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CellularPathologyCOPY-aimen n-use this > Mechanism of Oncogenesis > Flashcards

Mechanism of Oncogenesis Flashcards

1
Q

What are the lifestyle factors contributing to cancer onset?

A
  • obesity + weight
  • diet
  • smoking + alcohol
  • exercise
  • genetics
  • hormones
  • sun + UV
  • Workplace causes
  • infections + HPV
  • air pollution and radiation
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2
Q

Describe the age range in prevalence of cancer

A

50-74yo = 1/2 of cancer cases
75+yo = 1/3 of cancer cases
Male>female.

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3
Q

How can cancer be prevented?

A

Most cancer cases are linked to lifestyle

= can be prevented through lifestyle changes

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4
Q

Why are there more 50-74 y/o in the population with cancer than any other age range?

A

More people aged 50-74 than aged 75+

in population overall = higher cancer cases, but higher incidence rates in 75+.

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5
Q

What is cancer?

A

Cancer = group of diseases caused by the uncontrolled growth of cells.

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6
Q

Where are the common categories of cancer?

A
  • Epithelial cell cancer = carcinoma
  • Mesoderm cell(bone and muscle) cancer = sarcoma
  • Glandular tissue cancer = adenocarcinoma
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7
Q

What are the features that characterise cancer?

A

Cancer is a group of diseases characterised by:

  • Abnormal cell proliferation
  • Tumour formation
  • Invasion of neighbouring normal tissue
  • Metastasis to form new tumours at distant sites
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8
Q

What are the hallmarks of cancer defined by Hanahan and Weinberg?

A
  1. Sustained proliferative signalling
  2. Evading growth suppressors
  3. Evade immune destruction
  4. Enabling replicative immortality
  5. Tumour-promoting inflammation
  6. Activating invasion + metastasis
  7. Inducing angiogenesis
  8. Genome instability + mutation
  9. Resisting cell death
  10. Deregulating cellular energetics
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9
Q

What is the consequence of carcinogens?

A

Carcinogens cause DNA mutation

DNA from tumours has many alterations - point mutations, deletions

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10
Q

How does carcinogenesis occur?

A

Mutations accumulate overtime - multi-step process that underlies carcinogenesis

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11
Q

What enables carcinogenesis occur?

A

Failed DNA repair mechanisms = mutations accumulate

Mutations accumulate after evading the cell’s DNA repair mechanisms

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12
Q

When is apoptosis induced during cancer?

A

Severe cell damage = induces apoptosis

e.g. irreparable DNA damage

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13
Q

What mechanisms are available in the body to fight cancer?

A

Many mechanisms exist for blocking carcinogenesis but over-burdening the system = cells escape immune surveillance

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14
Q

Why does age play a major factor in cancer development?

A

↑ age = ↑ mutations accumulate = cancer

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15
Q

How do Germ Line mutations lead to cancer?

A

Germ line mutations = alter egg/sperm DNA (point mutations/deletions)

inheritable

(But most cell mutations affect somatic cells)

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16
Q

Explain how somatic mutations cause cancer?

A

Somatic mutations = non-inheritable mutation

All cells in a primary tumour arise from a single cell. Initiating cancer development is clonal.

Depends on interaction with other tumour cells and the tumour microenvironment

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17
Q

Why are somatic mutations such a common cause of cancer?

A

Only one of the 10^14 cells in body need to be transformed to create a tumour.

Mutations accumulate

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18
Q

Why is cancer hard to cure?

A

Tumour cells can ‘evolve’= subclonal selection allowing a growth advantage and heterogeneity of cells in a tumour

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19
Q

When are normal cells converted to cancerous tumour cells?

A

Loss of balance between proliferation/apoptosis = normal healthy cells -> tumour cells

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20
Q

What causes cells to proliferate?

A

Growth factors = cell proliferation signals

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21
Q

When does apoptosis occur?

A

Severe cell damage(e.g. irreparable DNA damage) activates apoptosis

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22
Q

Which processes regulate cell number?

A

Growth, Apoptosis and Differentiation

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23
Q

What is the cell growth and apoptosis pathway regulated by?

