Mechanisms of Oncogenesis Flashcards
What are some risk factors of cancer?
Smoking Obesity and weight Alcohol Workplace Sun and UV Physical activity Hormones Infections and HPV Inherited genes Air pollution and radon Diet and healthy eating
Define cancer
Hallmarks/Characteristics of Cancer
Cancer = A group of disease characterised by specific hallmarks:
- Abnormal cell proliferation
- Tumour formation
- Invasion of neighbouring normal tissue
- Metastasis to form new tumours at distant sites
- Ability to supply themselves w nutrients
What are some different types of cancers classification according to origin?
- Cancer in epithelial cells (85%) = Carcinomas
- Cancers from mesoderm cells (bone/muscle) = Sarcomas
- Cancers in glandular tissue = Adenocarcinomas
What are the Hallmarks of cancer ?
- Deregulating cellular energetics
- Sustaining proliferative signalling
- Evading growth suppressors
- Avoiding immune destruction
- Enable replicative immortality
- Tumour-promoting inflammation
- Activating invasion and metastasis
- Inducing angiogenesis
- Genome instability and mutation
- Resisting cell death
What are some characteristics of the cancer DNA ?
DNA from tumour cell has been shown to contain mutated DNA - point mutations/deletions - due to carcinogen exposure
Mutations accumulate over time (a multi-step process underlies carcinogenesis)
Evades DNA repair mechanisms, apoptosis to remove damaged cells, immune system
What are the 2 diff types of cell that mutations can occur in in cancer?
- Egg/Sperm Cell mutations - Germ line mutation = These are inheritable mutations and can increase risk of developing cancer
- Somatic cell mutation - non-inheritable, but can be passed on to daughter cells in cell division
Outline Somatic cell mutations and what they can cause
Somatic cell has alteration in DNA , cell division - Clonal cells.
All cells in a primary tumour arise from a single cell - Initiation of tumorigenesis (development of cancer) is clonal.
Continued accumulation of mutations
10^14 cells in body
Tumour cells can evolve - subclonal selection allowing a growth advantage + heterogeneity of cells in a tumour.
Depends on: Tumour cells interact with surrounding tumour cells + the tumour microenvironment (e.g. immune cells)
Describe the process through which a normal cell can become a tumour cell - Proliferation
Proliferation in response to diff signals - GFs, hormones, IL, cytokines
+ Counterbalancing processes - DNA damage = cell cycle arrest, apoptosis
The control of cell division within a tissue is important in self renewing when proliferation must balance cell loss.
There are signals which induce proliferation e.g.
Growth factors :EGF, PDGF
Cytokines: Growth hormones, interleukins
Hormones: Oestrogen
Process is controlled however and balanced with Apoptosis
Programmed cell death as a result of irreparable damage
What is the typical cell life cycle ?
Normal cells
Proliferation (growth + division)
Differentiation
Perform function
Apoptosis
(Programmed cell death)
-Mutations in the genes regulating these processes = imbalanced cell growth/cell death = continual division = ⬆ cell number = clinical tumour
What problems can arise in the cell life cycle?
Regulation of the cell life cycle processes is vital and if mutations are acquired in the genes that regulate this, it means :
Cells are not balanced between cell division/ cell death
Cells continue dividing = ↑ cell number = tumour
Carcinogenesis
What are the genes which regulate the processes relating to cell growth? What can go wrong with them?
Oncogenes + tumour suppressor genes regulate cell growth processes.
Oncogenes = Normal genes that regulate cell growth. Can be activated to be oncogenic are called proto-oncogenes
An oncogene is a pro-oncogene that has been mutated in a way which leads to signals that cause uncontrollable growth = accelerates cell growth
Mutation 1: Accelerated cell division
Tumour suppressor genes inhibit cell growth + tumour formation.
Braking signals during G1 phase of cell cycle to stop/slow the cell cycle before the S phase.
Mutated tumour suppressor genes = disables the normal brake mechanism = cancer
Mutation 1 = Susceptible to cancer
Mutation 2 = Leads to cancer
Acquire 2 mutations within tumour suppressor gene = cut off brakes in car = can’t stop car.
In tumorigenesis, mutations in both genes speed up cell growth
What are 3 assumptions which are made when it comes to cancer ?
- 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 cell of the same type
- Once a malignant cell is generated, the mean time to tumour detection is generally constant
What are the 5 models of carcinogenesis ?
Model 1 - Mutational - Chemical carcinogens
Model 2 - Genome instability - knudson’s 2-hit hypothesis
Model 3 - Non-genotoxic - cancer modulators.
Model 4 - Darwinian - how tumours evolve
Model 5 - Tissue organisation - tissue environment, tissue structure
These models overlap = non-exclusive, not distinct
Models for cells to become tumorigenic
Outline Model 1 - Chemical carcinogens and how it can cause cancer
Cancer is a multi step process which includes :
1 - Initiation
2 - Promotion
3 - Progression
Chemical carcinogens can alter any of these 3 processes to induce carcinogenic effects
Alter DNA structure
Damage not repaired = damage accumulates
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.
