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EMS - MoD > 21. Carcinogenesis - molecular hallmarks of cancer cells > Flashcards

21. Carcinogenesis - molecular hallmarks of cancer cells Flashcards

1
Q

What happens due to a carcinogen when normal cells are turned into a neoplasia?

A
  • oncogene activation

- tumour supressor gene inactivation

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2
Q

How do mutations occur?

A
  • induced by carcinogens

- arise as random spontaneous replication error in a cell population

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3
Q

What is the basic process of mutations and clonal expansion?

A
  • initiating mutation
  • clonal expansion (more cells with the mutation)
  • second mutation + clonal expansion
  • third mutation + clonal expansion (more cells with multiple mutations)

etc

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4
Q

What do caretaker genes do?

A

Maintain genetic stability by repairing damaged DNA and replication errors

  • DNA repair genes
  • controlling accuracy of mitosis
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5
Q

What do mutated forms of caretaker genes cause?

A

Genomic instability

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6
Q

What is genetic instability important for?

A

Enabling specific genetic alterations to accumulate in carcinogenesis

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7
Q

Cells require a greatly enhanced level of mutational frequency in order to become malignant. In some tumours, what is this enhanced level of mutation the result of?

A

High level of exposure to mutagenic agents, such as lung cancer and tobacco smoke or skin cancer and UV irradiation

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8
Q

In most tumours, level of exposure to mutagenic agents is not high enough for transformation. What is found in those tumours?

A

Mutational inactivation of genes that are involved in protecting the integrity of the genome (caretaker genes) - this results in higher levels of mutation than normal

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9
Q

How are caretaker genes different from TSGs?

A

Caretaker genes maintain genetic stability and suppress carcinogenesis.

TSGs act as drivers of carcinogenesis when inactivated

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10
Q

What are 2 types of TSG?

A
  • gatekeepers

- caretakers

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11
Q

What do gatekeepers do?

A

Play important roles in regulating normal growth

  • negative regulators of the cell cycle and proliferation
  • positive regulators of apoptosis
  • positive regulators of cell differentiation
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12
Q

Carcinogens induce molecular abnormalities in TSGs. What do these cause?

A

Reduced/lack of protein expression or inactivation of protein - LOSS OF FUNCTION

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13
Q

What types of mutations occur in TSGs?

A
  • point mutations
  • deletions/insertions
  • chromosomal rearrangements
  • epigenetic silencing (promoter methylation)
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14
Q

Inactivating mutations in caretaker TSGs do not contribute directly to the tumorigenic phenotype. What do they instead do?

A

They create the conditions whereby mutations have a chance to arise in gatekeeper TSGs

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15
Q

What is normally the ‘1st hit’ in TSG inactivation?

A

A point mutation in the coding sequence of the gene

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16
Q

Every cell in the body will carry the ‘1st hit’ in what circumstances?

A

In the case of familial cancer syndromes

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17
Q

Why is a ‘2nd hit’ required for complete loss of function of a TSG ?

A

Because the single remaining normal copy of the TSG is capable of doing the job of two genes (the mutant version is recessive to the normal version)

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18
Q

How common are the types of event that causes the ‘2nd hit’ in TSG inactivation?

A

Three orders of magnitude more common than point mutations (1st hit)

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19
Q

What types of event cause the ‘2nd hit’ in TSG inactivation?

A
  • chromosomal non-disjunction
  • gene conversion
  • mitotic recombination
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20
Q

What is the most common feature of tumour cells?

A

Aneuploidy caused by chromosomal non-disjunction

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21
Q

What is the main consequence of aneuploidy in tumour cells?

A

Providing the ‘2nd hit’ that completely inactivates an important tumour suppressor gene (TSG)

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22
Q

Chromosomal recombination through crossovers can happen in somatic cells during mitosis, as well as in meiosis. What can this create?

A

In the presence of a ‘1st hit’, it can create a daughter cell that is now homozygous for this mutation and has therefore lost the function of a TSG

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23
Q

Familial cancer syndromes can involve inheritance of a mutant copy of what?

