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molecular basis of disease > mechanism of oncogenesis > Flashcards

mechanism of oncogenesis Flashcards

1
Q

What is the historical background of cancer?

A
  1. ancient Egypt(2500 - 1600BC)
    -only one case related to cancer and ancient Greek were the first to discover it.
  2. Hippocrates 460 BC - 370BC)
    - carcinos - greek word for crab or crayfish describes appearance.
    veins stretched to all sides as crab feet.
  3. Celsus (25BC - 50AD)
    - translated carinos into latin cancer, also meaning crab.
  4. Galen (2nd centuary AD) called benign tumours oncos, Greek for swelling reserving Hippocrates Carinos for malignant tumours.
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2
Q

What were early treatments for tumours?

A

Ancient Egypt:
-procedure to remove breast cancer was cauterization (burning a part of body to remove or close off a part).

Ancient Greece: 
according to 
1. Hippocrates, cancer was the result of an excess black bile. 
2. Galen also pointed out most common types of cancers found in women were in the uterus and breast. 
3. Treatment was based on the "Humour theory" of 4 bodily fluids:
-black bile 
- yellow bile
-blood
-phlegm 
=> treatment consisted --diet 
-blood letting 
- laxatives

=> surgery was undertaken to remove tumours followed by the cauterization of the surrounding vessels to stop excessive hemorrhage.

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3
Q

What are statistics of cancer?

A
  1. incidence:
    -every 2 mins someone in UK is diagnosed with cancer
    -359,960 new cases of cancer in 2015, 990 cases every day.
  2. Mortality
    - every 4 mins someone in the UK dies from cancer
  3. Risk
    1 in 2 people in UK born after 1960s will be diagnosed with some form of cancer in their lifetime.
  4. cancer survival rates have doubled
  5. 4/10 cancer cases are linked to lifestyle - we can control
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4
Q

What are some lifestyle risks?

A
  • air pollution
  • work space
  • smoking
  • overweight
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5
Q

What is cancer?

A
  • many signalling pathways affected
  • it is a group of diseases not linear.
  • abnormal cell proliferation
  • tumour formation
  • invasion of neighbouring normal tissue
  • metastasis to form new tumours at distant sites.
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6
Q

What is a carcinoma?

A
  • cancer that occurs in epithelial cell

- 85% of cancers are carcinoma

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7
Q

What is sarcomas?

A

caners derived from mesoderm cells (bone and muscles)

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8
Q

What is adenocarcinomas?

A
  • cancers found in glandular tissue
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9
Q

What are 6 hallmarks/features of cancer?

A
  1. abnormal cell proliferation
  2. evading growth suppressors
  3. enabling replicative immortality(tumour formation)
  4. activating invasion and metastasis
  5. inducing angiogenesis
  6. resisting cell death
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10
Q

What are 2 characteristics that were added to features/hallmark of cancer?

A
  1. genome instability

2. tumour inflammation

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11
Q

What are 2 emerging hallmarks?

A
  1. avoiding immune destruction

2. reprogramming energy metabolism

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12
Q

The cell has many mechanism in place to regulate normal cell growth, and repair damaged ones, how does this make cancer a disease of genome at cellular level?

A
  1. Carinogens cause alterations to DNA - mutations
  2. DNA from tumour has been shown to contain many alteration from point mutation to deletions
  3. The accumulation of mutations over time represents the multi-step process that underlies carcinogenesis
    4 we have active DNA repair system and if it is not repaired
  4. apoptosis is induced to prevent mutation leading to cancer

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

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13
Q

What determines if cancer is inherited?

A
  • where it occurs
  • germline(egg and sperm) mutations pass on to offspring
  • inherited predisposition increases risk
  • somatic cancer is non heritable
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14
Q

What makes initiation of the development of cancer clonal?

A
  • All mutations in a tumour cell initially comes from a mutation in the somatic cell , so all cells in a primary tumour comes from a single body cell.
  • mutation in only one out of 10^14 cells in the body is needed to be transformed to create a tumour.
  • Heterogeneity = sub clonal selection allowing a growth advantage and (tumour cells ‘evolve’)
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15
Q

Why is it so important to maintain cell proliferation, differentiation and apoptosis within cells?

