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Cancer > Hallmarks of cancer > Flashcards

Hallmarks of cancer Flashcards

1
Q

What are the TWO common types of tumour suppressor

A

p53 and RB1

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2
Q

What is the Role of p53?

A
  • p53 is a transcription factor which blocks the cell cycle in response to cellular damage
  • Induces apoptosis if DNA is irreplaceable
  • Leads to changes in gene expression
  • Most commonly mutated gene in cancers
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3
Q

What is the role of RB1?

A

Blocks the cell cycle by binding and
inhibiting E2F transcription factors which means the cell cycle cant proceed past G1/S
-RB1 itself is inhibited by phosphorylation (via cyclin D-CDK4) which releases E2F transcription factor which can go on to express genes.

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4
Q

What conditions activate p53?

A
  • Low oxygen
  • DNA damage
  • Chemotherapeutic agents
  • Other stress
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5
Q

What are the TWO types of Proto-oncogenes

A

MYC and RAS

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6
Q

What is MYC?

A

This is a transcription factor which partners with MAX and promotes cell growth therefore leading to changes in gene expression

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7
Q

What is RAS?

A
  • This is a G protein which binds to GDP when inactive and GTP when active
  • Activated by growth factors and activates downstream signalling pathways= gene expression
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8
Q

What 4 factors can cause cell death?

A

Damage, infection, ischaemia or cancer

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9
Q

How does intrinsic apoptosis occur?

A

When there is internal damage apoptosis occurs though the mitochondrial pathway. Cytochrome C is released from the mitochondria and activation of the capase cascade occurs.

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10
Q

How does extrinsic apoptosis occur?

A

This process is usually activated by the immune system via the Fas/FasL or TNf/TNF-R1 receptors and then activation of the capase cascade

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11
Q

What is the capase cascade?

A

consists of cystine proteases causing cleavage of proteases and then organised cell disassembly

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12
Q

How are cancer cells resistant of apoptosis?

A

Upregulation of survival signals Bcl2 and down regulation of pro-apoptotic signals Bax

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13
Q

What is necrosis?

A

pro-inflammatory signals released and imune cells recruited which can promote angiogenisis growth factors released which promote proliferation. BUT necrosis is not always good as can promote cancer. This is more lysis and affects groups of cells not a singular one.

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14
Q

Why are telomeres important in mortality?

A

Telomeres are the repetitive sections at the end of a chromosome and each time a cell divides the telomere gets shorter, unless telomerase is active to restore them.

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15
Q

Where is telomerase normally found?

A

In germ cells or stem cells

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16
Q

Do normal cells have telomeres?

A

No, telomeres shorten after each division until they cease to work leading to senescence

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17
Q

What is Alternative Telomere lengthening?

A

Cells don’t express telomerase,
Fusion between ends of different chromosomes.
these are oncogenic changes

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18
Q

What does EGFR stand for?

A

Epidermal Growth Factor Receptor

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19
Q

What does EGFR do?

A

Senses growth signals and leads to increased proteins needed for cell division through the RAS/RAF/MEK/ERK pathway or the PI3K pathway

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20
Q

How do we normally deactivate the EGFR signalling?

A
  1. Phsphotases used to remove kinases

2. Turn off RAS proteins

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21
Q

What drugs target EGFR signalling by inhibiting binding of EGF?

A

Cetuximab an antibody that blocks the receptor

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22
Q

What drugs inhibit EGFR activation and therefore signalling?

A

Erlotinib and Gefitinib, they look like ATP (which is required for activation of EGFR) but don’t behave like ATP

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23
Q

Why is combination anti-cancer therapy so effective?

A

For resistance against two or more therapies, multiple mutations must occur in the same cell and much less likely to occur quickly enough

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24
Q

Give 4 examples of steroid hormone receptors

A

estrogen receptor, androgen receptor, progesterone receptor, retonic acid receptor

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25
Q

What is the MOA for an estrogen receptor being activated?

A

This receptor is activated in the cytoplasm where the ligand -estradiol diffuses into the cell and binds to the receptor displacing chaperone proteins and this dimerising, migrating into the nucleus. The dimer associates with co-activators or co-repressors to modify transcription of target genes.

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26
Q

What is the MOA for Tamoxifen

A

Metabolised to active form by CYPD26 and then binds to ER with a much higher affinity than estrogen and is an antagonist for estrogen mostly in the breast but in bone and uterus can be agonist. This is a SERM

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27
Q

How does Fulvestrant work?

A

Anti-estrogen (NOT SERM) prevents dimerisation/ activation and increases degradation delevtive ER down regulator (SERD)

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28
Q

How do cancer cells achieve REPLICATIVE IMMORTALITY

A

Reactivating telomerase (90% of cancer cells)

29
Q

What histone deacetylase inhibitors are available?

A

Vorinostat, Romidepsin and Panobinostat

30
Q

Hw can transcription be affected??

A

Changes in protein levels, changes in DNA structure, changes in DNA sequence

31
Q

What is p53?

A

This a tetramer which is a transcription factor, it binds to target promoters to regulate transcription

32
Q

What can mutations in RB tumour suppressor cause?

A

missed exons

33
Q

What is the role of microRNAs?

A

Repress gene expression, mutations of them can cause dysregulation!

34
Q

How do cancer cells acquire the vast amount of protein needed to proliferate?

A

Oncogenic mutatations increase activity and abundance of ribosomes and translation factors via PI3K/MTORC pathway

35
Q

What does ubiquination do?

