3 - MECHANISM OF ONCOGENESIS

Question 1

What are some factors that can be targeted to prevent and reduce the risk of cancer 8

Answer 1

• smoking: smoking is the most important preventable cause of cancer in the world
• obesity and weight: small changes you can stick with help keep weight off for good
• hormones: changes in our hormone levels can affect the risk for cancer
• alcohol: the less you drink, the lower the risk of cancer
• workplace causes of cancer: some jobs can affect people’s risk of cancer or may have done in the past
• sun and UV: overexposure to UV light from the sun or sunbeds is the main cause of skin cancer
• physical activity: around 3400 cases of cancer in the UK each year could be prevented by keeping active
• infections and HPV: you can’t catch cancer, but some infections such as human papilloma virus can increase the risk

Question 2

What is cancer 4

Answer 2

Cancer is a group of diseases characterised by specific hallmarks.

Cancer is the name for a group of diseases characterised by:

• Abnormal cell proliferation
• Tumour formation
• Invasion of neighbouring normal tissue
• Metastasis to form new tumours at distant sites

Question 3

Define Carcinoma 1

Answer 3

Carcinoma is a category of types of cancer that develop from epithelial cells.

Specifically, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that arises from cells originating in the endodermal, mesodermal or ectodermal germ layer during embryogenesis.

Approximately 85% of cancer occur in epithelial cells

Question 4

Define Sarcomers 1

Answer 4

A sarcoma is a cancer that arises from transformed cells of mesenchymal (connective tissue) origin.

Connective tissue is a broad term that includes bone, cartilage, fat, vascular, or hematopoietic tissues, and sarcomas can arise in any of these types of tissues.

Cancers derived from mesoderm cells (bone and muscle)

Question 5

Define Adenocarcinomas 1

Answer 5

A malignant tumour formed from glandular structures in epithelial tissue.

Cancers found in glandular tissue are called adenocarcinomas

Question 6

How do cancers provide themselves with nutrients 1

Answer 6

Provide themselves with nutrients as a result of angiogenesis

Question 7

What are the hallmarks of cancer 10

Answer 7

1. • evading growth suppressors
2. • enabling replicative immortality
3. • activating invasion and metastasis
4. • inducing angiogenesis
5. • resisting cell death
6. • deregulating cellular energetics
7. • sustained proliferative signalling
8. • avoiding immune destruction
9. • genome instability and mutation
10. • tumour-promoting inflammation

Two enabling characteristics: genome instability and tumour inflammation

Two emerging hallmarks: avoiding immune destruction and reprogramming energy metabolism

Question 8

Evidence Suggest that Cancer is a Disease of the Genome at the Cellular Level 6

Answer 8

• Carcinogens cause mutations to the DNA. DNA from tumours show that many alterations (from point mutations to deletions) take place.
• The accumulation of mutations over time represents the multi-step process that underlies carcinogenesis
• This accumulation occurs only after the cells defence mechanism of DNA repair have been evaded
• In cases of severe damage cell apoptosis is induced
• Many mechanisms exist for blocking carcinogenesis but over burdening the system increases the possibility that cells will escape surveillance
• The longer we live the more time there is for DNA to accumulate mutations that may lead to cancer. Cancer is more prevalent as lifespan has increased.

Question 9

How can an accumulation of mutations occur in DNA 1

Answer 9

This accumulation occurs only after the cells defence mechanism of DNA repair have been evaded

Question 10

Germline mutations 2

Answer 10

• Germline mutation can be passed onto offspring
• IN risk of developing cancer

Question 11

Somatic mutations and tumour cells 9

Answer 11

• Somatic mutations constitute almost all mutations in tumour cells
• All cells in a primary tumour arise from a single cell, initiation of the development of cancer is clonal
• Only one of the 1014 cells in body need to be transformed to create a tumour
• Continued accumulation of mutations
• Tumour cells can ‘evolve’- sub clonal selection allowing a growth advantage and explain and heterogeneity of cells in a tumour
• Dependent on interaction with other tumour cells and the tumour microenvironment
• Somatic mutations can be passed on/inherited
• Takes 1 cell to undergo transformation to initiate the process
• Tumour cells can interact with the cells around them

Question 12

What can help convert a Normal Cell to a Tumour Cell 3

Answer 12

A cell proliferates in response to lots of different signals

GF, hormones, interleukins, cytokines

There are processes in the body that will counteract them though e.g. apoptosis

Question 13

Growth, Apoptosis and Differentiation Regulate Cell Numbers

Answer 13

.

