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Molecular Basis of Disease(Sem 4) > Mechanisms of Oncogenesis > Flashcards

Mechanisms of Oncogenesis Flashcards

1
Q

What are some risk factors of cancer?

A 
Smoking
Obesity and weight 
Alcohol
Workplace 
Sun and UV
Physical activity 
Hormones
Infections and HPV 
Inherited genes 
Air pollution and radon 
Diet and healthy eating
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2
Q

Define Cancer and what hallmarks characterises it ?

A

Abnormal cell proliferation

Tumour formation

Invasion of neighbouring normal tissue

Metastasis to form new tumours at distant sites

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3
Q

What are some different types of cancers ?

A

85% Cancer in epithelial cells =Carcinomas
Cancers from mesoderm (bone /muscle ) cells =Sarcomas
Cancers in glandular tissue =Adenocarcinomas

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4
Q

What are the Hallmarks of cancer ?

A
  • Deregulating cellular energetics
  • Sustaining proliferative signalling
  • Evading growth suppressors
  • Avoiding immune destruction
  • Enable replicative immortality
  • Tumour-promoting inflammation
  • Activating invasion and metastasis
  • Inducing angiogenesis
  • Genome instability and mutation
  • Resisting cell death
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5
Q

What are some characteristics of the cancer DNA ?

A

DNA from tumours has been shown to contain many alterations from point mutations to deletions

The accumulation of mutations over time represents multi-step process that underlies carcinogenesis

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6
Q

What are the two types of mutations which can happen in cancer?

A
  1. Egg/Sperm Cell mutations -Germ line mutation

These are inheritable mutations and can increase risk of developing cancer

2.Somatic cell mutation

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7
Q

Outline Somatic cell mutations and what they can cause

A

Somatic cell has alteration in DNA , cell division - Clonal cells.

All cells in a primary tumour arise from a single cell , initiation of developmental of cancer is clonal.

Continued accumulation of mutations

10^14 cells in body

Tumour cells can evolve allowing a growth advantage and explain and heterogeneity of cells in a tumour.

Tumours can interact with the tumour micro environment

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8
Q

Describe the process through which a normal cell can become a tumour cell

A

The control of cell division within a tissue is important in self renewing when proliferation must balance cell loss.

There are signals which induce proliferation for e.g.
Growth factors :EGF,PDGF
Cytokines: Growth hormones 
,interleukins 
Hormones: Oestrogen

Process is controlled however and balanced with Apoptosis

Programmed cell death as a result of irreparable damage

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9
Q

What is the typical cell life cycle ?

A

Normal cells

Proliferation (growth + division)

Differentiation

Perform function

Apoptosis
(Programmed cell death )

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10
Q

What problems can arise ?

A

Regulation of the cell life cycle processes is vital and if mutations are acquired in the genes that regulate this means :

Cells are not balanced between cell death and dividing

They will continue dividing and this will increase cell number which leads to tumours

Carcinogenesis

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11
Q

What are the genes which regulate the processes relating to cell growth ?What can go wrong with them

A

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

An oncogene is a pro-oncogene that has been mutated in a way which leads to signals that cause uncontrollable growth

Mutation 1:Accelerated cell division

Tumour suppressor genes inhibit both growth and tumour formation. They act as braking signals during phase G1 of the cell cycle to stop/slow the cell cycle before the S phase.
If tumour suppressor genes are mutated the normal brake mechanism will be disabled . This causes cancer

Mutation 1=Susceptible to cancer

Mutation 2= Leads to cancer

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12
Q

What are three assumptions which are made when it comes to cancer ?

A

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

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13
Q

What are the five models of carcinogenesis ?

A
  1. Mutational -Chemical carcinogens
  2. Genome instability
  3. Non-genotoxic
  4. Darwinian
  5. Tissue organisation

These models overlap

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14
Q

Outline Model 1-Chemical carcinogens and how it can cause cancer

A

Cancer is a multi step process which includes :
Initiation , promotion and progression

Chemical carcinogens can alter any of these three processes to induce 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.

Chemical carcinogens can induce DNA damage and act in a genotoxic (damage to genetic information within a cell ) manner

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15
Q

What are the four groups of Carcinogens ?Provide examples for each

A

1.Chemical
polycyclic aromatic hydrocarbons ,aromatic amines,azo dyes,nitrosamines,carbamates,halogenated compounds ,alkylating agents

2.Physical
RAdiation-Ioninsing /Ultraviolet
Asbestos

3.Heritable
Predisposition

4.Viral
Hepatitis B
Epstein Barr

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16
Q

What are chemical carcinogens ?

A

Four of the major groups are polycyclic aromatic hydrocarbons , aromatic amines, nitrosamines and alkylating agents exert their effects by adding functional grous to DNA bases called DNA adducts

Example -Coal Tar Benzo(a)pyrene , polycyclic hydrocarbon

Found in cigarrete smoke

17
Q

What are pro-carcinogens ?

A

These are any substance which is transformed into carcinogens through metabolism.

They are converted into carcinogens through microsomal enzymes

18
Q

How do we know if a chemical is actually a carcinogen ?

A

By doing an Ames test which is a test to determine the mutagenic activity of chemicals by observing whether they cause mutations in sample bacteria.

A rat liver extract is taken and combined with a salmonella strain which only grows in Histidine.
This mixture is then plated and grown in an agar media which lacks histidine.

