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)
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
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
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
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
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
