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’?

Question 18

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

Question 19

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

Question 20

What are the driving forces behind carcinogenesis?