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Cellular Pathology > Mechanisms of Oncogenesis > Flashcards

Mechanisms of Oncogenesis Flashcards

1
Q

Cancer is a group of diseases characterised by 4 things, list these?

A
  1. Abnormal Cell proliferation
  2. Tumour Formation
  3. Invasion of neighbouring normal tissue
  4. Metastasis ( to form new tumours at distant sites
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2
Q 
What are :
-Carcinomas
-Sarcomas
-Adenocarcinomas
????????????????????
A 
Carcinomas = Cancers in epithelial cells 
Sarcomas = Cancers derived from mesoderm cells (bone and muscle)
Adenocarcinomas = Cancers found in glandular tissue
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3
Q

What are 6 hallmarks of cancer that Hanahan and Weinberg created?

A
  1. Resisting Cell death
  2. Inducing Angiogenesis
  3. Activating Invasion and metastasis
  4. Enabling replicative immortality
  5. Sustaining proliferative signalling
  6. Evading Growth Suppressors
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4
Q

In 2011 , the hallmarks of cancer were modified to add two enabling characteristics, what are these?

A
  1. Genome Instability

2. Tumour Inflammation

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5
Q

What are the two emerging hallmarks of cancer?

A
  1. Avoiding immune destruction

2. Reprogramming energy metabolism

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6
Q

The older we live , are we more likely or less likely to develop cancer?

A

MORE

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7
Q

Explain how carcinogens cause cancer from DNA damage at the cellular level?

A
  1. Carcinogens cause mutations (from point mutations to deletions)
  2. Cells defence mechanism of DNA repair evaded
  3. As nothing to repair the damage, there is accumulation of mutations over time (represents multi-step process of carcinogenesis)
  4. The longer we live, more time for DNA to accumulate mutations
  5. Cancer
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8
Q

In cases of severe DNA damage, what happens?

A

Apoptosis

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9
Q

We have many mechanisms to prevent carcinogenesis , so how do we still get cancer?

A

Many mechanisms exist for blocking carcinogenesis but
over burdening the system increases the possibility
that cells will escape surveillance

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10
Q

Whats the difference between somatic and germ line mutations?
Out of the two which are more common?

A 
Germline = Mutations in the egg and sperm that can pass to offspring
Somatic = Mutations in all other cells - Majority are somatic and non-inheritable but can be passed onto daughter cells in mitosis
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11
Q

Why is cancer referred to as “clonal”?

A

Because all cells in a primary tumour arise from a single cell

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12
Q

How can tumour cells evolve if they’re clonal?

A

Initially tumourgeneisis is clonal but as more mutations are acquired they become heterogeneous
Sub clonal selection allowing a growth advantage

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13
Q

What is the heterogeneity of tumour cells dependant upon?

A

Interaction with other tumour cells and the tumour microenvironment

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14
Q

Give an example of 3 things that promote cell proliferation?

A
  1. Growth Factors (EGF, PDGF)
  2. Cytokines (Interleukins, Growth Hormone)
  3. Hormones (Oestrogen)
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15
Q

What process will balance out cell proliferation to prevent tumours from forming?

A

Apoptosis!

DNA damage -> Cant be repaired->Apoptosis

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16
Q

What happens if a mutation occurs in the genes that regulate the balance between cell growth and cell death?

A

Increased Cell number —> Clinically Detectable tumour

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17
Q

Whats the difference between a proto-oncongene and an oncogene?

A

A proto-oncogene is a normal gene that regulates growth

An an oncogene is a mutated proto-oncogene that promotes signals that lead to uncontrolled growth-Cancer

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18
Q

What is a tumour suppressing gene?

A

Inhibit growth and tumour formation- act as braking signals during G1 phase to stop/slow cell cycle before S phase

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19
Q

How would a tumour suppressor gene loose its function and what would be the result of this?

A

They have to acquire two individual mutations to lose its function
The result would be uncontrolled cell growth -Cancer

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20
Q

What are the three assumptions needed for Multistage Carcinogenesis

A
  1. Malignant transformation of a singe cell is sufficient to give rise to a tumour
  2. Any cell in a tissue is as likely to be transformed to as any other of the same type
  3. Once a malignant cell is generates the mean time to tumour detection is generally constant
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21
Q

The 5 models of carcinogenesis are exclusive , what does this mean?

A

They overlap, they are not each to their own

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22
Q

Explain Model 1: Chemical Carcinogenesis ?

A

o Cancer is a multi-step process that includes initiation, promotion and progression
 Chemical carcinogens can alter any of these process to induce their carcinogenic effects
 Carcinogens work by altering the structure of DNA
o 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
o In the majority of instances chemical carcinogens can induce this DNA damage and act
in a genotoxic manner

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23
Q

What are the 4 classes of carcinogens?

