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BIOL0027 > Cancer as a Disease of Ageing > Flashcards

Cancer as a Disease of Ageing Flashcards

1
Q

What is above the basal lamina?

A

Basal cell layer

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2
Q

What is above the basal cell layer?

A

Differentiating cells

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3
Q

Describe the process of cancer formation

A

Basal layer cells over divide - invade differentiating cell layer above - dysplasia
Basal layer cells takeover differentiating cell layer - forms carcinoma
Basal layer cells invade connective tissue under basal lamina - forms malignant carcinoma
Malignant carcinoma invades capillaries - travels in blood - adheres to capillary walls in other tissues - escapes from capillary (extravasation) - proliferates - metastasis

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4
Q

Name the 4 DNA repair methods

A

Base-excision repair
Nucleotide-excision repair
Recombinational repair
Mismatch repair

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5
Q

What is base-excision repair?

A

Replacement of single incorrect base

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6
Q

What is nucleotide-excision repair?

A

Replacement of incorrect nucleotide

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7
Q

When is nucleotide-excision repair performed?

A

When DNA helical structure distorted by damage

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8
Q

When is recombinational repair performed?

A

When double-strand break in DNA

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9
Q

What are the consequences of severe DNA damage?

A

Senescence
Apoptosis - depletes stem cell pool - pro-ageing
Mutations - cancer, ageing

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10
Q

Give an example of virus that can cause cancer

A

Sarcoma virus

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11
Q

What is the normal structure of cells in a dish and what is the result of infecting them with sarcoma virus?

A

Normally form monolayer

After infection - become more rounded - duplicate - form cluster

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12
Q

Give an example of a chemical agent that can cause cancer

A

Coal tar

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13
Q

How can oncogenes be identified?

A

Inject DNA fragments into mouse fibroblasts - grow in dish
Cells containing oncogene form focus of morphologically-transformed cells
Inject focus cells into mice - form tumour

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14
Q

Define a proto-oncogene

A

Non-transforming DNA sequence - with mutation could become oncogene

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15
Q

Define an oncogene

A

Transforming version of same proto-oncogene DNA sequence

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16
Q

How can the cancer-forming mutation in an oncogene be identified?

A

Transfect increasingly smaller fragments of oncogene into fibroblasts
Find region causing transformation
Sequence
Compare to proto-oncogene - identify mutation

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17
Q

Which mutation types can cause a proto-oncogene to become an oncogene?

A 
Point mutation
Oncogene amplification (CNV)
Translocations between chromosomes
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18
Q

Name an example of a translation between chromosomes that causes a proto-oncogene to become an oncogene

A

Philadelphia transformation

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19
Q

What is the Philadelphia transformation?

A

In chronic myelogenous leukemia
abl gene translocation from chromosome 9 to 22
BCR promoter now controls abl expression
Overexpression of fusion protein (BCR-abl) - tyrokine kinase
Drives cell division, inhibits DNA repair

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20
Q

What are the multiple hits needed for transformed cell formation in colon carcinoma?

A

1st hit - APC mutation - tumour suppressor gene
2nd hit - RAS mutation
3rd hit - PI3K/TGF-beta mutation

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21
Q

What do proto-oncogenes stimulate and what normally counterbalances this?

A

Growth

Counterbalanced by tumour suppressor genes

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22
Q

How is it determined if a cancer allele is dominant/recessive?

A

Cell fusion experiment - fuse normal cell and cancer cells

2 possible products - hybrid cell tumorigenic (mutation dominant), hybrid cell non-tumorigenic (mutation recessive)

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23
Q

What is Knudson’s two hit hypothesis?

A

Two hits needed for tumour development
In familial retinoblastoma - inherit one mutant allele - only one somatic mutation required - acquiring 2nd mutant allele easier - early onset
In sporadic retinoblastoma - must undergo 2 somatic mutations

24
Q

Is Knudson’s two hit hypothesis correct?

A

No - number of hits require depends on tumour type and specific mutations acquired

25
Q

What are microRNAs and how can they play a role in cancer?

A

Bind to 3’ UTR – inhibit mRNA translation

Dysregulated in cancer – downregulate tumour suppressor genes

26
Q

How can epigenetic mechanisms be involved in cancer?