A

A gatekeeper or caretaker gene

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24
Q

What is the risk of cancer for a carrier of a mutant copy of a gatekeeper/caretaker gene?

A

70-90% lifetime risk of developing cancer, depending on the syndrome

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25
Q

What TSG gene is involved in retinoblastoma cancer syndrome?

A

RB1 (gate)

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26
Q

What TSG gene is involved in Li-Fraumeni cancer syndrome?

A

p53 (gate/care)

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27
Q

What TSG gene is involved in Familial adenomatous polyposis cancer syndrome?

A

APC (gate)

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28
Q

What TSG gene is involved in Familial breast cancer syndrome?

A

BRCA1, BRCA2 (care)

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29
Q

What TSG gene is involved in Hereditary non-polyposis colorectal cancer syndrome?

A

hMLH1, hMSH2 (care)

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30
Q

What are the principal tumours in Li-Fraumeni syndrome?

A

Sarcomas

Breast

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31
Q

What are the principal tumours in FAP?

A

Colorectal

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32
Q

What are the principal tumours in HNPCC?

A

Colon

Endometrial

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33
Q

What are the stages from proto-oncogene to cancerous cell?

A
  • proto-oncogene
  • cancer-promoting agent (UV light, chemicals etc)
  • oncogene
  • cancerous cell
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34
Q

What do proto-oncogenes do?

A

Promote cell proliferation, survival, angiogenesis, and negative regulation of apoptosis

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35
Q

What do mutations in proto-oncogenes lead to?

A

Activated versions of or increased expression of proto-oncogenes (gain of function)

Oncogenes

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36
Q

What do oncogenes do?

A

Cause increased levels of cell proliferation, survival, angiogenesis and inhibition of apoptosis

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37
Q

How many copies of the oncogene needs to be activated to induce a gain in function?

A

Only 1 copy

Mutated gene is dominant to the other normal parental gene

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38
Q

What are the different types of mechanism of oncogene activation?

A
  • translocation
  • point mutation
  • amplification
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39
Q

Translocation is one of the possible mechanisms of oncogene activation. Explain this works

A

Translocation of a proto-oncogene from a low transcriptionally active site to an active site = aberrant expression of the oncogene

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40
Q

Point mutation is one of the possible mechanisms of oncogene activation. Explain how this works

A

Substitution of a single base pair can alter an amino acid in the protein causing it to become hyperactive

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41
Q

Amplification is one of the possible mechanisms of oncogene activation. Explain how this works

A

Amplification by insertion of multiply copies of an oncogene = increased expression

42
Q

What is involved in multi-step tumorigenesis?

A
  • multi-step process involving activation of oncogenes/inactivation of TSGs
  • minimum of 3 genetic alterations needed to transform a normal cell into a neoplastic cell
43
Q

In multi-step tumorigenesis, how many genetic alterations are needed to transform a normal cells into a neoplastic cell?

A

At least 3

44
Q

What are the acquired functional capabilities of cancer cells?

A
  • self-sufficiency in growth signals
  • insensitivity to antigrowth signals
  • tissue invasion and metastasis
  • limitless potential for replication
  • sustained angiogenesis
  • evading apoptosis
45
Q

Cancer cells have self-sufficiency in growth signals. How is this different to normal cells?

A

Normal cells require the stimulus of positive growth factors before they enter the cell cycle and divide. Tumour cells acquire the ability to grow in the absence of these factors

46
Q

What occurs in growth-stimulatory signal transduction?

A

Signals are processed and integrated by complex circuits within the cell, which decide where cell growth and division is appropriate or not. Signal transduction is the passage of these signals from outside the cell, through the cell membrane, across the cytoplasm and into the nucleus, where changes in gene expression can take place

47
Q

What are signals passed between cells carried by and what do they activate?

A

Small proteins called growth factors (GFs)

These bind to and activate complex proteins straddling the cell membrane called growth factor receptors (GFRs)

48
Q

What do activated GFRs do?

A

They stimulate a cascade of signalling events that culminate in the nucleus with changes in gene expression

49
Q

What happens in terms of growth factor signalling in most cancer cells?