A

=> to regulate cell number - balance between cell proliferation and apoptosis, if too much cells = tumour forms.

Normally cells:

  1. proliferate (grow and divide)
  2. differentiate
  3. perform their specialised functions
  4. apoptosis (when they are old)

=> mutation in DNA that alters the function of normal genes involved in growth and apoptosis can affect the balance, cells will continue to divide, increased cell number = clinically detectable tumour

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16
Q

What are oncogenes?

A
  • a oncogene is a proto- gene that has been mutated in a way that leads to signals that cause uncontrolled growth, ie: cancer
    (like pushing down on gas pedal)
  • normal genes that can be activated to be oncogenic are called proto-oncogenes.
    -only 1 copy needs to be mutated in order to cause proto oncogene to become an oncogene and cause cancer
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17
Q

What are tumour suppressor genes?

A
  • inhibit both growth and tumour formation
  • they act as a braking signal during phases G1 of the cell cycle, to stop or slow the cell cycle before phase S.
  • if tumour suppressor genes are mutated then normal brake mechanism will be disabled, resulting in uncontrolled growth.
  • both genes must be mutated in order to cause cancer, recessive
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18
Q

What are 5 models of carcinogenesis?

A
  1. mutational (chemical carcinogens)
    2.genome instability
  2. non-genotoxic
  3. Darwinian
  4. tissue organisation
    => for cell to be tumourgeneic you can have more than one model: non exclusive
19
Q

What are chemical carcinogen?

A
  • cancer is a multi step process that includes
    => initiation
    => promotion
    => 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.
20
Q

What are specific chemicals that can induce cancer?

A
  • coal tar
  • chimney smoke
  • benzene
  • hardwood dust
  • radium
21
Q

What are 4 classes within mutation (model 1) carcinogens?

A
  1. chemical (10 groups)
  2. physical (radiation and asbestos)
  3. heritable ( genetic predisposition)
  4. viral (hepatitis B and Epstein Barr)
22
Q

What are the 4 major chemical carcinogens and how do they work?

A

1.polycyclic aromatic hydrocarbons
2. aromatic amines
3. nitosamines
4. alkylating agents
=> exert their effects by adding functional chemical groups to DNA bases called DNA adducts

23
Q

What chemical does coal tar contain?

A
  • benzo[a]pyrene (BP), a polycyclic hydrocarbon
  • BP is a pro-carcinogen => carcinogen(benzo(a)pyrene epoxide) by microsomal enzymes so only becomes carcinogenic inside body.
24
Q

What is Ames test?

A
  • a test to determine mutagenic activity of chemicals by observing whether they cause mutations in sample bacteria.
    -rat liver extract mixed with histamine induced salmonella ( histidine is mutagenic chemical so allows mutations) increasing salmonella colony
    -control with no histidine = no growth.
    if you replace histidine with another mutagenic chemical this should have the same effect and show colony growth.
25
Q

How does physical carcinogens cause DNA damage?

A

-act by imparting energy into biological material
Energy -> changes bonding of molecules -> biological effects
-radiation is the primary physical agent
ionising radiation -> DNA breaks pyrimidine dimers -> translocations mutations (if fail to repair)

26
Q

How does heritable carcinogens - syndromes predispose to cancer?

A
  • inherited germline mutation, has an increased risk of developing certain tumours but are rarely involved in causing cancer immediately.
    -monogenic hereditary disease = mutation in a single gene which could be present in DNA repair mechanism,
    if the affected gene has a controlling or DNA repair function on cell cycle = deficiency in DNA repair would cause more DNA damage to accumulate, and increase the risk for cancer = leading to tumour.
27
Q

What are examples of DNA repair defects leading to cancer?

A
  1. ataxia telangiectasia
  2. Bloom’s syndrome
  3. Fanconi’s anemia
  4. Li-Fraumeni syndrome
  5. Lynch type II
  6. Xeroderma pigmentosum
28
Q

What are chromosomal abnormalities?

