural selection pressures that may result in that tumour cell being selected to grow
- Tumour cells may also be exposed to artificail selection pressures, e.g. therapy, which may lead to the tumour cells becoming resisitant to it
- On rare occassions the tumour cells may be exposed to a selection pressure that is harmful to them which will cause them to die
The first 4 models of carcinogenesis are all based on the somatic mutation theory. What is the somatic mutation theory?
- A theory that states that 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
- If unrepaired these mutations will eventually lead to carcinogenesis
The tissue organisation model (model 5) of carcinogenesis is based on the tissue organisation field theory. What is the tissue organisation field theory?
- A theory that states that carcinogenesis is primarily a problem of tissue organization
- Carcinogenic agents destroy the normal tissue architecture thus disrupting cell-to-cell signaling and compromising genomic integrity
- Also states that the DNA mutations that occur during carcinogenesis are random and the effect, not the cause, of these tissue-level events.
What are some of the ways that the immune system will respond to cancer?
- Protect from virus-induced tumours
- Eliminate pathogens
- Identify and eliminate tumour cells
What is the name for the process of the immune system responding to the presence of cancer?
- Immune surveillance
Cancers are able to develop by evading immune surveilance. What is the name of this process?
- Cancer immunoediting
Explain the 3 phases of cancer immunoediting
- A cell or a group of cells is exposed to a carcinogen which leads to DNA damage/accumulation of mutations in those cells which eventually causes them to become tumour cells
- Cells can be prevented from becoming tumour cells if the DNA damage is repaired
- If DNA damage can’t be repaired and cells become tumour cells then first satge of cancer immunoediting occurs: Elimination
- Elimination - The immune system is able to eradicate developing tumours
- If elimination is incomplete and a few tumour cells aren’t eliminated they enter stage 2: Equilibrium
- Equilibrium - Tumour cells remain dormant. Immune system exerts a potent and relentless selection pressure on the tumour causing it to be suppressed. During this phase some of the tumour may mutate or give rise to genetic variants that allow it to survive, grow and enter the next phase (Longest of the phases, around 20 years)
- If tumour cells are able to override suppression by immune system they enter stage 3: Escape
- Escape - Expanding tumour populations becomes clinically detectable