A
  1. Chemical
  2. Physical
  3. Heritable
  4. Viral (Hep B, Epstein Barr)
24
Q

What are the two subgroups of physical carcinogens?

A
  1. Radiation (Ionising and Ultraviolet)

2. Asbestos

25
Q

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
Give one example of this?

A

Coal Tar
-Contains benzo[a]pyrene, a polycyclic hydrocarbon
-Benzo[a]pyrene is commonly found in cigarette smoke
- Is not carcinogenic by itself but gets converted in the body
 BP ranks high in the measure of how easy it enters into
cells

26
Q

What is the AMES test?

A

A test to determine the mutagenic activity of chemicals by observing whether they cause mutations in sample bacteria
Add chemical and then plate it to get many colonies: suggests there’s mutations in the bacteria so they are carcinogenic

27
Q

Explain the steps of an AMES test?

A
  1. Take rat liver extract and combine with salmonella strain that
    only grows in presence of histidine
  2. Plate mixture onto agar plate that lacks histidine
  3. Overnight incubation
  4. If many colonies formed, suggests there has been a change in the bacteria and they can now grow in
    the absence of histidine
     Confirms chemical is carcinogenic
28
Q

What is the difference between physical and chemical carcinogens?

A

Physical carcinogens act by imparting (passing on) energy into biological material
Energy -> Changes bonding in molecules -> Biological effects

29
Q

How far does UV radiation penetrate?

What can protect you against UV radiation?

A

UV radiation doesn’t penetrate lower than the skin

UV protection sunscreen is enough to protect you against this

30
Q

What does the pro-carcinogen benzo(a)pyrene get converted to because of microsomal enzymes?

A

It gets converted to the carcinogen benzo(a)pyrene epoxide through G—>T transversions

31
Q

In hereditary malignant syndromes the increased risk of cancer is due to what?

A

The mutation of a single gene (monogenic hereditary diseases)
These mutated genes usually have a controlling function on the cell cycle or the repair of DNA damage ( Decrease in DNA repair -> Accumulation of DNA damage->Increase risk of cancer)

32
Q

List 3 examples of DNA repair defects

A
  1. Ataxia Telangiesctasia
  2. Bloom’s syndrome
  3. Fanconi’s anaemia
  4. Li-Fraumeni syndrome
  5. Lynch Type II
  6. Xeroderma Pigmentosum
33
Q

List 2 examples of Chromosomal Abnormalities

A
  1. Down’s Syndrome

2. Klinefelters Syndrome

34
Q

Explain how chromosomal abnormalities increase your risk of cancer?

A

They pre-dispose you to different types of cancers due to already present mutations

35
Q 
The following questions are about Ataxia Telangiectasia
-What are the symptoms?
-How it is caused?
-Which checkpoint is it involved in
-
-Which cancer does it predispose you to?
A
  • Causes neuromotor dysfunction, dilation of blood vessels and telangiectasia (Spider veins in the eyes)
  • So usually if you have breaks in dsDNA , the ATM gene would activate P53 which would arrest the cell cycle, dna repair and apoptosis but in ataxia you have a mutation in the ATM gene so no cell cycle arrest blah blah
  • Involved in checkpoint 1 and 2
  • The cancer predisposition is Lymphoma , Leukaemia and breast cancer
36
Q

The following questions are about Bloom’s syndrome

  • What are the symptoms?
  • How is it caused/ mutation?
  • What is the cancer that is pre-disposes you to?
A
  • Symptoms : Short stature, rarely exceed 5 ft , skin rash that develops after exposure to sun
  • Caused by a mutation in the BLM gene-provides instructions for coding a member of the RecQ helicase family that helps maintain the structure and integrity of DNA
  • Cancer is predisposes you to in Skin cancer, Basal cell carcinoma and squamous cell carcinoma
37
Q

The following questions are about Lynch type

  • What symptoms does it cause?
  • What mutation is it caused by?
  • What cancer does it predispose you to?
A
  • Doesn’t cause any symptoms, you don’t know you have Lynch until you have cancer - first signs of womb and bowel cancer
  • Caused by mutations in DNA mismatch (MMR) genes . Notably MLH1,MSH2,MSH6 and PMS2
  • The cancer is predisposes you to is colorectal cancer
38
Q

On a very rare occasion viruses can cause cancer, when would this be the case?

A

-Usually due to the latent phase of infection -the latent phase shows a very restrictive pattern of gene expression and these can include oncongene

39
Q

What are the 3 properties required of tumourigenic viruses?