Chemical carcinogens can induce DNA damage and act in a genotoxic (damage to genetic information within a cell ) manner
e.g. benzene, arsenic, asbestos
What are the 4 groups of Carcinogens?
Provide examples for each
- Chemical - organic compounds
polycyclic aromatic hydrocarbons ,aromatic amines,azo dyes,nitrosamines,carbamates,halogenated compounds ,alkylating agents - Physical
Radiation - Ioninsing /Ultraviolet
Asbestos - Heritable
Genetic Predisposition to cancer - Viral
Hepatitis B
Epstein Barr
-viruses associated with tumours
What are chemical carcinogens ?
4 of the major groups are: -Polycyclic aromatic hydrocarbons -Aromatic amines -Nitrosamines -Alkylating agents Exert their effects by adding functional groups to DNA bases called DNA adducts
Example - Coal Tar Benzo(a)pyrene = a polycyclic hydrocarbon
Found in cigarrete smoke
procarcinogen -> carcinogen (in body by microsomal enzymes, G->T transversion)
What are pro-carcinogens ?
Pro-carcinogens = any substance which is converted into carcinogens through metabolism (microsomal enzymes)
How do we know if a chemical is actually a carcinogen ?
Ames test = A test to determine the mutagenic activity of chemicals by observing whether they cause mutations in sample bacteria.
A rat liver extract is taken and combined with a salmonella strain which only grows in Histidine.
Plate mixture and grow in an agar plate which lacks histidine.
Overnight incubation, There should be very little colonies.
However following addition of the chemical, if the bacteria does grow many colonies, this suggests that change in bacteria = grow in absence of histidine = the chemical is carcinogenic
How do chemical carcinogens exert their effects?
Chemical carcinogens exert their effects by adding functional groups to DNA bases called DNA adducts
How do physical carcinogens exert their effects?
Physical carcinogens alter the bonding of molecules by imparting energy into the biological material
What are physical carcinogens ?
These impart energy into the biological material, altering the bonding of molecules
2 types - UV radiation, Ionizing radiation
DNA damage causes DNA breaks + pyrimidine dimers.
Failed DNA damage repair following this = translocations, mutations
Why does sunscreen protect against UV radiation?
UV radiation only penetrates skin-deep, so sunscreen protects.
What are heritable carcinogens and what effects do they have ?
Genetic predisposition to cancer -
DNA damage is a risk factor for cancer development
Can be mutation in a single gene - DNA damage repair mechanism = allows mutations to accumulate = ⬆ risk of cancer
An inherited germline mutation has an increased risk of developing certain tumours but are rarely involved in causing cancer immediately .
In most hereditary malignancy syndromes , the elevated cancer risk is due to a mutation of a single gene = monogenic hereditary diseases
The affected genes usually have a controlling function on the cell cycle or the repair of DNA damage.
A deficiency in DNA repair would cause more DNA damage to accumulate and increase the risk of cancer
Examples of syndromes causing DNA repair defects - predispose to cancer
Ataxia telangiectasia Bloom's syndrome Fanconi's anaemia Li-Fraumeni syndrome Lynch type 2 Xeroderma pigmentosum
Examples of chromosomal abnormalities - predispose to cancer
Down’s syndrome
Klinefelter syndrome
What is Ataxia telangiectasia and how can it lead to Cancer?
This is a neuromotor dysfunction causing vasodilation
Telangiectasia = spider veins
Mutation in ATM gene which codes for serine/threonine kinase (Phosphorylation of CHECK 1, CHECK 2, activation of p53, DNA repair/cellcyclearrestapoptosis) that is recruited and activated by dsDNA breaks leading to cell cycle arrest , DNA repair and apoptosis.
Mutation = this doesn’t happen = predisposed to cancer
Cancer predisposition : Leukaemia and breast cancer
Outline Bloom Syndrome and how it may lead to cancer
Short stature, <5 feet tall, skin rash develops following sun exposure.
Mutation in the BLM gene that provides instructions for coding a member of the RecQ helicase family that help maintain the structure and integrity of DNA
Mutation in this BLM gene = cancer
Cancer predisposition: Skin cancer, Basal cell carcinoma, Squamous cell carcinoma
Outline Lynch Syndrome and how it can lead to cancer
LS doesn’t cause any symptoms
First sign that person has LS: Symptoms of bowel + womb cancer.
LS is due to Mutations in DNA mismatch repair (MMR) genes - MLH1, MSH2, MSH6 and PMS2
Cancer predisposition : Colorectal cancer, bowel cancer, womb cancer
Identify how infectious agents can be carcinogens
Viruses capable of causing a wide range of human disease - small pox, common cold.
