Mechanism of Oncogenesis Flashcards
What is cancer?
Cancer is the name for a group of diseases characterised by:
- abnormal cell division
- tumour formation
- invasion of neighbouring normal tissue
- metastasis to form new tumours at distant sites
Carcinoma
a cancer arising in the epithelial tissue (i.e. of the skin or of the lining of the internal organs)
> malignant
Sarcoma
a cancer arising in the connective tissue (made of mesodermal cells) of bone and muscle
Adenocarcinoma
a cancer arising from glandular epithelial cells
Hallmarks of cancer
- Sustaining proliferative signalling
- Evading growth suppressors
- Avoiding immune destruction
- Activating invasion and metastasis
- Enabling replicative immortality
- Tumour-promoting inflammation
- Inducing angiogenesis
- Genome instability & mutation
- Resisting cell death
- Deregulating cellular energetics
Cancer is considered a…
disease of the genome at the cellular level (mutations):
- DNA from tumours has been shown to contain many alterations from point mutations to deletions
- The accumulation of mutations occurs only after the cells defence mechanism of DNA repair have been evaded.
Effect of carcinogens on DNA
Carcinogens cause alterations to the DNA (Mutations)
Mutations in different cell types
Germline mutations
Somatic mutations
Germline mutations
Mutation within sperm/egg cell; this can be passed on to offspring
>increased risk of developing cancer
>rarely involved in causing cancer immediately
Somatic mutations
Mutations that affect somatic cells; this can’t be passed on to offspring
- constitute almost all mutations in tumour cells
- only one cell needs to be mutated, and then cancer initiation is clonal
- tumour cells can evolve; sub-clonal selection allowing a growth advantage, explaining the heterogeneity of cells in a tumour
Balance between cell proliferation and cell apoptosis
Cells will respond to different signals such as growth factors, cytokines, hormones etc. which will allow them to proliferate, but at the same time there is a balancing act in cell loss by apoptosis as a result of irreversible DNA damage.
How are cell numbers regulated?
Growth, apoptosis and differentiation regulate cell numbers:
- cells proliferate and grow
- they differentiate
- perform a specific function
- then finally undergo apoptosis
This pathway is regulated by lots of different genes
How is the balance between cell proliferation and cell apoptosis affected?
mutations which alter the function of normal genes involved in this pathway:
proliferation
differentiation
perform function
apoptosis pathway
we lose the ability to regulate the processes involved in controlling cell number, and cell number will continue to increase. Eventually it will get to a point where there is a clinically detectable tumour
Which genes regulate growth?
Normal 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 are tumour suppressor genes?
Tumour suppressor genes inhibit both growth and tumour formation. They act as braking signals during G1 phase of the cell cycle to stop or slow the cell cycle before the S phase
What happens if tumour suppressor genes are mutated?
the normal brake mechanism will be disabled, resulting in uncontrolled growth, i.e. cancer.
Tumour cells arise as a result of either…
- Activation of oncogenes
- Suppression/Mutation of tumour suppressor genes
Assumptions made about carcinogenisis
3 assumptions are made about 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
Models of carcinogenesis
There are 5 models of carcinogenesis (non-exclusive)
Model 1 of Carcinogenesis: Carcinogens
- Cancer is a multi-step process that includes initiation, promotion and progression
- Chemical carcinogens can alter any of these processes by inducing irreversible DNA damage (mutations) and act in a genotoxic manner
- Accumulation of irreversible DNA damage leads to cancer
Types of carcinogens
Chemical Carcinogens
- Bulk of carcinogens
- 10 groups: polycyclic aromatic hydrocarbons, aromatic amines, azo dyes, nitrosamines, carbamates, halogenated compounds, alkylating agents
Physical Carcinogens
- Radiation (Ionising or Ultraviolet)
- Asbestos
Heritable Carcinogens
- Predisposition (inherited mutations)
Viral Carcinogens
- Hepatitis B
- Epstein Barr
Smoking and cancer
There are cancer-causing chemicals (chemical carcinogens) in tobacco and cigarette smoke. These chemicals have many other uses
What do the chemical carcinogens in cigarette smoke do to DNA?
Four of the major groups of polycyclic aromatic hydrocarbons, aromatic amines, nitrosamines and alkylating agents found in cigarette smoke exert their effect by adding functional groups to DNA bases called DNA adducts.
Effect of benzo(a)pyrene on DNA
Benzo(a)pyrene is a polycyclic hydrocarbon commonly found in cigarette smoke (together with 81 other carcinogens).
Benzo(a)pyrene by itself is actually not carcinogenic, but is referred to as a pro-carcinogen. It is only when it is taken into our bodies and comes into contact with microsomal enzymes that it is converted into as the carcinogen benzo(a)pyrene epoxide. This has the effect of changing G nucleotides to T nucleotides within DNA (mutations).
Other than cigarette smoke, what else is benzo(a)pyrene found in?
Coal tar
How can we determine whether something is carcinogenic?
Ames test:
-this test determines the mutagenic activity of chemicals by observing whether they cause mutations in simple bacteria (e.g. Salmonella strain)
Physical carcinogens
Physical carcinogens act by imparting energy into the biological material. By imparting the energy, it causes changes in the bonding of molecules, inducing biological effects.