A
  1. Stable Association with cells (Chromosomal Integration and Episome-chromosome association)
  2. Must Not kill cells (Non-permissive host - virus cant replicate, suppression of viral lytic cycle , viral release by budding)
  3. Must evade immune surveillance of infected cells (Immune suppression , viral antigens not expressed at cell surface during latent phase - the few that are expressed are not detected by the immune system
40
Q

List 3 examples of DNA viruses and the cancers they are associated with

A
  1. Epstein-Barr Virus : Burkitt’s lymphoma and Nasopharyngeal carcinoma (does usually not give symptoms)
  2. Papiloma Viruses : Cervical Carcinoma and Warts
  3. Hepatitis B and C : Hepatoma
41
Q

Give an example of a RNA retrovirus?

A

HTLV-1 : Adult T-cell leukaemia lymphoma

42
Q

What does Model 2: Genome Instability address?

A

The high freq. of mutations that happen

43
Q

What is Knudsons Hypothesis (also known as the the ‘ two hit’ hypothesis for hereditary cancers?

  • What was the hypothesis developed for originally?
  • What types of retinoblastoma was studied with statistical analysis?
A

The main concept is that at least TWO events (mutations etc) are necessary for carcinogenesis
Of course the cell with the 1st mutation (which might be inherited) has to survive long enough to has the 2nd mutation = carcinogenesis.
This would explain the difference of age at diagnosis in sporadic tumours - people will have the 2nd event at different times.
The hypothesis was actually developed for retinoblastoma (Knudson discovered the RB1-TSG that causes retinblastoma when both copies are mutated
-Performed analysis on inherited and sporadic (occurs much later in life) types

44
Q

What is Model 3: Non Genotoxic state?

A

Obvs non-genotoxic effects this can include modulators of cancer risk - they act through functional changes (+epigenetic events)rather than genome changes

45
Q

List 5 examples of non-genotoxic carcinogens

How do they induce cancer

A
  1. Tumour promoters
    2.Endocrine Modifers
    3.Receptor-mediators
    4.Immunosuppressants or inducers of tissue-specific toxicity
    5.Inflammatory responses
    In high proportions of them –> Multiple pathways affected -> Cancer
46
Q

What does model 4:: Darwinian state?

A

So Dawrinian sounds like Darwin … because its about carcinogenesis by mutation and selection model of clonal expansion ie the role of the environment in selecting cells that have some acquired advantage
The initial tumour is clonal and as more mutations acquired they differentiate
The model relies on natural selection

47
Q

What is artificial selection? Give an example

A

Man-made techniques to enhance an advantageous trait ie chemotherapy - select for cells that are dividing uncontrollably only

48
Q

What is Model 5?

A
  • Tissue Organisation
    To understand the changes that occur during cancer it is important to understand cell and tissue organisation and mechanisms that control growth and structure
49
Q

What is a tissue? Give some examples pls x

A

A group of cells with a similar function

For eg: Epithelial, Connective muscle and nervous muscle

50
Q

What are the two theories of the forces driving carcinogenesis?

A

Somatic mutation theory (SMT)
and
Tissue Organisation field theory (TOFT)

51
Q

What is the somatic mutation theory (SMT)?

A

Single somatic cell-> Accumulates DNA mutations->Damage genes that control cell proliferation /cycle
Neoplastic lesions (damage to abnormal growth) are the results of DNA-level events
So to conclude a SINGLE catastrophic event triggers carcinogenesis

52
Q

What is the Tissue Organisation Field Theory (TOFT)?

A

Extra cellular changes cause deterioration of the tissue micro-environment this change is tissue structure affects how cells communicate which can result in cancer
Carcinogenic agents DESTROY the normal tissue organisation –> disrupt cell-cell signalling and compromising the 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

53
Q

What is the immune response to cancer?

Why might this not work sometimes?

A

-PROTECT from virus-induced tumours
-ELIMINATE pathogens
-IDENTIFY and eliminate tumour cells
-IMMUNE surveillance
It may not work due to the concept of cancer immunoediting

54
Q

What are the 3 E’s in cancer immunoediting? Explain each one briefly

A

1.Elimination
-Eradicate developing tumours
-Plethora (abundance) of immune cells that work to eradicate the tumour
-This is not 100% effective , 1 or 2 cells will enter the 2nd phase
2 . Equilibrium
- Tumour cells remain dormant and enter equilibrium
-Potent and relentless pressure that contains the tumour
-Some of the tumour may mutate or give rise to genetic variants that survive, grow and enter the next phase (longest phase approx 20yrs)
3.Escape
-Expanding tumour population becomes clinically detectable
-Pressure from the immune system to keep cells suppressed but as shown in model 4 cells constantly acquiring new mutations

55
Q

What are some prevention and reducing risks of cancer?

A 
o Alcohol
o Obesity and weight
o Diet and healthy eating
o Physical activity
o Smoking
o Sun and UV
o Hormones

Cellular Pathology (13 decks)

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