15. Mechanism 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
• Cancers derived from mesoderm cells (bone and muscle) are sarcomas
• Cancers found in glandular tissue are called adenocarcinomas

Question 2

List the hallmarks of cancer

Answer 2

• evading growth suppressors
• avoiding immune destruction
• enabling replicative immortality
• tumour-promoting inflammation
• activating invasion and metastasis
• inducing angiogenesis
• genome instability and mutation
• resisting cell death
• deregulating cellular energetics
• sustained proliferative signalling

Question 3

Explain how evidence suggests that cancer is a disease of the genome at the cellular level.

Answer 3

• 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 4

Describe tumour cells

Answer 4

• 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 5

Describe oncogenes and tumour supressor genes

Answer 5

• 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

With the multi-stage carcinogenesis, what are the three assumptions made?

Answer 6

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 mean time to tumour detection is generally constant

Question 7

What are the five models of cancer?

Answer 7

1) Mutational
2) Genome instability
3) Non-genotoxic
4) Darwinian
5) Tissue organisation

Question 8

Describe the first model of cancer.

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..

Question 9

List the several classes of carcinogenesis.

Answer 9

CHEMICAL, 10 groups:

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

PHYSICAL:

• Radiation (ionising and UV)
• Asbestos

HERITABLE:
- Predisposition

VIRAL:

• Hepatitis B
• Epstein Barr

Question 10

How do some chemical carcinogens (such as aromatic hydrocarbons) exert their effects?

Answer 10

• 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)!
• BP ranks high in the measure of how easy it enters into cells

Question 11

What is the Ames test?

Answer 11

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

Question 12

How do physical carcinogens act?

Answer 12

• Unlike chemical carcinogens physical carcinogens act by imparting energy into the biological material.
• Radiation is the primary physical agent
• Several types of radiation can act as carcinogens

Question 13

Heritable carcinogens. Expand.

Answer 13

• 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 14

List some syndrome predisposing to cancer.

Answer 14

DNA REPAIR DEFECTS

• ataxia telangiectasia
• Bloom’s syndrome
• Fanconi’s anaemia
• Li-Fraumeni syndrome
• Lynch type II
• xeroderma pigmentosum

CHROMOSOMAL ABNORMALITIES

• Down’s syndrome
• Klinefelter’s syndrome

Question 15

How do viruses cause cancer?

Answer 15

• Viruses capable of causing a wide range of human disease from small pox to common cold
• Most harm caused when viruses multiply inside the infected cell, kill the cell and release progeny to further infect other cells
• The cell may also transform into a tumour cell and so lead to tumour cell division

Question 16

What are some properties required of tumourigenic viruses?

Answer 16

• Stable association with cells
- chromosomal integration
Episome

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

• Must evade immune surveillance of infected cells
- immune suppression
viral antigens not expressed at cell surface

Question 17

List some viruses that are associated with human cancer

Answer 17

DNA VIRUSES

• Epstein-Barr viru ~ (Burkitt’s lymphoma, nasopharyngeal carcinoma)
• papilloma viruses ~ (cervical carcinoma, warts)
• hepatitis B and C ~(hepatoma)

RNA RETROVIRUSES
- HTLV-I (Adult T-cell leukaemia, lymphoma)

Question 18

Describe the second model of cancer

Answer 18

It’s 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 19

Describe the third model of cancer

Answer 19

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)

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 20

Describe the forth model of cancer.

Answer 20

This is carcinogenesis by Mutation and Selection-Model of Clonal Expansion.

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.

Question 21

Describe the fifth model of cancer

Answer 21

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 22

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

Answer 22

These are the somatic mutation theory (SMT) and the tissue organization field theory (TOFT).

Question 23

Describe the SMT

Answer 23

• Somatic mutation theory.
• 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
• Here, single catastrophic event triggering carcinogenesis

Question 24

Describe TOFT

Answer 24

• Tissue organisation field theory.
• 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 random and the effect, not the cause, of the tissue-level events.
• Here, carcinogenesis as general deterioration of the tissue microenvironment due to extracellular causes

Question 25

What is the immune system’s response to cancer?

Answer 25

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 26

What is cancer immunoediting?

Answer 26

• REMEMBER THE 3 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