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Semester 2 Molecular Medicine > Molecular pathology of Tumours > Flashcards

Molecular pathology of Tumours Flashcards

1
Q

What are the properties of malignant cells?

A
  • Disordered proliferation
  • Disordered apoptosis
  • Disordered differentiation
  • Disordered relationship between proliferating cells and the surrounding environment (invasion, metastasis, angiogenesis)
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2
Q

What are the stages of the invasion of malignant cells?

A
  • Normal: normally stratified epithelium
  • Dysplasia: Some loss of stratification
  • Carcinoma in situ: Total loss of stratification; immature cells throughout the basement membrane intact
  • Invasion
  • Metastasis: secondary tumour in lymph nodes
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3
Q

Describe the process of clonality

A

1) A mutation gives a cell an advantage and so it survives and proliferates
2) A second mutation increases the advantage and the cells survive and proliferate
3) A third mutation increases the advantage further and makes the cell invasive
4) Dangerous cell survival, proliferation and invasion
Even when it gets to this stage, the cells in the tumour continue to mutate so they aren’t all genetically identical

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4
Q

What is neoplastic behaviour?

A

The ability to grow without reference to normal control mechanisms: sustained proliferation even after the stimulus has been removed

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5
Q

What are oncogenes?

A
  • Initial drivers of neoplastic behaviour

* It is a gene which has the potential to cause cancer

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6
Q

What is the name of a cell which has the potential to become an oncogene?

A

Proto-oncogene

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7
Q

What are the ways a photo-oncogene can become an oncogene?

A

1) Mutation in the coding sequence produces a hyperactive protein made in normal amounts
2) Gene amplification: the region of a chromosome can be duplicated producing a protein which is overproduced
3) Chromosome rearragement: either:
• Nearby regulatory DNA sequence caused normal protein to be overproduced
• Fusion to the transcribed gene produces hyperactive fusion protein

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8
Q

Give an example of a oncogene being produced from a mutation in the coding sequence

A

Ras: Change of amino acid 12 from Glycine to Valine, locks the gene onto the ‘on’ position
• Once mutated, it can’t lose the GTP so remains bound and in the on position
• Interference with intracellular signalling

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9
Q

Give an example of an oncogene being produced from a gene amplification

A

HER 2- growth factor in breast cancer

• Increased/activation of growth factor receptor

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10
Q

What drug is used to target HER 2?

A

Herceptin

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11
Q

Give an example of an oncogene being produced from a chromosome rearrangement

A

Philadelphia chromosome in chronic myeloid leukaemia

• From the fusion to transcribed gene

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12
Q

Give an example of the oncogenes involved with transcription factors

A

myc: direct stimulation of cell cycle dependent on transcription
- -> Burkitts lymphoma

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13
Q

Which oncogene increases the amount of growth factor?

A

sis in fibrosarcoma

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14
Q

Describe how a mutation in a tumour suppressor gene can result in caner

A
  • Normal cell mutates and inactivates a tumour suppressor gene
  • this has no effect as we have 2 tumour suppressor genes
  • A second mutation event inactivates this second copy
  • The tumour suppressor gene has been eliminated, stimulating cell survival and proliferation
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15
Q

What is retinoblastoma?

A
  • Rare childhood eye tumour which can affect one or both eyes
  • 2/3 cases only affects one eye
  • 1/3 cases affects both eyes
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16
Q

Explain how research in retinoblastoma has helped to understand tumour suppressor genes

A

• Knudson’s two hit hypothesis
If one is affected:
• Normally 2 copies of retinoblastoma gene (RB1)
• Mutation in one copy of the RB1 gene
• in a small proportion there is a mutation in the second copy of the same cell resulting in no working RB1 protein

If both are affected
• Inherited the loss of one of the RB1 genes
• Therefore only one mutation is needed in any of the retinal cells is needed in order to get the tumour

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17
Q

Why does mutating RB drive carcinogenesis?

A
  • Active Rb binds to transcription factors and prevents the DNA synthesis
  • Phosphorylation of Rb allows transcription (inactive Rb)
18
Q

What type of tumour suppressor is RB and how does it work to suppress the tumour?

A
  • Gatekeeping tumour suppressor
  • Promotes death of cells, especially those with DNA damage
  • Inhibits proliferation
  • Sends negative signals to the cell
19
Q

APC gene

A

Underlies Familial Adenomatous Polyposis Coli (colon cancer)
• Controls the transcription of genes required for proliferation which result in the formation of polyps

20
Q

What are caretaker tumour suppressor genes?

A
  • Maintains the integrity of the genome by promoting DNA repair
  • Nucleotide excision repair (recognises abnormal bases)
  • Mismatch repair (e.g. if G was paired with T)
  • DNA double strand break repairs
21
Q

Which cancer would result from faulty nucleotide excision repair damage?