A

There is deregulation of signal transduction

Oncogene-encoded proteins are able to trick the cell into believing that it has encountered growth factors in its surroundings and as a result, the cells will begin to proliferate

50
Q

Name one of the most common oncoproteins

A

RAS

A membrane bound signal transduction protein

51
Q

Which family is the oncoprotein RAS part of?

A

It is a member of a family of guanine nucleotide binding proteins called G-proteins

52
Q

RAS will be in what form in a normal cells that is not proliferating?

A

It will be in its inactive form, bound to a GDP molecule

53
Q

What happens to RAS when a stimulatory signal is received?

A

The RAS protein discards the GDP and acquires a GTP molecule instead. The shifts the RAS into its active signal transducing configuration

54
Q

How does RAS become inactive again after the stimulatory signal subsides?

A

It cleaves a phosphate group from the GTP, which reverts the protein into its inactive GDP-bound state

55
Q

What occurs in cancer cells that carry an activated RAS oncogene?

A

Mutations alter one of the amino acids involved in the cleaving of the phosphate group from GTP. This means that an activated RAS cannot revert back into its inactive state. This fools the cell into believing that a continual positive growth signal is being received from its surroundings.

56
Q

Cancer cells have an insensitivity to antigrowth signals. How is this different from normal cells?

A

In normal cells, once the required level of cell division has taken place, they will respond to negative growth factors and leave the cell cycle. Tumour cells are unable to respond to these factors

57
Q

What do RB protein do?

A

It is a key regulator of the cell cycle by preventing progression from G1 to S phase

58
Q

What is RB protein activated by?

A

Negative growth factors - they inhibit progression of cell cycle by activating Rb protein

59
Q

Inactivation of RB gene is a common event in tumours. What does it result in?

A

Resistance to negative growth regulation

60
Q

What does RB protein stand for?

A

Retinoblastoma protein

61
Q

What does RB do in a non-proliferating cell?

A

It binds to and suppresses the activity of transcription factors whose function is to switch on genes that are required for proliferation ie. progression through the cell cycle

62
Q

What happens to the RB protein in a proliferating cell?

A

It is phosphorylated and therefore inactivated by kinase enzymes that have been switched on via a proliferation signal transduction pathway

63
Q

Give an example of a negative growth factor

A

Transforming growth factor beta (TGFbeta)

confusing name!

64
Q

How do negative growth factors activate RB protein?

A

The stimulate the expression of proteins that inhibit the kinase enzymes

65
Q

How can cancer cells escape inhibition of proliferation by negative growth factors?

A

They can acquire mutational inactivation, or epigenetic silencing, of the RB tumour suppressor gene.

66
Q

Cancer cells have a limited potential for replication. How is this different from normal cells?

A

Normal cells have a finite life span. After a number of cell division, they senesce and die due to loss of DNA from the telomeres.

Tumour cells express telomerase that replaces the lost material and cells become immortal

67
Q

What do cancer cells express that allows them to become immortal?

A

Telomerase

68
Q

In normal cells, what shortens after each cell division?

A

Telomeres (the chromosome ends)

69
Q

How many times are normal cells able to divide before the enter a state called senescence?

A

No more than 50-60 times - after this, they can survive for an extended period of time but are unable to re-enter the proliferative cell cycle

70
Q

What can telomeres be compared to?

A

The aglets at the end of shoelaces

Telomeres act to prevent end to end fusion of chromosomal DNA molecules

71
Q

What is the DNA component of telomeres composed of?

A

Thousands of repeats of hexanucleotide sequence

72
Q

Why is a section of telomere lost from each chromosome after every cell division?

A

The tips of chromosomes cannot be replicated completely and a section of the hexanucleotide sequences are lost

73
Q

How do loss of sections of telomere eventually causes apoptosis of the cell?

A

As eventually the ends of chromosomes become exposed and are able to fuse with each other resulting in karyotypic chaos, which usually triggers apoptosis

74
Q

Telomere regeneration can be accomplished by which enzyme?

