Carciogenesis Flashcards

(93 cards)

1
Q

What is cancer?

A

A group of diseases all sharing similar characteristics

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2
Q

What are the characteristics that all cancers share?

A

They are all abnormal, uncontrolled growths of cells. They all show inappropriate proliferation, invasion, and metastasis

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3
Q

What are the characteristics of a benign tumour?

A
  • Slow growth
  • Non-invasive
  • No metastasis
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4
Q

What are the characteristics of a malignant tumour?

A
  • Rapid growth
  • Invasive
  • Potential for metastasis
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5
Q

What is the increase in incidence of cancer due to?

A
  • Lifestyle changes
  • Increased screening
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6
Q

What is carciogenesis?

A

The process of transformation of a ‘normal’ cell to a cancer cell

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7
Q

What are the stages in carciogenesis?

A
  1. Initiation
  2. Promotion
  3. Progression
  4. Transformation
  5. Evolution
  6. Metastasis
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8
Q

What happens in initiation?

A

A mutation in stem cells is acquried when they are exposed to a carcinogen, and you get unrepaired DNA damage

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9
Q

What happens in promotion?

A

There is induction of cell division, where the cancer starts from a single cell that has a selective advantage over other cells within the same tissue

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10
Q

How does promotion lead to progression?

A

Increased proliferation means increased mutations and therefore an increased advantage

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11
Q

What happens in progression?

A
  • Conversion
  • Propagation
  • Dedifferentiation
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12
Q

What is there a potential for in transformation?

A

Regression

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13
Q

What can be produced in cancer evolution?

A

A drug resistant clinical tumour

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14
Q

What happens in cancer metastasis?

A

Spread of transformed cells

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15
Q

What stages of carciogenesis can be used to treat cancer?

A

Can enter at any stage to try and prevent disease

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16
Q

What does mutation lead to in colorectal carciogenesis?

A

Inactivation of the APC gene

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17
Q

What will an inactivation of the APC gene in colorectal carcinogenesis cause?

A

May cause a change in frequency in division, which leads to an increase in stem cells. This will develop over time into a cluster of APC-less cells with stem cell properties

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18
Q

What might the ‘second hit’ be in colorectal carcinogenesis?

A

Inactivation of Ras

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19
Q

What is the result of the inactivation of Ras in colorectal carcinogenesis?

A

Increased selective advantage

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20
Q

What might the third hit be in colorectal carcinogenesis?

A

Inactivation of p53

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21
Q

What happens after the third hit in colorectal carcinogenesis?

A

Increased growth, starts to form an adenoma

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22
Q

What does the forth hit in colorectal carcinogenesis lead to?

A

The rapid development of cancer

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23
Q

What extracellular/environmental factors can cause genes to mutate?

A
  • Binding of ultimate carcinogens
  • Ionising radiation/UV
  • DNA translocation
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24
Q

What do ultimate carcinogens do?