A

Xeroderma Pigmentosa

22
Q

Which cancer would result from faulty DNA mismatch repair?

A

Hereditary non-polyposis colon cancer

23
Q

Which cancer would result from faulty DNA double strand break repairs?

A

Hereditary ovarian and breast cancer

24
Q

How does p53 act?

A
  • Caretaker gene and gatekeeper gene
  • Responds when a cell experiences DNA damage
  • If there is a small amount of damage, it promotes cell repair
  • If there is severe damage, it promote apoptosis
25
Q

What happens if a cell has a defective p53?

A

It won’t respond if there is a DNA change/damage
• may therefore acquire more mutations
• Could be beneficial or detrimental to the cell

26
Q

What is Li-Fraumeni syndrome?

A
  • Runs in families
  • Inherited defective p53
  • Many early onset cancers
27
Q

What is the main type of p53 mutation?

A

missense mutation 95% within the sequence-specific DNA binding, prevents binding to DNA, activating target genes

28
Q

What does p53 detect?

A
  • Lack of nucleotides
  • UV radiation
  • Ionising radiation
  • Oncogene signalling
  • Hypoxia
  • Blockage of transcription
29
Q

What are the actions of p53

A
  • Cell cycle arrest (senescence or return to proliferation)
  • DNA repair
  • Block of angiogenesis
  • Apoptosis
30
Q

Describe how a tumour can arise from inhibited apoptosis

A
  • Decreased apoptosis can result in a tumour
  • BCL-2 gene
  • Follicular lymphoma
  • BCL-2 coding region under control of an enhancer, expressed at higher amounts
  • Increased cell survival, decreased death
31
Q

What is a telomere?

A
  • TTAGG
  • Protects information
  • When the telomere is short, it is hard for the cell to replicate
32
Q

What is telomerase?

A

An enzyme in a eukaryote which repairs the telomeres of chromosomes so that they don’t become progressively shorter during successive rounds of chromosome replication

33
Q

What happens to a normal cell in terms of proliferation as time goes on?

A

It stops dividing and eventually dies because the telomere gets too short

34
Q

What happens to a cell that is expressing telomerase in terms of proliferation as time goes on?

A

It can proliferate for a much longer amount of time (‘immortal’)

35
Q

What will more aggressive tumours express more of?

A

Telomerase

36
Q

Describe the angiogenesis signalling cascade

A
  • A tumour needs a blood supply in order to survive
  • Cancer cells can detect the amount of oxygen and if low, it expresses VEGF (vascular endothelial growth factor)
  • VEGF migrates and effects adjacent endothelial cells and stimulates them to grow
  • MMPs (matrixmetalloproteinase) digest the extracellular matriculates and then migrates and divides
37
Q

Describe the characteristics of the capillaries formed during angiogenesis stimulated by VEGF

A
  • Not as stable as other vessels
  • approx. 10 times more permeable than normal capillaries (due to the abnormal structure and the increased amounts of VEGF)
38
Q

How do cancer cells invade via angiogenesis?

A
  • Cells enter the bloodstream
  • They adhere to the blood vessel wall within an organ]
  • The cells then escape from the blood vessels to form micro metastasis
  • Invades the organ forming full size metastasis
39
Q

What are the stages a cell goes through before it can migrate?

A
  • Loosening of intracellular junctions: Tumour cells detach from each other because of reduced adhesiveness
  • Attachment: Cells then attach to the basement membrane via the laminin receptors
  • Degradation: cells secrete proteolytic enzymes, including type IV collagenase and plasminogen activator
  • Migration: Degradation of the basement membrane and tumour cell migration follow
40
Q

What stages of a cancer invasion and metastasis are difficult and which are easy?

A

Easy:
• survival in the circulation
• Arrest in capillary or other small vessel
• Exit into remote tissue or organ

Difficult:
• Escape from parent tissue: Invasiveness causing entry into the vessel
• Colonisation: Survival of cells in foreign tissue
• Initial growth of cells in foreign tissue
• persistence of growth

41
Q

What are the 7 things needed by a cancer to be deadly

A
  • Self sufficient in growth signals
  • Insensitivity to growth-inhibitory signals
  • Evasion of apoptosis
  • Defects in DNA repair
  • Limitless replicative potential
  • Sustained angiogenesis
  • ability to invade and metastasise
42
Q

What is the Volgelstein multistep model?

A
  • Normal epithelium
  • Tumour suppressor gene (APC) is lost
  • Excessive epithelial proliferation
  • Oncogene (Ras) activated
  • Small tumour forms
  • Another tumour suppressor gene (p530 lost
  • Tumour becomes invasive
  • Rapid accumulations of mutations
  • Metastasis

Semester 2 Molecular Medicine (27 decks)

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