A

Telomerase

Can replace lost telomere sequences using an RNA template

75
Q

Is there telomerase expression in normal cells?

A

Normally expressed early in embryogenesis but expression is lost in cells once they differentiate

76
Q

How many human tumour cells express telomerase?

A

85-90%

77
Q

Cancer cells can evade apoptosis. How is this different to normal cells?

A

Normal cells have an inbuilt protection against abnormal stress or growth called programmed cell death/apoptosis

Tumour cells tend to lose the ability to respond in this way

78
Q

What gene is a key player in apoptosis?

A

TP53

79
Q

What does P53 do?

A

Induces cell cycle arrest to allow repair of DNA damage

But also induces apoptosis if there is too much damage

80
Q

What does TP53 inactivation lead to?

A

Loss of apoptotic response

This is the most common genetic abnormality in human tumours (>50% of tumours)

81
Q

Which syndrome does inherited mutation of TP53 cause?

A

Li-Fraumeni syndrome

82
Q

Initially it was found that DNA damage was most effective at triggering P53-induced apoptosis but we now know that a range of insults are just as effective including what?

A
  • hypoxia
  • demethylation of DNA
  • viral infection
  • depletion of ribonucleotides
  • blockage of RNA or DNA synthesis
83
Q

Why is sustained angiogenesis important in cancer cells?

A

Tumours greater than 2mm need to stimulate a new blood supply (angiogenesis) or the cells in the middle of the growth will die from lack of oxygen/nutrients

84
Q

How do cancer cells carry out angiogenesis?

A

Growth factors/angiogenic factors such as vascular endothelial growth factor are often produced by tumours and these stimulate growth of new vessels

85
Q

How is vascular endothelial growth factor (VEGF) induced?

A

Hypoxia stabilises HIF-1 transcription factor, this induces VEGF

86
Q

What do VEGF do?

A

Stimulates growth of new vessels

Actively recruits endothelial cells that process to construct new capillaries and vessels

87
Q

How significant is angiogenesis?

A

Angiogenesis is small in dysplasia but extensive in invasive tumours

Also key for metastatic spread of malignant tumour cells

88
Q

Cancer cells are often able to invade tissue and metastasise. How is this different from normal cells?

A

Normal cells are unable to detach from their neighbouring cells or grow into new compartments outside their own tissue

However, malignant tumour cells acquire the ability to invade new tissues and detach and migrate to other sites in the body

89
Q

What are epithelial cells held tightly together by?

A

Adhesion molecule E-cadherin

90
Q

Tumour cells which are able to invade new tissues show which feature?

A

Loss of E-cadherin through mutation or hypermethylation of the gene

91
Q

What does loss of E-caherin result in?

A

Epithelial-mesenchymal transition (EMT)

92
Q

Mesenchymal cells are motile and secrete proteases. What does this allow them to do?

A

Break through the basement membrane and invade the underlying stroma

93
Q

What does metastasis involve?

A

The spread of malignant cells via the blood/lymphatic system to secondary sites and the formation of secondary tumours

94
Q

PSA is used to diagnose prostate cancer. How accurate is it?

A

1/3 with raised PSA do not have prostate cancer

Not very sensitive or specific

95
Q

What is CA-125 serum antigen used for?

A

Used in the detection and monitoring of ovarian cancer - but not very sensitive or specific

96
Q

What is a better technique to diagnose and predict prognosis than serum protein markers?

A

Gene expression profiling

97
Q

Give an example of what gene expression profiling has been used in?

A

Acute myeloid leukaemia (AML)

  • different subtypes with different translocations - the different types correlate with prognosis outcome
98
Q

Overexpression of which gene is found in around 30% of breast tumours? And what does it code for?

A

HER2

Codes for a positive growth factor receptor

So over expression causes cells to become more responsive to, or independent of, positive growth factors.

99
Q

Which drug targets HER2 and what type of drug is it?

A

Herceptin

It is an antibody drug targeted to HER2

100
Q

What does herceptin do?

A

It dampens the effects of an overactive HER2 receptor

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