Mechanism of Oncogenesis Flashcards
What are the lifestyle factors contributing to cancer onset?
- obesity + weight
- diet
- smoking + alcohol
- exercise
- genetics
- hormones
- sun + UV
- Workplace causes
- infections + HPV
- air pollution and radiation
Describe the age range in prevalence of cancer
50-74yo = 1/2 of cancer cases
75+yo = 1/3 of cancer cases
Male>female.
How can cancer be prevented?
Most cancer cases are linked to lifestyle
= can be prevented through lifestyle changes
Why are there more 50-74 y/o in the population with cancer than any other age range?
More people aged 50-74 than aged 75+
in population overall = higher cancer cases, but higher incidence rates in 75+.
What is cancer?
Cancer = group of diseases caused by the uncontrolled growth of cells.
Where are the common categories of cancer?
- Epithelial cell cancer = carcinoma
- Mesoderm cell(bone and muscle) cancer = sarcoma
- Glandular tissue cancer = adenocarcinoma
What are the features that characterise cancer?
Cancer is 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 the hallmarks of cancer defined by Hanahan and Weinberg?
- Sustained proliferative signalling
- Evading growth suppressors
- Evade immune destruction
- Enabling replicative immortality
- Tumour-promoting inflammation
- Activating invasion + metastasis
- Inducing angiogenesis
- Genome instability + mutation
- Resisting cell death
- Deregulating cellular energetics
What is the consequence of carcinogens?
Carcinogens cause DNA mutation
DNA from tumours has many alterations - point mutations, deletions
How does carcinogenesis occur?
Mutations accumulate overtime - multi-step process that underlies carcinogenesis
What enables carcinogenesis occur?
Failed DNA repair mechanisms = mutations accumulate
Mutations accumulate after evading the cell’s DNA repair mechanisms
When is apoptosis induced during cancer?
Severe cell damage = induces apoptosis
e.g. irreparable DNA damage
What mechanisms are available in the body to fight cancer?
Many mechanisms exist for blocking carcinogenesis but over-burdening the system = cells escape immune surveillance
Why does age play a major factor in cancer development?
↑ age = ↑ mutations accumulate = cancer
How do Germ Line mutations lead to cancer?
Germ line mutations = alter egg/sperm DNA (point mutations/deletions)
inheritable
(But most cell mutations affect somatic cells)
Explain how somatic mutations cause cancer?
Somatic mutations = non-inheritable mutation
All cells in a primary tumour arise from a single cell. Initiating cancer development is clonal.
Depends on interaction with other tumour cells and the tumour microenvironment
Why are somatic mutations such a common cause of cancer?
Only one of the 10^14 cells in body need to be transformed to create a tumour.
Mutations accumulate
Why is cancer hard to cure?
Tumour cells can ‘evolve’= subclonal selection allowing a growth advantage and heterogeneity of cells in a tumour
When are normal cells converted to cancerous tumour cells?
Loss of balance between proliferation/apoptosis = normal healthy cells -> tumour cells
What causes cells to proliferate?
Growth factors = cell proliferation signals
When does apoptosis occur?
Severe cell damage(e.g. irreparable DNA damage) activates apoptosis
Which processes regulate cell number?
Growth, Apoptosis and Differentiation
What is the cell growth and apoptosis pathway regulated by?
Cell growth + apoptosis pathway is regulated by:
- Oncogenes
- Tumour suppressor genes
Acquiring a mutation in one of these genes will cause a loss in regulation
What is the consequence in mutations of cell number regulation pathways?
Mutation usually causes an increase in cell no. to the point where you have a clinically detectable tumour
mutations = loss of ability to regulate cell number = ↑ cell number (proliferation) = tumour
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 to cause uncontrolled growth- i.e., cancer.
(This is like pushing down on the gas pedal)
What is the role of tumour suppressor genes?
Tumour suppressor genes 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 is the effect of mutations in tumour suppressor genes?
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?
- Malignant transformation of 1 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 5 molecular mechanisms of cancer?
5 Models of Carcinogenesis:
5 Models of Carcinogenesis:
- Mutational - Chemical carcinogens(DNA mutations = damage DNA = genotoxic)
- Genome Instability
- Non-genotoxic - Clonal expansion/Epigenetics
- Darwinian - Clonal expansion/Cell selection
- Tissue organisation - Microenvironment
What does the process of cancer involve?
Cancer is a multi-step process that includes initiation, promotion and progression.
What is the effect of chemical carcinogens on the multistage process of cancer?
Chemical carcinogens can alter initiation/promotion/progression to induce their carcinogenic effects
What evidence supports the idea that cancer is due to DNA damage (Model 1) ?
