Mechanisms of oncogenesis

Question 1

What is cancer?

Answer 1

Cancer is the name for a group of diseases characterised by:
1. Abnormal cell proliferation
2. Tumour formation
3. Invasion of neighbouring normal tissue
4. Metastasis to form new tumours at distant sites

→ Cancer is a disease of increasing lifespan

Question 2

How is cancer classified?

Answer 2

According to their origin

Question 3

What is a carcinoma?

Answer 3

Cancer that occurs in epithelial cells (approx. 85% of cancer)

Question 4

What is a sarcoma?

Answer 4

Cancers derived from mesoderm cells bone and muscle

Question 5

What is a adenocarcinoma?

Answer 5

Cancers found in glandular tissue

Question 6

How does evidence Suggest that Cancer is a Disease of the Genome at the Cellular Level?

Answer 6

→ Carcinogens cause alterations to the DNA - Mutations
→ DNA from tumours has been shown to contain many alterations from point mutations to deletions
→ 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 if 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 7

How do tumour cells arise/evolve/what is needed for this to go on and cause effects etc?

Answer 7

→ 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

Question 8

What happens in the conversion of a normal cell to a tumour cell?

Answer 8

Proliferation and Control:
→ Control of cell division within a tissue is particularly important in rapidly self renewing tissues when proliferation must balance cell loss

Signals that drive proliferation include:
→ Messages
→ Growth factors: EGF, PDGF
→ Cytokines: growth hormone, interleukins,
→ Hormones: osetrogen

You also have things to counteract/balance that, for example:
→ Apoptosis-programmed cell death as a result of
irreparable damage
→ The pathway a normal cell takes:

Normal cell –> Proliferation, division and growth -> Differentiation -> Perform function –> Apoptosis

→ This process is in balance and under tight control
→ Mutations in DNA that alter the function of
normal genes involved in growth apoptosis and differentiation can affect his balance
→ With some division of cells, Total cell number
increases which can lead to carcinogenesis/a detectable tumour if division is not regulated/high numbers of divisions.

Question 9

What genes regulate the proliferation/division of cells etc? What are they both?

Answer 9

Oncogenes and Tumour Suppressor Genes regulate:

→ 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

→ 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

Question 10

What are some assumptions to multistage carcinogenesis?

Answer 10

→ 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

Question 11

List the 5 models of carcinogenesis and their main focus

Answer 11

The models overlap but these are:
model 1 - ‘mutational’- chemical carcinogens
model 2 - ‘genome instability’- familiarity and genome instability
model 3 - ‘non-genotoxic’- clonal expansion/ epigenetics
model 4 - ‘Darwinian’- clonal expansion/cell selection
model 5 - ‘tissue organisation’-microenvironment/morphostats

Question 12

Describe model 1- chemical carcinogens

Answer 12

→ Cancer is s 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.
→ In the majority of instances chemical carcinogens can induce this DNA damage and act in a genotoxic manner.
→ Experiments were done to find which specific carcinogenic agents are implicated in the causation of which specific cancers eg benzene-acute leukaemia

Question 13

Name some classes of carcinogens and examples

Answer 13

Chemical - 10 groups:
→ polycyclic aromatic hydrocarbons, aromatic amines,
azo dyes, nitrosamines, carbamates, halogenated compounds, alkylating agents

→ Four of the major groups polycyclic aromatic hydrocarbons, aromatic amines, nitrosamines and alkylating agents
→ These exert their effects by adding functional groups to DNA bases called DNA adducts
→ One example is coal tar, which contains benzo[a]pyrene, a polycyclic hydrocarbon
Benzo[a]pyrene is commonly found in cigarette smoke (together with 81 other carcinogens)!

Physical
→ Radiation
→ Asbestos

Heritable
→ Predisposition

Viral
→ Hepatitis B
→ Epstein Barr

Question 14

What is the aim of the aims test?

Answer 14

A test to determine the mutagenic activity of chemicals by observing whether they cause mutations in sample bacteria.
(looking at colonies on an agar plate)

Question 15

How do physical carcinogens work?

Answer 15

Unlike chemical carcinogens physical carcinogens act by imparting energy into the biological material

Energy —> Changes in bonding of molecules —> Biological effects

Radiation is the primary physical agent
Several types of radiation can act as carcinogens
for example:
→ Ionizing radiation (X-rays, nuclear radiation)
→ U.V. radiation

Damage leads to DNA breaking Pyrimidine dimers
and failure of repair leads to Translocations and Mutations

Question 16

What are heritable carcinogens- syndromes predisposing to cancer?

Answer 16

→ DNA damage is a risk factor for cancer development

Germline mutations:
→ present in egg or sperm
→ can be inherited
→ cause cancer family syndrome
→ 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

Question 17

What are some examples of DNA repair defects?

Answer 17

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

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.

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 18

What properties are required for tumorigenic viruses to give it this label?

Answer 18

→ Stable association with cells
→ Must not kill cells
→ Must evade immune surveillance of infected cells

Question 19

What are some viruses associated with human cancer?

Answer 19

DNA viruses e.g.
→ Epstein-Barr virus
→ papilloma viruses
→ hepatitis B and C
→ RNA retroviruses e.g.
→ HTLV-I Adult T-cell leukaemia, lymphoma

Question 20

What research/findings are there for Model 2 Genome Instability as a model of carcinogenesis?

Answer 20

→ Knudson’s Hypothesis for Hereditary Cancers
→ First proposed by Carl Nordling in 1953 and then formulated by Knudson in 1971
→ 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 21

What findings are there for model 3 of carcinogenesis- ‘non genotoxic’?

Answer 21

→ Non-genotoxic is characterized 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:
1. tumour promoters (1,4-dichlorobenzene),
2. endocrine-modifiers (17β-estradiol),
3. receptor-mediators (2,3,7,8-tetrachlorodibenzo-p-dioxin),
4. immunosuppressants (cyclosporine) or
inducers of tissue-specific toxicity and inflammatory responses (metals such as arsenic and beryllium- which also came up in model 1 so there is overlap)

→ 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

Question 22

What findings are there for model 4 of carcinogenesis- ‘Darwinian’?

Answer 22

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 and invade
→ Selection will include resistance to therapy
→ Some mutations may be deleterious for tumour

Question 23

What findings are there for model 5 of carcinogenesis- Tissue Organisation?

Answer 23

→ 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 24

What are the driving forces behind carcinogenesis?

Answer 24

→ Two drastically different approaches to understanding the forces driving carcinogenesis have crystallized through years of research.
→ These are the somatic mutation theory (SMT) and the tissue organization field theory (TOFT).

SMT: 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 single catastrophic event triggering carcinogenesis

TOFT:
→ 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. Carcinogenesis as general deterioration of the tissue microenvironment due to extracellular causes

Question 25

Give an example of a process in the body that involves lots of the above models discussed

Answer 25

The Immune Response in Cancer:
→ We all have tumour cells! But being kept in check by immune system

The immune system will:
→ Protect from virus-induced tumours
→ Eliminate pathogens
→ Identify and eliminate tumour cells
→ Immune surveillance

→ Despite this tumours can still arise-

Concept of cancer immunoediting
The Three Es:

→ 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