A

Cell growth + apoptosis pathway is regulated by:

  • Oncogenes
  • Tumour suppressor genes

Acquiring a mutation in one of these genes will cause a loss in regulation

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24
Q

What is the consequence in mutations of cell number regulation pathways?

A

Mutation usually causes an increase in cell no. to the point where you have a clinically detectable tumour

mutations = loss of ability to regulate cell number = ↑ cell number (proliferation) = tumour

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25
Q

What are proto-oncogenes?

A

Normal genes that can be activated to be oncogenic

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26
Q

What is an oncogene?

A

An oncogene is a proto-oncogene that has been mutated to cause uncontrolled growth- i.e., cancer.

(This is like pushing down on the gas pedal)

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27
Q

What is the role of tumour suppressor genes?

A

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.

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28
Q

What is the effect of mutations in tumour suppressor genes?

A

If tumour-suppressor genes are mutated, the normal brake mechanism will be disabled, resulting in uncontrolled growth, i.e. cancer

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29
Q

What are the 3 assumptions of multistage carcinogenesis?

A
  • Malignant transformation of 1 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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30
Q

What are the 5 molecular mechanisms of cancer?

5 Models of Carcinogenesis:

A

5 Models of Carcinogenesis:

  1. Mutational - Chemical carcinogens(DNA mutations = damage DNA = genotoxic)
  2. Genome Instability
  3. Non-genotoxic - Clonal expansion/Epigenetics
  4. Darwinian - Clonal expansion/Cell selection
  5. Tissue organisation - Microenvironment
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31
Q

What does the process of cancer involve?

A

Cancer is a multi-step process that includes initiation, promotion and progression.

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32
Q

What is the effect of chemical carcinogens on the multistage process of cancer?

A

Chemical carcinogens can alter initiation/promotion/progression to induce their carcinogenic effects

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33
Q

What evidence supports the idea that cancer is due to DNA damage (Model 1) ?

A

Many cancer cells carry multiple mutations in critical genes = supports that cancer arises through the accumulation of irreversible DNA damage.

Model 1 of Carcinogenesis

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34
Q

What is the major consequence of chemical carcinogens (Model 1)?

A

Chemical carcinogens induce DNA damage and act in a genotoxic manner.
> specific chemicals can induce cancer

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35
Q

What are the different classes of carcinogens?

A
  • chemicals
  • physical
  • heritable
  • viral
  • environmental
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36
Q

What are the different types of chemical carcinogens?

A

10 groups:

  • Polycyclic hydrocarbons
  • Aromatic amines
  • Nitrosamines
  • Alkylating agents
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37
Q

Give examples of physical carcinogens

A

Asbestos
Ionising Radiation
UV Radiation

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38
Q

What is the effect of heritable carcinogens?

A

Patients have a predisposition to cancer

39
Q

Name some viral carcinogens

A

Hepatitis B Virus

Epstein Barr Virus

40
Q

How do chemical carcinogens lead to cancer?

A

Chemical carcinogens add functional groups to DNA bases(DNA adducts)

41
Q

Give an example of a DNA adduct caused added due to chemical carcinogens

A

Coal tar, which contains benzopyrene(polycyclic hydrocarbon) - cigarette smoke

42
Q

Outline how Benzo[a]pyrene can become carcinogenic

A

Benzopyrene(alone) = procarcinogen.

Becomes a carcinogen when taken in + in contact with microsomal enzymes (Benzopyrene epoxide) : G -> T

43
Q

What is the purpose of the Ames test?

A

Ames test determines whether a chemical is mutagenic by observing whether they cause mutations in sample bacteria.

44
Q

Outline how an Ames test is carried out

A

Ames test uses salmonella (strain of bacteria that requires histidine) mixed with liver extract and plated on a plate with minimal histidine - this produces no growth as in absence of histidine

Introducing a carcinogen will produce colonies if the compound is mutagenic

45
Q

How do physical carcinogens lead to cancer?

A

Physical carcinogens impart energy into the biological material, altering chemical bonding (not changing DNA=chemical carcinogens)

46
Q

What is the most common physical cancerous agent?

A

Several types of radiation = carcinogens

47
Q

How does UV radiation lead to skin cancer?