Question 14

Oncogenes 3

Answer 14

Normal genes regulate growth

Normal genes that can be activated to be oncogenic are called proto-oncogenes.

An oncogene is a proto-oncogene that has been mutated in a way that leads to signals that cause uncontrolled growth- i.e., cancer.
This is like pushing down on the gas pedal.

Oncogenes are normal genes within your cells that regulate cell growth –> compared to racing cars –> the accelerator pedal and so a mutation will put your foot down on the pedal and eventually hit a brick wall which is cancer

Question 15

Tumour Suppressor Genes 4

Answer 15

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.

If tumour-suppressor genes are mutated, the normal brake mechanism will be disabled, resulting in uncontrolled growth, i.e. cancer.

Tumour suppressor genes need 2 mutations to stop their function  like taking away the brakes of a car. You lose the ability to stop the car

Question 16

What do Tumour Suppressor Genes do in the cell cycle 2

Answer 16

They act as braking signals during phase G1 of the cell cycle, to stop or slow the cell cycle before S phase.

Question 17

3 assumptions of multistage carcinogenesis 3

Answer 17

1. Malignant transformation of a single cell is sufficient to give rise to a tumour
2. Any cell in a tissue is as likely to be transformed as any other of the same type
3. Once a malignant cell is generated the meantime to tumour detection is generally constant

Question 18

Molecular Mechanisms of Cancer - Five models of carcinogenesis 5

Answer 18

Molecular Mechanisms of Cancer - Five models of carcinogenesis 5

Model 1: Mutational

Model 2: Genome instability

Model 3: Non-genotoxic

Model 4: Darwinian

Model 5: Tissue organisation

MGDTN - My Giant D To Night

Question 19

Model 1 Chemical Carcinogens - overview 3

Answer 19

Cancer is a multi step process that includes initiation, promotion and progression. Chemical carcinogens can alter any of these process to induce their carcinogenic effects.

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 and act in a genotoxic manner.

Carcinogens alter the structure of DNA  If this damage is not repaired, you will get an accumulation of the damage

Question 20

Model 1 Chemical Carcinogens:

Specific carcinogenic agents implicated in the causation of certain cancer - table

Answer 20

.

Question 21

Model 1 Chemical Carcinogens

Types/Classes of carcinogens 4

Answer 21

1. Chemical
2. Physical
3. Heritable
4. Vital

Question 22

Model 1 Chemical Carcinogens

Types/Classes of carcinogens - Example of Chemical 10

Answer 22

• • polycyclic aromatic hydrocarbons
• • aromatic amines
• • azo dyes
• • nitrosamines
• • carbamates
• • halogenated compounds
• • alkylating agents

Question 23

Model 1 Chemical Carcinogens

Types/Classes of carcinogens - Example of Physical 2

Answer 23

• • radiation (ionising and UV)
• • asbestos

Question 24

Model 1 Chemical Carcinogens

Types/Classes of carcinogens - Example of Heritable 1

Answer 24

• predisposition

Question 25

Model 1 Chemical Carcinogens

Types/Classes of carcinogens - Example of Viral 2

Answer 25

• Hepatitis B
• Epstein Barr

Question 26

Model 1 Chemical Carcinogens

Other uses of cancer-causing chemicals in tobaccos and cigarette smoke

Answer 26

.