There should be very little colonies however following addition of the chemical, if the bacteria does grow this suggests that there may have been mutations

19
Q

What are physical carcinogens ?

A

These impart energy into the biological material altering the bonding.

E.g. UV radiation
Ionizing radiation

DNA breaks which forms pyrimidine dimers however failed repair following this can cause translocation mutations

20
Q

What are heritable carcinogens and what effects do they have ?

A

DNA damage is a risk factor for cancer development

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 hereditary malignancy syndromes , the elevated cancer risk is due to a mutation of a single gene = monogenic hereditary diseases

The affected genes usually have a controlling function on the cell cycle or the repair of DNA damage.

A deficiency in DNA repair would cause more DNA damage to accumulate and increase the risk of cancer

21
Q

What are some DNA repair defects due to ?

A 
Ataxia telangiectasia 
Bloom's syndrome
Fanconi's anaemia
Li-Fraumeni syndrome 
Lynch type 2
xeroderma pigmentosum
22
Q

What are some chromosomal abnormalities ?

A

Down’s syndrome

Klinefelter syndrome

23
Q

What is Ataxia telangiectasia and how can it lead to Cancer ?

A

This is a neuromotor dysfunction causing dilating of blood vessels
Telangiectasia = spider veins

Mutation in ATM gene which codes for serine /threonine kinase (Phosphorylation of CHECK 1 , CHECK 2 and activation ofp53 and DNA repair ) that is recruited and activated by dsDNA breaks leading to cell cycle arrest , DNA repair and apoptosis .

Cancer predisposition : Leukaemia and breast cancer

24
Q

Outline Blooms Syndrome and how it may lead to cancer

A

Short stature , rarely exceeds 5 feet tall, skin rash that develops follwing sun exposure.

Mutation in the BLM gene that provides instructions for coding a member of the RecQ helicase family that helps maintain the structure and integrity of DNA

Cancer predisposition: Skin cancer , basal cell carcinoma and squamous cell carcinoma

25
Q

Outline Lynch Type and how it can lead to cancer

A

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

26
Q

Identify how infectious agents can be carcinogens

A

Viruses capable of causing a wide range of human disease from small pox to the common cold.

Most harm is caused when viruses multiply inside the infected cell , which kills the cell and releases progeny ( descendant ) to further infect other cells

During latent phase of infection , restricticted pattern of gene expression and these can include oncogenes.

27
Q

What properties does a virus need to have to be a tumourigenic virus ?

A

Must have stable association with cells:
-Chromosomal integration
Episome

Must not kill cells :
Non-permissive host (virus cannot replicate )
Suppresion of viral lytic cycle
Viral release by budding

Must evade immune surveillance of infected cells:
During latent phase very few genes are expressed
Immune suppression
Viral antigens not expressed at cell surface

28
Q

Describe viral carcinogenesis

A

Viral gene products act as transcription factors

Virus carries mutated cellular gene ( oncogene )

Viral integration into the cellular genome distrupts cellular genes

Viral gene products inactivate cell cycle regulatory proteins

Viral infection results in immunodeficiency

29
Q

What viruses are associated with human cancer?

A 
DNA viruses:
Epstein -Barr Virus 
Papilloma viruses
Hepatitis B and C 
Burkitts's lymphoma
Nasopharyngeal carcinoma 
Cervical carcinoma 
Warts 
Hepatoma

RNA retroviruses :
HTLV-I
Adult T- cell leukaemia
Lymphoma

30
Q

Outline Model 3 - Non genotoxic

A

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

Important modulators of cancer risk (diet, obesity , hormones and insulin resistance ) do not seem to act through DNA structural changes but through functional changes (epigenetics )

Carcinogens that induce cancer via non-genotoxic mechansism:
tumour promoters
endocrine modifiers
receptor modifi

31
Q

Outline Model 3 - Non genotoxic

A

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

Important modulators of cancer risk (diet, obesity , hormones and insulin resistance ) do not seem to act through DNA structural changes but through functional changes (epigenetics )

Carcinogens that induce cancer via non-genotoxic mechanism:
tumour promoters
endocrine modifiers
receptor mediators
Immunosuppressants
Inducers of tissue specific toxicity and inflammatory responses

32
Q

Outline Model 4 - Darwinian

A

(NATURAL SELECTION)
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/invade

Selection will include resistance to therapy

Some mutations may be deleterious for tumour

33
Q

What are tissues

A

Groups of cells with similar function are known as tissues: epithelial connective and nervous

34
Q

What is the somatic mutation theory (SMT)?

A

Single catastrophic event triggering carcinogenesis

Cancer is derived from a single somatic cell that has successively accumulated multiple DNA mutations

These mutations damage genes which control cell proliferation and cell cycle

According to SMT , neoplastic lesions are the results of DNA -level events

35
Q

What is the tissue organisation field theory ?

A

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

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

36
Q

How does the immune system respond to cancer ?

A

The immune system will :

  1. Protect from virus induced tumours
  2. Eliminate pathogens
  3. Identify and eliminate tumour cells

Immune surveillance

Despite this tumours can still arise -Cancer immunoediting

37
Q

Outline the three E’s and Cancer immunoediting

A

Elimination:
The immune system is able to eradictae 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

Escape
The expanding tumour populations becomes clinically detectable

Molecular Basis of Disease(Sem 4) (28 decks)

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