A
  1. Skin exposed to ionising / UV radiation
  2. DNA damage = DNA breaks + pyrimidine dimers form
  3. Failed DNA repair
  4. Translocation mutations occur
48
Q

What are heritable carcinogens?

A

syndromes predisposing to cancer

49
Q

What is the major heritable carcinogen?

A

DNA damage is a risk factor for cancer development

Accounts for 5% of all cancers

50
Q

Describe the effect of germline mutations in cancer

A

Inherited germline mutation causes increased risk of developing certain tumours but are rarely involved in causing cancer immediately

51
Q

Are heritable cancers due to a single or multiple gene mutations?

A

In most known hereditary malignant syndromes, elevated cancer risk is due to a mutation of a single gene (monogenic hereditary diseases)

52
Q

What is a common factor among cancerous genes?

A

Cancerous genes usually control cell cycle/DNA repair

53
Q

How does failed DNA repair increase cancer risk?

A

DNA repair defect = ↑ DNA mutations accumulate = ↑ cancer risk

54
Q

Which DNA repair defects cause syndromes predisposing to cancer?

A

DNA Repair Defects cause syndromes that predispose to cancer:

  • Ataxia telangiectasia
  • Bloom’s syndrome
  • Fanconi’s anaemia
  • Li-Fraumeni syndrome
  • Lynch type II
  • Xeroderma pigmentosum
55
Q

What chromosomal abnormalities lead to syndromes predisposing to cancer?

A

Chromosomal Abnormalities which predispose to cancer:

  • Down’s syndrome (trisomy 21)
  • Kleinefelter’s Syndrome (XXY)
56
Q

What is ataxia telangiectasia?

A

A neuromotor dysfunction, dilation of blood vessels

telangiectasia = spider veins

57
Q

How does a DNA defect cause ataxia telangiectasia?

A
  • Mutation in ATM gene
  • ATM encodes a serine/threonine kinase which is activated by dsDNA breaks, causing cell cycle arrest/DNA repair/apoptosis
58
Q

Which cancers are predisposed by ataxia telangiectasia?

A

Cancers predisposed by ataxia telangiectasia: lymphoma, leukaemia and breast cancer

59
Q

What is Bloom’s syndrome?

A
  • short stature(rarely exceed 5 feet)

- skin rash - develops after sun exposure

60
Q

Describe the DNA defect that causes Bloom’s syndrome

A
  • Mutation in BLM gene

- BLM gene encodes a RecQ helicase = help maintain DNA structure + integrity

61
Q

What are the cancers predisposed by blooms syndrome?

A

skin cancer: basal cell carcinoma, squamous cell carcinoma

62
Q

What is Lynch type?

A

Mutations in DNA mismatch repair (MMR) genes, notably MLH1, MSH2, MSH6 and PMS2.

63
Q

Describe the signs of Lynch type?

A

LS doesn’t cause any symptoms.

Symptoms of bowel and womb cancer.

64
Q

What cancer can Lynch type lead to?

A

Cancer predisposition: colorectal cancer

65
Q

What diseases are viruses responsible for?

A

Viruses capable of causing a wide range of human disease from common cold-smallpox

66
Q

When are viruses most dangerous?

A

Viruses multiply inside the infected cell, kill the cell and release progeny to infect other cells

67
Q

When do cells become very proliferative?

A

Most viruses are very proliferative when they infect a cell, exhibiting a lytic cycle: express all the genes found in their genome

Viruses produce lots of viral capsids that can be released for further infection

68
Q

How do viruses become cancerous?

A

In rare circumstances, viruses switch from lytic to latent cycle, which is a restrictive pattern of gene expression and some viruses can become tumorigenic; allow transformation of cells

69
Q

What are the 3 required properties of tumorigenic viruses?

A

Tumorigenic viruses:

  1. Stable association with cells
  2. Must not kill cells
  3. Must evade immune surveillance of infected cells
70
Q

How do tumorigenic viruses form stable associations with cells?

A

Viruses form stable associations with cells by integrating into chromosomes

71
Q

How do tumorigenic viruses avoid killing cells?

A

Tumorigenic virus:

  • Virus does not replicate
  • Virus suppresses its lytic cycle
  • Virus is released by budding
72
Q

How do tumorigenic viruses evade immune surveillance of infected cells?