Question 27

Model 1 Chemical Carcinogens

Chemical carcinogens 4,2

Answer 27

1. polycyclic aromatic hydrocarbons
2. aromatic amines
3. nitrosamines
4. alkylating agents

Exert their effects by adding functional groups to DNA bases called DNA adducts

DNA adduct –> a segment of DNA bound to a cancer-causing chemical

Question 28

What is a DNA adduct 1

Answer 28

DNA adduct –> a segment of DNA bound to a cancer-causing chemical

Question 29

Model 1 Chemical Carcinogens

Chemical carcinogens - Example, coal tar 6

Answer 29

1. One example is coal tar, which contains benzo[a]pyrene, a polycyclic hydrocarbon, it’s a pro carcinogen.
2. Taken into our body and comes into contact with enzymes, then it becomes carcinogenic via G to T conversions
3. Benzo[a]pyrene is commonly found in cigarette smoke (together with 81 other carcinogens)!
4. BP ranks high in the measure of how easy it enters into cells.
5. Benzo[a]pyrene is only harmful if it is inside your body  it is converted to a carcinogen due to G-T transversions
6. Benzopyrene goes to benzopyrene epoxide

Question 30

Model 1 Chemical Carcinogens

Define Ames Test 1

Answer 30

A test to determine the mutagenic activity of chemicals by observing whether they cause mutations in sample bacteria

Question 31

Model 1 Chemical Carcinogens

Ames Test 5

Answer 31

A test to determine the mutagenic activity of chemicals by observing whether they cause mutations in sample bacteria.

Uses bacteria

Take rat liver extract and combine it with salmonella strain that will only grow in the presence of histidine. If you plate that mixture onto an agar plate that lacks histidine, following overnight incubation, you should have very few colonies on the plate.

If you get some colonies, it is due to natural reversion.

If you get lots of colonies, it shows that there is a change in the bacteria and so it can now grow in the absence of histidine

Question 32

Model 1 Chemical Carcinogens

How do physical carcinogens act 1

Answer 32

Physical carcinogens act by imparting energy into the biological material.

Question 33

Model 1 Chemical Carcinogens

What does radiation do as a primary physical agent 6

Answer 33

Radiation is the primary physical agent

Several types of radiation can act as carcinogens

Energy alters molecules and bonding

Exposure to sun is one of the biggest risks for melanoma (skin cancer)

If the pyrimidine dimers/DNA breaks aren’t repaired, it will lead to permanent mutations

UV radiation and Ionizing radiation

UV doesn’t penetrate lower than your skin

Question 34

Model 1 Chemical Carcinogens

DNA Repair Defects - Ataxia telangiectasia

What is it? Where does the mutation occur? Cancer predisposition? 3

Answer 34

Ataxia telangiectasia- neuromotor dysfunction, dilation of blood vessels, telangiectasia = spider veins

Mutation in ATM gene, codes for a serine/threonine kinase that is recruited and activated by dsDNA breaks leading to cell cycle arrest, DNA repair and apoptosis -cell cycle arrest

Cancer predisposition: lymphoma, leukaemia and breast cancer

Question 35

Model 1 Chemical Carcinogens

DNA Repair Defects - Bloom’s syndrome

What is it? Where does the mutation occur? Cancer predisposition? 3

Answer 35

Bloom’s Syndrome -short stature, rarely exceed 5 feet tall, skin rash that develops after exposure to the sun

Mutation in BLM gene that 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.

Question 36

Model 1 Chemical Carcinogens

DNA Repair Defects - Lynch type

What is it? Where does the mutation occur? Cancer predisposition? 3

Answer 36

Lynch type- LS doesn’t cause any symptoms. Sometimes the first sign that a person has LS is when the symptoms of bowel and womb cancer develop.

Mutations in DNA mismatch repair (MMR) genes, notably MLH1, MSH2, MSH6 and PMS2.

Cancer predisposition: colorectal cancer

Question 37

Model 1 Chemical Carcinogens

Heritable carcinogens - Syndromes Predisposing to Cancer 7

Answer 37

Accounts for 5% of all cancers

An inherited germline 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

A deficiency in DNA repair would cause more DNA damages to accumulate, and increase the risk for cancer.