A

Bind to DNA and alter the sequence

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25
What effect does ionising radiation and UV have on DNA?
Causes strand breaks and cross links
26
When may DNA translocation cause mutations?
When it is translocation to transcriptionally active regions
27
What intracellular factors can cause mutations?
* Misinterpretation of code * Polymerase slippage/base misalignment * Ineffective repair
28
What can all mutations potentially affect?
Cellular signalling
29
What can act as initiating stimuli in carcinogenesis?
* Chemical carcinogens * Oncogenic viruses * Radiation * UV light * Oxygen free radicals * Replication errors
30
When can oxygen free radicals act as an initiating stimuli for carcinogenesis?
When there is an imbalance between their production (which happens naturally) and their removal
31
What are the categories of directly acting carcinogens?
* Alkylating and acylating agents * Weak carcinogens
32
Give three examples of alkylating or acylating agents that can act as carcinogens
* Dimethylsulphate * Chlorambucil * Dichloromethane
33
What can act as a weak carcinogen?
Cytotoxic drugs
34
Give an example of a class of procarcinogens
Polycyclic aromatic hydrocarbons
35
When might polycyclic aromatic hydrocarbons be produced?
During the combusion of organic compounds, *e.g coal, petrol, cooked foods, tobacco, smoke*
36
What does exposure to polycyclic aromatic hydrocarbons typically cause tumours?
Lung and colon
37
Where is aflatoxin found?
In fungus found on peanuts and other foodstuffs
38
What are the steps in the metabolic toxification of aflatoxin?
Aflatoxin B1 + Mfo --\> Aflatoxin-2,3-epoxide Alfatoxin-2,3-epoxide is highly reactive, so will react with DNA to form a DNA adduct
39
What does exposure to aflatoxin correlate to?
The risk of liver cancer
40
Where is liver cancer related to aflatoxin prevalent?
In hot regions
41
How can you determine aflatoxin exposure?
* Can measure content in food * Can measure DNA adduct
42
What happens to genes in cancer?
* Oncogenes are activated * Tumour supressor genes are inactivated
43
What mutations can occur to a gene?
* Alteration of bases * Strand break * Base oxidation * Deletion of bases * Adducts of carcinogens and base * Chromosomal translocation/rearrangement * Gene amplification
44
Describe the severity of different DNA strand breaks?
If it's a single strand break, the body can normally repair it. Double strand breaks normally can't be repaired
45
How does an adduct mutation cause cancer?
A chemical binds to the base, and so repair mechanisms either can't get part that point on the DNA, or don't know what base to replicate
46
What mechanisms are in place to prevent mutations causing cancer?
* Repair mechanisms * Mismatch and excision repair * p53
47
What causes single point mutations?
Mutagens
48
What are the type of single point mutations?
* Transitions * Transversions
49
What is a transition mutations?
* Purine -\> purine (A -\> G, G -\> A) * Pyrimidines -\> pyrimidines (C -\> T, T -\> C)
50
What is a transversion mutation?
* Purine -\> Pyramidine * Pyramidine -\> Purine
51
What causes structural chromosomal abberations?
Clastogens
52
What structural chromosomal aberrations can occur?
* Translocations * Inversions * Deletions * Insertions * Chromatid interchanges
53
What causes genome mutations?
Aneugens
54
What is aneuploidy?
An increase in the number of chromosomes in the cell
55
What is the most common nucleophilic binding site on DNA?
N7
56
Is N7 on guanine highly mutagenic or not?
No, it is easily repaired
57
What is the guanine N7 commonly used for?
Monitoring
58
What guanine nucleophilic binding sites are highly mutagenic?
N2 and N3
59
How does mutagenesis by adduct formation occur?
1. An adduct binds to the base 2. After the first replication, the adduct is maintained in the sequence for one copy 3. After replication of the copy with the adduct, you get a different amino acid, resulting in a different protein and therefore different structure
60
What proportion of base changes result in pernament mutation?
Fewer than 1:1000
61
What are the DNA repair pathways?
* Excision repair * Error-prone repair * Mismatch repair * Defects in DNA replication
62
What can be removed in excision repair?
* Base * Nucleotide
63
What enzymes perform base excision?
DNA glycosylases
64
What does nucleotide excision remove?
Bases with bulky adducts
65
Is excision repair error prone or error free?
Error free
66
What is error-prone repair a response to?
Severe DNA damage
67
What happens in error-prone repair?
Low fidelity DNA polymerases recognise specific lesions, and restore the original sequence ## Footnote *Accepts error, but fixes gross changes*
68
What is mismatch repair?
Proofreading by exonuclease part of DNA polymerase
69
How does repair occur in mismatch repair?
* Correcting mismatched bases in new strand during DNA replication * Genetic recombination
70
How are defects in DNA replication used in repair?
* Genome rearrangements * Chromosome loss
71
What things can act as promoting agents?
* Chemical promoters * Hormones * Inflammation * Microbial infection
72
Give 4 classes of chemical promoters
* Phorbol esters * Phenols * Xenoestrogens * Saccharin
73
Give three examples of where inflammation and infection can act as promoters
* Chronic irritation * Endoparasites * Bacterial infection
74
Give an example of an endoparasite that can act as a promoter
Schistosoma haematobium
75
Give an example of a bacterial infection that can act as a promoter
Helicobacter pylori
76
What factors increase the risk of breast cancer?
* Older age at menopause * Post-menopausal hysterectomy * Oral contraceptives * Alcohol * Obesity * Younger age at menarche
77
What factors decrease the risk of breast cancer?
* More children * Breastfeeding * Pre-menopausal hysterectomy
78
What factors increase the risk of getting cancer?
* Hereditary * Carcinogens * Radiation * Chemicals * Viruses * Diet
79
How can food act as carcinogens?
* Can contain carcinogens/mutagens * Can contain toxins * Calories can alter the hormone balance * Inflammation/oxidative stress inducers * Hot drinks/food can cause inflammation in mouth and oesophagus
80
What foods increase the risk of cancers?
* Alcohol * Red meat intake * Animal fat * Salted fish * BBQ and chargrilled foods * Salt-preserved foods * Contaminated foods
81
What evidence is there for the link between certain foods and cancer?
* Migration studies * Intervention trials
82
What are the components of the diet?
* Macronutrients * Micronutrients * Other compounds; *procarcinogens, promoters, alcohol*
83
What are the categories of macronutrients?
* Fats * Carbohydrates * FIbres
84
What are the categories of micronutrients?
* Antioxidants * Carotenoids * Polyphenols
85
What does red meat consumption increase the risk of?
Colon cancer
86
What effect does cooking red meat have on its carcinogenic risk?
It increases the heterocyclic amine concentration by 50-100x. HA's are mutagenic.
87
What happens to heterocyclic amines in the liver?
They are metabolised to genotoxic metabolites
88
What has shown heterocyclic amines to be mutagenic?
Ames test
89
What has shown heterocyclic amines to be carcinogenic?
In vivo models
90
What can increase the HA levels in food?
Increasing the cooking time
91
What can reduce the HA levels in food?
Marinating
92
What are the sources of acrylamide?
* Used as drinking water clarifier * Found in cigarette smoke
93
What is the problem with acrylamide?
It is a genotoxic metabolite, which adducts with DNA in vivo ## Footnote *However, the human evidence for cancer is scarce*