A

CpG methylation of tumour suppressor genes – silence

27
Q

Name the cellular processes typically altered in cancer cells

A 
Cell cycle
Cellular signalling pathways for growth, differentiation, death – control cell number
Cellular metabolism
DNA repair
Genomic stability
Interaction with extracellular matrix and micro-environment
Interaction with immune system
Ability to metastasise
28
Q

How is the cell cycle altered in cancer cells?

A

Damaged cell continues division – causes cells with genomic instability

29
Q

How is DNA repair altered in cancer cells?

A

Impaired

Increases mutation rate – predisposes to cancer

30
Q

What is the effect of genomic instability in cancer cells?

A

Required for cancer cell growth

31
Q

What is the main method of ATP synthesis used by cancer cells and what is the impact of this?

A

Glycolysis

Use more glucose

32
Q

What are the products of glycolysis in cancer cells?

A

Less ATP

More cellular building blocks – enables increased cell division

33
Q

What does p53 enable?

A

Enables G1 arrest, DNA repair, senescence, apoptosis

34
Q

Mutation in which cell cycle regulator is common in cancer?

A

p53

35
Q

How is inflammation linked to cancer?

A

Chronic inflammation predisposes to cancer

36
Q

Mutations in which inflammation-related genes are linked to cancer?

A

Inflammatory cytokine genes

37
Q

What is intratumour heterogeneity and what is the impact on treatment aims?

A

Within tumour each region slightly different – different mutations
Aim to treat common mutations – in all areas of tumour

38
Q

What are the hallmarks of cancer mutation effects?

A 
Evade growth suppressors
Avoid immune destruction
Replicative immortality – by preventing telomere shortening
Tumour-promoting inflammation
Enable metastasis
Induce angiogenesis – supply tumours with nutrients
Cause genome mutation and instability
Resist cell death
Upregulated nutrient sensing
Sustain proliferative signalling
39
Q

Name the hallmarks of ageing

A 
Genomic instability
Telomere shortening
Epigenetic alterations
Loss of proteostasis
Deregulated nutrient sensing
Mito dysfunction
Cellular senescence
Stem cell exhaustion
40
Q

How can ageing processes increase cancer risk?

A

Mutation accumulation
Tissue microenvironment changes – increase risk of malignant cell growth
Increased senescent cells
Weaker immune system

41
Q

How do stem cells change with age?

A

Accumulate DNA damage – genomic instability

42
Q

What are the 2 possible outcomes of DNA damage in stem cells?

A

Additional mutations – forms cancer

Apoptosis/senescence – depletes stem cell pool – ageing/degenerative disease

43
Q

How could treatments to improve DNA repair help to prevent cancer and ageing?

A

Prevent stem cell damage accumulation

44
Q

What is the effect of p53 depletion in mice?

A

Increases cancer incidence

Shortest lifespan

45
Q

What is the effect of p53 truncation (hyperactivity) in mice and what does this suggest?

A

More cells sent to apoptosis – pro-ageing
Intermediate lifespan
Lowest cancer incidence
Protection from cancer could be pro-ageing

46
Q

What is the effect of WT p53 in mice?

A

Intermediate cancer incidence

Longest lifespan

47
Q

What are super-p53 mice?

A

3 copies of p35

Under endogenous promoter – not always active

48
Q

What are the characteristics of super-p53 mice and what does this suggest?

A

Normal ageing
Protection from cancer
Only more p53 when needed decreases cancer – without affecting lifespan – can have cancer and ageing protection

49
Q

What key trait do Daf-2 mutant C. elegans have?

A

Long-lived

50
Q

What is the effect of crossing Daf-2 mutant with ovarian cancer model C. elegans and what does this suggest?

A

Offspring protected from ovarian cancer – as Daf-2 sends cancer cells to apoptosis
Mutation that increases lifespan also inhibits tumour growth

51
Q

What is the effect of dietary restriction in mice?

A

Extends lifespan

Prevents cancer

52
Q

Which type of cancer drugs also extends lifespan?

A

mTOR inhibitors

53
Q

Which drug extends C. elegans lifespan and prevents colon cancer?

A

Aspirin (anti-inflammatory)

54
Q

Why might aspirin not be a suitable drug to prevent ageing and cancer?

A

Increases bleeding risk

55
Q

Why does decreasing Myc expression extend mouse lifespan?

A

Can be increased Myc copies in cancer cells – Myc activates more oncogenes

56
Q

Which type of cancer drugs could also be anti-ageing drugs?

A

Drugs that inhibit growth pathways

BIOL0027 (20 decks)

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