These mutations affect genes that regulate cell cycle, apoptosis and DNA damage repair

If you have this mutation you have a predisposition to that type of cancer due to the inability to repair DNA

Question 38

Model 1 Chemical Carcinogens

Syndromes Predisposing to Cancer - DNA repair defects 6

Answer 38

1. • Ataxia Telangiectasia
2. • Bloom’s syndrome
3. • Fanconi’s anaemia
4. • Li-Fraumeni syndrome
5. • Lynch type II
6. • xeroderma pigmentosum

Question 39

Model 1 Chemical Carcinogens

Syndromes Predisposing to Cancer - Chromosomal Abnormalities 2

Answer 39

1. • Down’s syndrome
2. • Klinefelter’s syndrome

Question 40

Model 1 Chemical Carcinogens

Identifying Infectious Agents as Carcinogens - Viral infection process 5

Answer 40

• Most harm caused when viruses multiply inside the infected cell, kill the cell and release progeny to further infect other cells
• Viral infections when they infect, will be very proliferative –> they will exhibit a lytic cycle –> cell will lyse, releasing more viruses
• Viruses can switch from a lytic to a latent pathway, and they could allow transformation of cells into tumor cells.
• Most of the damage is done as part of their lytic cycle
• Viruses can be associated with cancer in rare cases and is shown usually later on.

Question 41

Model 1 Chemical Carcinogens

Properties required of tumourigenic viruses 3

Answer 41

1. Stable association with cells
2. Must not kill cells
3. Must evade immune surveillance of infected cells

Question 42

Model 1 Chemical Carcinogens

Properties required of tumourigenic viruses - Stable association with cells 1

Answer 42

Chromosomal integration episome

Episome - a genetic element inside some bacterial cells, especially the DNA of some bacteriophages, that can replicate independently of the host and also in association with a chromosome with which it becomes integrated.

Question 43

Define Episome 1

Answer 43

A genetic element inside some bacterial cells, especially the DNA of some bacteriophages, that can replicate independently of the host and also in association with a chromosome with which it becomes integrated.

Question 44

Model 1 Chemical Carcinogens

Properties required of tumourigenic viruses - Must not kill cells 3

Answer 44

• non-permissive host (virus cannot replicate)
• suppression of viral lytic cycle
• viral release by budding

Question 45

Model 1 Chemical Carcinogens

Properties required of tumourigenic viruses - Must evade immune surveillance of infected cells 2

Answer 45

• immune suppression
• viral antigens not expressed at cell surface

Question 46

Model 1 Chemical Carcinogens

Viral carcinogenesis 5

Answer 46

.

Question 47

Model 2 Genome Instability 7

Answer 47

• It’s Knudson’s Hypothesis for Hereditary Cancers.
• It was first proposed by Carl Nordling in 1953 and then formulated by Knudson in 1971.
• It was developed by Knudson for retinoblastoma, which became the basis of the ‘two-hit’ hypothesis
• and led to the formulation of the theory of ‘tumour suppressor genes’(TSGs) and then to the discovery of Rb1, the TSG that causes retinoblastoma when both copies are mutated.
• Knudson performed statistical analysis on cases of retinoblastoma of which there are two types: the inherited type and the sporadic type.
• Knudson suggested that multiple hits were required to cause cancer. So, for example, if the first mutated allele was inherited the second mutation would lead to cancer. In the sporadic forms of the tumour both mutations had to take place and hence this could explain the difference of age at diagnosis.
• 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.

Question 48

Model 2 Genome Instability

What became the basis for the ‘two-hit’ hypothesis? 1

What did this lead to? 2

Answer 48

Knudson for retinoblastoma, became the basis of the ‘two-hit’ hypothesis
This led to the formulation of the theory of ‘tumour suppressor genes’ (TSGs) and then to the discovery of Rb1, the TSG that causes retinoblastoma when both copies are mutated.

Question 49

Model 2 Genome Instability

What did Knudson discover about retinoblastoma? 2

Answer 49

Retinoblastoma of which there are two types: the inherited type and the sporadic type.

Question 50

Model 2 Genome Instability

Multiple hits theory 4

Answer 50

• Multiple hits were required to cause cancer.
• So, for example, if the first mutated allele was inherited the second mutation would lead to cancer.
• In the sporadic forms of the tumour both mutations had to take place and hence this could explain the difference of age at diagnosis.
• 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.

Question 51

Model 3 Non Genotoxic 5

Answer 51

Non-genotoxic is characterised by an emphasis on non-genotoxic effects.

