Mechanisms of Oncogenesis

Question 1

What is cancer?

Answer 1

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

Cancer is a disease of increasing lifespan…

Over 200 different types of cancer have been classified, often according to their origin:

Approximately 85% of cancer occur in epithelial cells-carcinomas
Cancers derived from mesoderm cells (bone and muscle) are sarcomas
Cancers found in glandular tissue are called adenocarcinomas

Question 2

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

Answer 2

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 3

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

Answer 3

Tumour cells

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 4

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

Answer 4

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 e.g.:
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 5

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

Answer 5

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 6

What are some assumptions to multistage carcinogenesis?

Answer 6

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 7

List the 5 models of carcinogenesis and their main focus

Answer 7

They do overlap but:

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 8

Describe model 1- chemical carcinogens

Answer 8

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 9

Name some classes of carcinogens and examples

Answer 9

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
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 10

What is the aim of the ames test?

Answer 10

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 11

How do physical carcinogens work?

Answer 11

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

e.g.:

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 12

What are heritable carcinogens- syndromes predisposing to cancer?

Answer 12

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 13

What are some examples of DNA repair defects?

Answer 13

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 14

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

Answer 14

Stable association with cells

Must not kill cells

Must evade immune surveillance of infected cells

Question 15

What are some viruses associated with human cancer?

Answer 15

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 16

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

Answer 16

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 17

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

Answer 17

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:

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- 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 18

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

Answer 18

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 19

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

Answer 19

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 20

What are the driving forces behind carcinogenesis?

Answer 20

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
organization
carcinogenic agents destroy the normal tissue architecture thus disrupting cell-to-cell signaling and compromising genomic integrity
the DNA mutations are randon and the effect, not the cause, of the tissue-level events.

carcinogenesis as general deterioration of the tissue microenvironment due to extracellular causes

Question 21

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

Answer 21

e.g 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

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