What is the primary physical carcinogen?
Radiation
Types of radiation which can act as carcinogens
Several types of radiation can act as carcinogens:
- Ionising radiation (X-rays, nuclear radiation)
- UV radiation
Effect of radiation on DNA
These cause DNA damage by causing:
- DNA breaks
- Pyrimidine dimers
These can be repaired, however if there is failed repair, it causes translocations and mutations.
Heritable carcinogens (account for 5% of all cancers)
An inherited germ-line mutation has an increased risk of developing certain tumours but are rarely involved in causing cancer immediately
In most known hereditary malignant syndromes, the elevated cancer risk is due to a mutation of a single gene (monogenic hereditary diseases)
The affected genes concerned usually have a controlling function on the cell cycle or the repair of DNA damage
Syndromes predisposing to cancer include…
DNA Repair Defects:
- Ataxia telangiectasia
- Bloom’s syndrome
- Fanconi’s anaemia
- Li-Fraumeni syndrome
- Lynch type II
- Xeroderma pigmenotsum
Chromosomal Abnormalities:
- Down’s syndrome
- Klinefelter’s syndrome
Ataxia Telangiectasia
Neuromotor dysfunction, dilation of blood vessels (telangiectasia=spider veins)
· Mutation in ATM gene which normally codes for a serine/threonine kinase that is recruited and activated by dsDNA breaks leading to cell cycle arrest, DNA repair and apoptosis
· Cancer predisposition: lymphoma, leukaemia, breast cancer
Bloom’s Syndrome
· Short stature, rarely exceed 5 feet tall, skin rash that develops after exposure to the sun
· Mutation in BLM gene that normally provides instructions for coding a member of the RecQ helicase family that help maintain the structure and integrity of DNA
· Cancer predisposition: skin cancer, basal cell carcinoma and squamous cell carcinoma
Lynch Type II
· Lynch syndrome doesn’t cause any symptoms. Sometimes the first sign that a person has LS is when the symptoms of bowel and womb cancer develop
· Mutation in DNA mismatch repair (MMR) genes, notably MLH1, MSH2, MSH6 and PMS2
· Cancer predisposition: colorectal cancer
Viral Carcinogens
Most viruses will be proliferative inside a cell and exhibit cell lysis, which is when they are expressing the majority of the genes in their genome to produce viral capsids to be released after cell lysis to infect further cells.
In rare instances, there are viruses which will switch from a lytic cycle to a latent cycle. This demonstrates a restrictive pattern of gene expression. In those instances, some viruses are tumorigenic and allow the transformation of cells.
What are the properties required of tumorigenic viruses?
Stable Association with cell by either:
- Chromosomal integration with host chromosome
- Found as episomes
Must not kill cells
- Non-permissive host (virus cannot replicate)
- Suppression of viral lytic cycle
- Viral release by budding
Must evade immune surveillance of infected cells
- Immune suppression
- Viral antigens not expressed at cell surface
Viruses associated with human cancers
DNA Viruses
· Epstein-Barr virus (EBV) leads to Burkitt’s lymphoma, nasopharyngeal carcinoma
· Papilloma Virus leads to cervical carcinoma, warts
· Hepatitis B and C lead to hepatoma
RNA Retrovirus
· HTLV-I leads to adult T-cell leukaemia, lymphoma
Model 2 of Carcinogenesis: Genome Instability
‘Two hit’ hypothesis:
-at least two events (e.g. mutations) are necessary for carcinogenesis and that the cell with the first event must survive in tissue long enough to sustain a second event
Model 3 of Carcinogenesis: Non-Genotoxic Carcinogens
Non-genotoxic carcinogens are modulators of tumorigenesis which don’t alter DNA directly, but 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 (metals such as arsenic and beryllium)
Model 4 of Carcinogenesis: Darwinian
Cells undergoing expansion will take into account SELECTIVE PRESSURE with an aim to try and survive.
If a normal cell during its life cycle accumulates a change/mutation due to exposure to a carcinogen, there will be:
1) Sequential accumulation of mutations due to exposure to carcinogens
2) Tumour cells will be selected FOR ability to grow and invade
3) Selection will include resistance to therapy
4) Some mutations may be deleterious for tumour (rare)
Model 5 of Carcinogenesis: Tissue Organisation
Forces driving carcinogenesis:
Somatic Mutation Theory (single catastrophic event triggering carcinogenesis)
- 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
Tissue Organisation Field Theory
- Carcinogenesis is primarily a problem of tissue organisation/architecture
- Carcinogenic agents destroy normal tissue architecture thus disrupting cell-to-cell signalling and compromising genomic integrity
- The DNA mutations are random and are 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 in cancer?
The immune system will:
- Protect from virus-induced tumours
- Eliminate pathogens
- Identify and eliminate tumour cells by immune surveillance
How can tumours still arise despite the immune response?
Via concept of cancer immunoediting
What is cancer immunoediting?
Cancer immunoediting is also known as the three Es.
Elimination
-the immune system is able to eradicate developing tumours
Equilibrium (~20 years)
-when incomplete removal is present the 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