Several important modulators of cancer risk (diet, obesity, hormones and insulin resistance) do not seem to act through a structural change in DNA but rather through functional changes including epigenetic events.

There is, however, a group of carcinogens that induce cancer via non-genotoxic mechanisms. Non-genotoxic carcinogens have been shown to 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)

Although little is known about this group of carcinogens it is known that in a high proportion of them, multiple pathways need to be altered for cancer induction.

Often referred to as modulators

Target function.

Arsenic and beryllium also came up in model 1

Question 52

Model 3 Non Genotoxic

Non-genotoxic carcinogens have been shown to act as: 5

Answer 52

Non-genotoxic carcinogens have been shown to 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)

Question 53

Model 4 Darwinian 6

How? 1 Considerations? 2 Process? 4

Answer 53

• This is carcinogenesis by Mutation and Selection-Model of Clonal Expansion
• Always takes into account that there is a selective pressure - natural selection and artificial selection
• It is based on the role of the environment in selecting cells that have some acquired advantage.
• There is the sequential accumulation of mutations due to exposure to carcinogens.
• The tumour cells will be selected for ability to grow and invade
• Selection will include resistance to therapy.
• Some mutations may be deleterious for tumour.
• Chemotherapy is artificial selection, can lead to production of resistant cell types
• Accumulation of mutations
• The cells don’t acquire the same mutations
• You have natural selection for the cells that will have a growth advantage

Question 54

Model 4 Darwinian

What does this model taken into account? 2

Answer 54

Always takes into account that there is a selective pressure - natural selection and artificial selection

Chemotherapy is artificial selection, can lead to production of resistant cell types

Accumulation of mutations

The cells don’t acquire the same mutations

You have natural selection for the cells that will have a growth advantage

Question 55

Model 5 Tissue Organisation 2

Answer 55

To understand the changes that occur during cancer it is important to understand the principles of cell and tissue organisation and mechanisms that control growth and structure.

TISSUES - groups of cells with similar function are known as tissues: epithelial, connective muscle and nervous.

Question 56

Forces driving carcinogenesis

Two drastically different approaches to understanding the forces driving carcinogenesis have crystallized through years of research.

What are they?

Answer 56

1. Somatic mutation theory (SMT)
2. Tissue organisation field theory (TOFT)

Question 57

What is the Somatic mutation theory 4

Answer 57

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 the cell cycle.
Thus, according to SMT, neoplastic lesions are the results of DNA-level events.

Here, a single catastrophic event triggers carcinogenesis.

Question 58

What is the tissue organisation field theory (TOFT) 4

Answer 58

• 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 the effect, not the cause, of the tissue-level events.
• Here, carcinogenesis is viewed as general deterioration of the tissue microenvironment due to extracellular causes.

Question 59

What is the immune response to cancer 3,3

Answer 59

• The immune system will:
• protect from virus-induced tumours
• eliminate pathogens
• identify and eliminate tumour cells
• This leads to immune surveillance.
• However, despite this, tumours can still arise.
• This is the concept of cancer immunoediting.

Question 60

What will the immune system do in response to cancer - overall 3

Answer 60

• protect from virus-induced tumours
• eliminate pathogens
• identify and eliminate tumour cells

Question 61

What does cancer immunoediting consist of? 3,3

Answer 61

ELIMINATION:
The immune system is able to eradicate developing tumours.

EQUILIBRIUM:
When incomplete removal is present, 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 (longest of the phases, around 20 years).

ESCAPE:
The expanding tumour populations becomes clinically detectable.

• When normal cells are exposed to carcinogens, they could become transformed –> these cells will have tumour antigens on their surface.
• The immune system will pick up the tumour antigens
• Cancer immunoediting is very important

Question 62

Cancer immunoediting - Elimination 1

Answer 62

The immune system is able to eradicate developing tumours.

Question 63

Cancer immunoediting - Equilibrium 3

Answer 63

When incomplete removal is present 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 (Longest of the phases, around 20 years).

Question 64

Cancer immunoediting - Escape 1

Answer 64

The expanding tumour populations becomes clinically detectable.