A
  • immune suppression

- downregulate MHC I expression = viral antigens not expressed at cell surface

73
Q

What are the DNA viruses associated with human cancer?

A 
Epstein-Barr virus		
Burkitt’s lymphoma 
nasopharyngeal carcinoma
HPVs	
cervical carcinoma
warts
hepatitis B and C
Hepatoma
74
Q

What are the RNA retroviruses associated with human cancers?

A

HTLV-I: Adult T-cell leukaemia, lymphoma

75
Q

What is the theory behind Genome Instability causing cancer?

A

Genome Instability = Knudson’s 2-Hit Hypothesis for Hereditary Cancers based on discovery of Rb = TSG that causes retinoblastoma when both gene copies are mutated

76
Q

How did knudson identify genome instability as a model of cancer?

A

Knudson performed statistical analysis on cases of retinoblastoma (2 types - inherited type, sporadic type)

77
Q

What were the results of knudsons’ analysis?

A

Knudson = Multiple hits are required to cause cancer.

  • If first mutated allele is inherited, the second mutation will lead to cancer.
  • In sporadic Rb tumour, both mutations must occur = difference of age at diagnosis (cell must survive for long enough)
78
Q

What is the non-genotoxic model of cancer?

A

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

79
Q

How do non-genotoxic effectors lead to cancer?

A

Several important modulators of cancer risk (diet, obesity, hormones, insulin resistance) do not change DNA structure, but functional changes (e.g. epigenetics)

80
Q

What are the effects of non-genotoxic carcinogens?

A

carcinogens that induce cancer via non-genotoxic mechanisms 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)
81
Q

How do non-genotoxic carcinogens cause cancer?

A

For cancer to occur, multiple pathways must be altered

82
Q

Describe the Darwinian model of cancer

A

Carcinogenesis by Mutation and Selection-Model of Clonal Expansion

The role of 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 and invade
83
Q

What are tissues?

A

Tissues = Groups of cells with similar function

  • Epithelial
  • Connective
  • Muscle
  • Nervous
84
Q

What are the 2 theories describing the forces driving carcinogenesis tissue organisation (Model 5)?

A

2 different approaches to understanding the forces driving carcinogenesis:

  1. Somatic mutation theory (SMT) -> Single catastrophic event triggering carcinogenesis
  2. Tissue organization field theory (TOFT) ->Carcinogenesis as general deterioration of the tissue microenvironment due to extracellular causes
85
Q

Outline the tissue organisation field theory

A
  1. Carcinogenesis is primarily a problem of tissue organisation
  2. Carcinogenic agents destroy the normal tissue architecture = disrupt cell-to-cell signalling, compromise genomic integrity
  3. The DNA mutations are random and the effect, not the cause, of the tissue-level event
86
Q

Outline the somatic mutation theory of cancer

A
  1. Cancer is derived from a single somatic cell that has successively accumulated multiple DNA mutations
  2. Those mutations damage the genes which control cell proliferation and cell cycle
  3. SMT = neoplastic lesions are the results of DNA-level events
87
Q

How does the immune system respond to cancer?

A
  • Protect from virus-induced tumours
  • Eliminate pathogens
  • Identify and eliminate tumour cells
    ↓
  • Immune surveillance
    ↓
  • Despite this tumours can still arise-
  • Concept of cancer immunoediting
88
Q

What are the 3 ‘E’s’ of cacer immunoediting?

A

Elimination
Equilibrium
Escape

89
Q

Describe how the immune system tries to eliminate cancer

A

The immune system is able to eliminate developing tumours

90
Q

What is equilibrium in cancer immunoediting?

A

When incomplete removal of tumour, tumour cells remain dormant(enter equilibrium).

91
Q

Describe what occurs during equilibrium phase of cancer immunoediting

A

The immune system exerts a potent pressure that contains the tumour
During this phase, some of the tumour may mutate and survive

92
Q

How long does the equilibrium phase of cancer immunoediting last?

A

(Longest of the phases, around 20 years)

93
Q

How can cancer risk be reduced?

A

Change lifestyle factors

CellularPathologyCOPY-aimen n-use this (13 decks)

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