A

Tags proteins that are no longer needed for degradation by proteasome

36
Q

What does MDM2 do?

A

Targets P53 for ubiquitinisation via proteasome

37
Q

How is cancer genetic?

A

with two or more mutations for example RAS like oncogene in the cytoplasm and MYC like oncogene in the nucleus.

38
Q

Give an example of a point mutation

A

P53 and RAS - changes in siingle nucleotides have dramatic effects on protein function

39
Q

Give an example of a deletion mutation

A

EGFR and INK4 removal or regions of DNA can inactivate genes and lead to truncated proteins

40
Q

Give an example of amplification mutations

A

MDM2 Increase the number of copies of a gene and also reduces the amount of p53 as ubiquitinates p53

41
Q

Give an example of a translocation mutation

A

Philadelphia chromosome- give rise to fusion proteins due to rearrangement of chromosomes by juxtaposing bits of genes.

42
Q

What is BCR and ABL?

A

BCR is a threonine kinase and GTPase

ABL is a signalling tyrosine kinase

43
Q

What drugs target BCR ABL?

A

Imatinib, Nilotinib, Dasatinib all tyrosine kinase inhibitors.

44
Q

Why is chronic inflammation a major risk factor for cancer?

A

Promotes mutagenisis (RNS and ROS produced during inflammation) Promotes tumour progression and metastasis.

45
Q

How does smoking cigarettes cause cancer?

A

p53 and KRAS mutations

46
Q

Hoes does infection cause cancer?

A

Insertion of the viruses own genome int the cell causing the cell to grow out of control
Long term inflammation can cause changes
Some infections can suppress the person’s immune system and their immune system normally is a barrier to contracting cancer.

47
Q

How does HPV virus cause cancer?

A

Produces oncogenic proteins E6 which targets p53 for degredation and E7 which interacts with RBP protein.

48
Q

How does Hwlicobacter pylori cause cancer

A

Causes ulceration which it chronic inflammation and increases ROS and RNS in the stomach and free radicals cause DNA damage =mutation. Can result in gastric carcinoma and malt lymphoma.

49
Q

How does radiation cause cancer?

A

Ionising radiation can dislodge electrons this can damage DNA by causing double stranded breaks or by producing free radicals that can attack DNA

50
Q

How does UV cause cancer?

A

cyclo pyrimidine dimers and 6-4 photoproducts between adjacent pyrimidine bases

51
Q

What other environmental mutagens are there?

A

occupational chemicals, natural products such as fungal toxins, medical mutagens such as chemo and atmospheric particles from vehicle exhaust

52
Q

How is obesity a risk factor for cancer?

A

Fat cells produce estrogen and other hormones, also inflammatory signals and recruitment of immune cells

53
Q

How does alcohol cause cancer?

A

There is no safe limit risk increases with intake, mouth throat, bowel ect. Alcohol is converted to acetylaldehyde which can damage DNA and inflammation of liver and can lead to generation of ROS and increas estrogen levels.

54
Q

How does physical activity reduce risk of cancer?

A

Affects hormone levels reducing insulin and estrogen lowering risk of breast and uterine cancers
Also, exercise moves potential carcinogens down the digestive tract quicker e.g. processed meat and alcohol.

55
Q

Does pregnancy reduce breast and ovarian cancer risk?

A

YES

56
Q

What are the inherited mutagens associated with predisposing individuals to breast cancer?

A

BRCA1 and BRCA2 (gives a 5 times higher risk)

57
Q

Under which condition can mutations in tumor supressor genes and oncogenes be inherited?

A

if they were present in germ cells

58
Q

Are cancer genetic or inherited?

A

Genetic

59
Q

What are the barriers to gene therapy?

A 
commercial barriers (material costs, licence and patent costs) 
Biological barriers ( many genes mutated variation within tumours requires majority of cancer cells to be affected- can't change every cell in a cancer but can change a gene)
60
Q

What are the four option for microRNA therapies?

A

anti-miRs to inactivate oncomirs
microRNA smonges to mop up oncomirs
microRNA mask to block oncomirs
upregulation of tumour supressor miRs (oligonucleotides to mimic TS miRs)

61
Q

What is an an antagomir

A

oligonucleotide complimentary to target miR

62
Q

What barriers are there to successful microRNA therapy?

A

olig-nucs only last a few mins in blod stream… stability issue, excretion issue as bind to albumin they are of large size and polarity so difficult to cross cell membranes. Biologically high doses of anti mirs are required per miR and they have many targets so might not get to right target also transient inhibition so repeated doses needed

63
Q

What are Monoclonal antibodies used for?

A

Make cells visible to the immune system, stop cells dividing, target therapies, diagnosis.

64
Q

How does Rituximab work?

A

targets CD20 on B cells which causes antibody mediated cytotoxicity which kills lymphomas and leukaemias

65
Q

How could we use MABs as delivery systems for therapy?

A

Radioimmunotherapy, antibody drug conjugates and antibody directed enzyme pro drug therapy

66
Q

What are the advantages of MABs?

A

good specificity large quantities well defined purity
Recombinant MABs reduce immun response problems
Can remove Fc region to make smaller

67
Q

Disadvantages of antibody fragments

A

reduced circulation half life controlled by Fc region
reduced binding activity
loss of immune effector region

68
Q

What is the role of cancer vaccines?

A

To modify the cancer patient’s immune system to fight cancer via induction of cytotoxic T lymphocytes

Cancer (6 decks)

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