A
  1. Down syndrome

2. Klinefelter’s syndrome

29
Q

What is Ataxia telangiectasia?

A

-neuromotor dysfunction
-dilation of blood vessels
-telangiectasia = spider veins
=> mutation in ATM gene, codes for serine/threonine kinase that is recruited and activated by dsDNA breaks leading to cell cycle arrest, DNA repair and apoptosis - cell cycle arrest

Muation in the ATM gene causes cancer predisposition:
lymphoma, leukaemia, and breast cancer.

30
Q

What is bloom’s syndrome?

A

-short stature
-skin rash
=> mutation in BLM gene that provides instructions for coding a member of the RecQ helicase family that help maintain the structure and integrety of DNA.

Loss of BLM function causes cancer predisposition:
basal cell and squamous cell carinoma

31
Q

What is Lynch type?

A

-causes no symptoms
=> mutations in DNA mismatch repair, MLH1, MSH2, MSH6 and PMS2

cancer predisposition: corectal cancer

32
Q

What are properties required for viruse to be tumorgenic?

A
  • viruses are associated with cancer in latent phase
    1. stable association with cells
    2. must not kill cells
    3. must evade immune surveillance of infected cells
33
Q

What are viruses associated with human cancer?

A

DNA viruses:
Epstein Barr virus => Burkitt’s lymphoma, nasopharangeal carcinoma
papilloma viruses => cervical carcinoma, warts
hepatitis B and C => hepitoma

RNA retroviruses
HTLV-I => adult t cell leukaemia, lymphoma

34
Q

What is immunoediting are three Es in cancer immunoediting?

A

The immune system is involved in keeping tumour cells in check.

  1. Elimination= eradicate developing tumours
    - immune system is able to eradicate (not all removed so move into the equilibrium)
  2. Equilibrium = incomplete removal, tumour cells remain dormant and enter equilibrium, where some tumours mutate to give rise to genetic variations.
  3. Escape = expanding tumour population becomes clinically detectable.
35
Q

What are forces driving carcinogenesis?

A
  1. somatic mutation theory
    - lesions are result of DNA level events
  2. tissue organisation field theory
    - DNA mutation are random and the effect, not the cause, of tissue level events.
36
Q

Why is cancer more prevalent with age?

A

=> the longer we live the more time there is for DNA to accumulate mutations that may lead to cancer. Cancer is more prevalent with life span.

37
Q

What are signals that induce proliferation in cells?

A

growth factors: EGF, PDGF
cytokines; growth hormones, interleukins
Hormones: oestrogen

38
Q

What is model 2 (genome instability)?

A
  • Developed by Knudson for retinoblastoma
  • ‘two -hit’ hypothesis = most tumour supressor genes require both alleles to be inactivated through mutation to cause phenotypic changes
  • led to the discovery of RB1 gene , which is the tumour supressor gene that causes retinoblastoma when mutated.
  • sporadic = random mutation not inherited.
39
Q

What is the model 3 (non genotoxic)?

A
  • diet, obesity, hormones and insulin resistance(epigenetic events) as modulators of cancer rather that structural change in DNA.
40
Q

What is model 4 (Darwanian)?

A
  • role of environment in selecting cells that have some acquired advantage.
  • sequential accumulation of mutation due to exposure to carcinogens
  • tumour cells will be selected for ability to grow and invade
  • selection will include resistance to therapy
41
Q

What is model 5 (tissue organisation)?

A
  • carcinogenesis is a problem of tissue organisation

- deterioration of the tissue microenvironment due to extracellular causes.

42
Q

Compare the somatic mutation theory (SMT) to organisation of field theory (TOFT)

A

SMT:

  • cancer 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 results of DNA -level events.
  • single catostrophic event triggering carcinogenesis

TOFT:

  • carcinogenesis is a problem of tissue organisation
  • carcinogenic agent destroy the normal tissue architecture thus disrupting cell to cell signalling and compromising genomic integrity
  • the DNA mutations are random and effect, not the cause, of tissue level events
43
Q

What is a process that shows the overlapping of model 1 -5?

A

immune system

molecular basis of disease (29 decks)

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