Viruses cause harm when multiply inside the infected cell, kill the cell (lysis) and release progeny (descendant) to further infect other cells
Most genome is expressed during this phase
During latent phase of infection , restricticted pattern of gene expression (e.g. viral oncogenes). -Viruses associated with cancer. express genes that cause cell to transform into tumour cell = tumorigenesis
What properties does a tumourigenic virus have?
Must have stable association with cells:
-Chromosomal integration
Episome
Must not kill cells :
Non-permissive host (virus cannot replicate )
Suppresion of viral lytic cycle
Viral release by budding
Must evade immune surveillance of infected cells:
During latent phase very few genes are expressed - nonimmunogenic genes = survive by avoid detection by immune system
Immune suppression
Viral antigens not expressed at cell surface
Describe viral carcinogenesis
Viral gene products act as transcription factors
Virus carries mutated cellular gene (oncogene)
Viral integration into the cellular genome disrupts cellular genes
Viral gene products inactivate cell cycle regulatory proteins
Viral infection results in immunodeficiency
What viruses are associated with human cancer?
DNA viruses: Epstein-Barr Virus Papilloma viruses Hepatitis B and C Burkitts's lymphoma Nasopharyngeal carcinoma Cervical carcinoma Warts Hepatoma
RNA retroviruses :
HTLV-I
Adult T-cell leukaemia
Lymphoma
Outline Model 2 - Genome Instability
Knudson’s 2-hit hypothesis
Studied tumour suppressors - Rb.
2 types - Familial Rb, Sporadic Rb
Sporadic Rb = develop tumour later in life, compared to familial Rb.
Need to acquire 2 hits for Rb alleles in order to develop that disease
Outline Model 3 - Non genotoxic
Non-genotoxic is characterised by an emphasis on non-genotoxic effects
Important modulators of cancer risk (diet, obesity , hormones and insulin resistance ) do not alter DNA structure but act through functional changes (epigenetics)
Carcinogens that induce cancer via non-genotoxic mechanisms:
- tumour promoters
- endocrine modifiers
- receptor mediators
- Immunosuppressants
- Inducers of tissue-specific toxicity and inflammatory responses - e.g. arsenic, beryllium (overlap, Model1)
High frequency of mutations occur to genome - continuous DNA damage + repair.
Tumour suppressors
Outline Model 4 - Darwinian
(NATURAL SELECTION)
Carcinogenesis by Mutation and Selection model of clonal expansion
The role of the 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/invade
Artificial Selection, resistance to therapy.
Chemotherapy = selecting for tumour cells that can overcome this selection pressure.
Some mutations may be deleterious for tumour.
Initial growth from a single tumour cell is clonal (identical cells) but as cell progresses, continual accumulation of mutations, cells acquire diff. mutations = evolving = natural selection for cells with growth advantage
What are tissues
Tissues = Groups of cells with similar function:
Epithelial tissue, connective tissue, nervous tissue, cardiac tissue, smooth muscle tissue
What is the Somatic Mutation Theory (SMT)?
A Single catastrophic event that triggers carcinogenesis
Cancer is derived from a single somatic cell that has successively accumulated multiple DNA mutations
These mutations damage genes which control cell proliferation and cell cycle - DNA damage repair, cell cycle, apoptosis
According to SMT , neoplastic lesions are the results of DNA -level events
What is the Tissue Organisation Field Theory ?
Carcinogenesis is a problem of general deterioration of the tissue microenvironment due to extracellular causes
Carcinogenesis is primarily a problem of tissue organisation
Carcinogenic agents destroy the 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
How does the immune system respond to cancer ?
The immune system will :
- Protect from virus induced tumours
- Eliminate pathogens
- Identify and eliminate tumour cells
Immune surveillance
Despite this, tumours can still arise - Cancer immunoediting
Group of cells (tissue, model 5) are exposed to carcinogens (model 1), radiation, viral infection, inherited genetic predisposition, chemical carcinogens = some cells transform. cell surface has tumour antigens for immune system to detect tumour antigens.
Despite this, tumours still arise = cancer immunoediting
Outline the three E’s and Cancer immunoediting
Elimination (immune surveillance):
Immune system eliminates developing tumour cells within tissues by detecting by tumour antigens on tumour cell surface
Equilibrium (cancer persistence):
When incomplete removal is present, tumour cells remain dormant and enter equilibrium. The immune system exerts a potent, relentless pressure that contains the tumour. During this phase, tumour cells mutate (model 4, Darwinian) or give rise to genetic variants that survive, grow and enter the next phase = select for cells that overcome the selection pressure, outgrow suppression = escape = cancer progression
Escape
The expanding tumour populations becomes clinically detectable
Which genes drive tumorigenesis?
What are the counterbalancing proteins?
Oncogenes
Tumour suppressors
Cancer can be described as a disease of ……
ageing
Risk of cancer increases w age
Live longer = accumulate changes, mutations etc.