Many cancer cells carry multiple mutations in critical genes = supports that cancer arises through the accumulation of irreversible DNA damage.
Model 1 of Carcinogenesis
What is the major consequence of chemical carcinogens (Model 1)?
Chemical carcinogens induce DNA damage and act in a genotoxic manner.
> specific chemicals can induce cancer
What are the different classes of carcinogens?
- chemicals
- physical
- heritable
- viral
- environmental
What are the different types of chemical carcinogens?
10 groups:
- Polycyclic hydrocarbons
- Aromatic amines
- Nitrosamines
- Alkylating agents
Give examples of physical carcinogens
Asbestos
Ionising Radiation
UV Radiation
What is the effect of heritable carcinogens?
Patients have a predisposition to cancer
Name some viral carcinogens
Hepatitis B Virus
Epstein Barr Virus
How do chemical carcinogens lead to cancer?
Chemical carcinogens add functional groups to DNA bases(DNA adducts)
Give an example of a DNA adduct caused added due to chemical carcinogens
Coal tar, which contains benzopyrene(polycyclic hydrocarbon) - cigarette smoke
Outline how Benzo[a]pyrene can become carcinogenic
Benzopyrene(alone) = procarcinogen.
Becomes a carcinogen when taken in + in contact with microsomal enzymes (Benzopyrene epoxide) : G -> T
What is the purpose of the Ames test?
Ames test determines whether a chemical is mutagenic by observing whether they cause mutations in sample bacteria.
Outline how an Ames test is carried out
Ames test uses salmonella (strain of bacteria that requires histidine) mixed with liver extract and plated on a plate with minimal histidine - this produces no growth as in absence of histidine
Introducing a carcinogen will produce colonies if the compound is mutagenic
How do physical carcinogens lead to cancer?
Physical carcinogens impart energy into the biological material, altering chemical bonding (not changing DNA=chemical carcinogens)
What is the most common physical cancerous agent?
Several types of radiation = carcinogens
How does UV radiation lead to skin cancer?
- Skin exposed to ionising / UV radiation
- DNA damage = DNA breaks + pyrimidine dimers form
- Failed DNA repair
- Translocation mutations occur
What are heritable carcinogens?
syndromes predisposing to cancer
What is the major heritable carcinogen?
DNA damage is a risk factor for cancer development
Accounts for 5% of all cancers
Describe the effect of germline mutations in cancer
Inherited germline mutation causes increased risk of developing certain tumours but are rarely involved in causing cancer immediately
Are heritable cancers due to a single or multiple gene mutations?
In most known hereditary malignant syndromes, elevated cancer risk is due to a mutation of a single gene (monogenic hereditary diseases)
What is a common factor among cancerous genes?
Cancerous genes usually control cell cycle/DNA repair
How does failed DNA repair increase cancer risk?
DNA repair defect = ↑ DNA mutations accumulate = ↑ cancer risk
Which DNA repair defects cause syndromes predisposing to cancer?
DNA Repair Defects cause syndromes that predispose to cancer:
- Ataxia telangiectasia
- Bloom’s syndrome
- Fanconi’s anaemia
- Li-Fraumeni syndrome
- Lynch type II
- Xeroderma pigmentosum
What chromosomal abnormalities lead to syndromes predisposing to cancer?
Chromosomal Abnormalities which predispose to cancer:
- Down’s syndrome (trisomy 21)
- Kleinefelter’s Syndrome (XXY)
What is ataxia telangiectasia?
A neuromotor dysfunction, dilation of blood vessels
telangiectasia = spider veins
How does a DNA defect cause ataxia telangiectasia?
- Mutation in ATM gene
- ATM encodes a serine/threonine kinase which is activated by dsDNA breaks, causing cell cycle arrest/DNA repair/apoptosis
Which cancers are predisposed by ataxia telangiectasia?
Cancers predisposed by ataxia telangiectasia: lymphoma, leukaemia and breast cancer
What is Bloom’s syndrome?
- short stature(rarely exceed 5 feet)
- skin rash - develops after sun exposure
Describe the DNA defect that causes Bloom’s syndrome
- Mutation in BLM gene
- BLM gene encodes a RecQ helicase = help maintain DNA structure + integrity
What are the cancers predisposed by blooms syndrome?
skin cancer: basal cell carcinoma, squamous cell carcinoma
What is Lynch type?
Mutations in DNA mismatch repair (MMR) genes, notably MLH1, MSH2, MSH6 and PMS2.
Describe the signs of Lynch type?
LS doesn’t cause any symptoms.
Symptoms of bowel and womb cancer.
What cancer can Lynch type lead to?
Cancer predisposition: colorectal cancer
What diseases are viruses responsible for?
Viruses capable of causing a wide range of human disease from common cold-smallpox
When are viruses most dangerous?
Viruses multiply inside the infected cell, kill the cell and release progeny to infect other cells
When do cells become very proliferative?
Most viruses are very proliferative when they infect a cell, exhibiting a lytic cycle: express all the genes found in their genome
Viruses produce lots of viral capsids that can be released for further infection
How do viruses become cancerous?
In rare circumstances, viruses switch from lytic to latent cycle, which is a restrictive pattern of gene expression and some viruses can become tumorigenic; allow transformation of cells
What are the 3 required properties of tumorigenic viruses?
Tumorigenic viruses:
- Stable association with cells
- Must not kill cells
- Must evade immune surveillance of infected cells
How do tumorigenic viruses form stable associations with cells?
Viruses form stable associations with cells by integrating into chromosomes
How do tumorigenic viruses avoid killing cells?
Tumorigenic virus:
- Virus does not replicate
- Virus suppresses its lytic cycle
- Virus is released by budding
How do tumorigenic viruses evade immune surveillance of infected cells?
- immune suppression
- downregulate MHC I expression = viral antigens not expressed at cell surface
What are the DNA viruses associated with human cancer?
Epstein-Barr virus Burkitt’s lymphoma nasopharyngeal carcinoma HPVs cervical carcinoma warts hepatitis B and C Hepatoma
What are the RNA retroviruses associated with human cancers?
HTLV-I: Adult T-cell leukaemia, lymphoma
What is the theory behind Genome Instability causing cancer?
Genome Instability = Knudson’s 2-Hit Hypothesis for Hereditary Cancers based on discovery of Rb = TSG that causes retinoblastoma when both gene copies are mutated
How did knudson identify genome instability as a model of cancer?
Knudson performed statistical analysis on cases of retinoblastoma (2 types - inherited type, sporadic type)
What were the results of knudsons’ analysis?
Knudson = Multiple hits are required to cause cancer.
- If first mutated allele is inherited, the second mutation will lead to cancer.
- In sporadic Rb tumour, both mutations must occur = difference of age at diagnosis (cell must survive for long enough)
What is the non-genotoxic model of cancer?
Non-genotoxic is characterized by an emphasis on non-genotoxic effects
How do non-genotoxic effectors lead to cancer?
Several important modulators of cancer risk (diet, obesity, hormones, insulin resistance) do not change DNA structure, but functional changes (e.g. epigenetics)
What are the effects of non-genotoxic carcinogens?
carcinogens that induce cancer via non-genotoxic mechanisms 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 and inflammatory responses (metals such as arsenic and beryllium)
How do non-genotoxic carcinogens cause cancer?
For cancer to occur, multiple pathways must be altered
Describe the Darwinian model of cancer
Carcinogenesis by Mutation and Selection-Model of Clonal Expansion
The role of 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 and invade
What are tissues?
Tissues = Groups of cells with similar function
- Epithelial
- Connective
- Muscle
- Nervous
What are the 2 theories describing the forces driving carcinogenesis tissue organisation (Model 5)?
2 different approaches to understanding the forces driving carcinogenesis:
- Somatic mutation theory (SMT) -> Single catastrophic event triggering carcinogenesis
- Tissue organization field theory (TOFT) ->Carcinogenesis as general deterioration of the tissue microenvironment due to extracellular causes
Outline the tissue organisation field theory
- Carcinogenesis is primarily a problem of tissue organisation
- Carcinogenic agents destroy the normal tissue architecture = disrupt cell-to-cell signalling, compromise genomic integrity
- The DNA mutations are random and the effect, not the cause, of the tissue-level event
Outline the somatic mutation theory of cancer
- 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
- SMT = neoplastic lesions are the results of DNA-level events
How does the immune system respond to cancer?
- 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’ of cacer immunoediting?
Elimination
Equilibrium
Escape
Describe how the immune system tries to eliminate cancer
The immune system is able to eliminate developing tumours
What is equilibrium in cancer immunoediting?
When incomplete removal of tumour, tumour cells remain dormant(enter equilibrium).
Describe what occurs during equilibrium phase of cancer immunoediting
The immune system exerts a potent pressure that contains the tumour
During this phase, some of the tumour may mutate and survive
How long does the equilibrium phase of cancer immunoediting last?
(Longest of the phases, around 20 years)
How can cancer risk be reduced?
Change lifestyle factors
