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People and Illness > PBL - Cancer metastases > Flashcards

PBL - Cancer metastases Flashcards

1
Q

List the 7 stages of cancer metastases.

A 
Reduced cell-cell adhesion
Altered cell-substratum adhesion
Increased motility
Increased proteolytic ability
Angiogenic ability
Ability to intravasate and extravasate
Ability to proliferate (locally and in ectopic sites)
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2
Q

Define invasion

A

Growth by infiltration and destruction of surrounding tissues

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3
Q

Define metastasis

A

Spread of the tumour to (and growth at) ectopic sites, via blood, lymph, intra-epithelial route or transcoelemic route

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4
Q

Describe the process of cancer metastases.

A 
Local invasion
Angiogenesis
Detachment 
Intravasation 
Transport 
Arrest
Extravasation 
Growth at ectopic site
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5
Q

Why are caherins called this?

A

They are dependent on calcium to function

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6
Q

What mediates cell-cell adhesion?

A

Extracellular cadherin domains

- while the intracellular cytoplasmic tail associates with a large number of adaptor and signalling proteins

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7
Q

What is E-cadherin for during development?

A

Responsible for separations of the different tissue layers and for cellular migration

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8
Q

What intracellular structure is E-cadherin bound to?

A

Beta and alpha-catenins, which are in turn attached to the actin-myosin cytoskeleton

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9
Q

How does E-cadherin help to prevent metastases?

A

E-cadherin adhesion inhibits invasion through the basement membrane and breaking up of the tumour cells to prevemt metastasis
The more E-cadherin expression, the less severe the tumour

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10
Q

Hoe can cancer metastases occur anyway?

A

The ECD promoter becomes inactivated
Mutations in the proteins that interact with ECD (beta-cadherin and APCs)
Mutation in the transcription factor that regulates E-cadherin

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11
Q

What are the principle receptors used to bind the extracellular matrix, and where are they found?

A

Integrins

- in basal epithelial cells and in focal adhesions of migrating cells

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12
Q

Specific integrins seem to promotes invasion/metastases, what are the possible mechanisms of this?

A

Decreased adhesion to the basement membrane surrounding epithelium
Increased migration through the stroma
Decreased adhesion to BM or endothelial cells
Binding sites for proteolytic enzymes

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13
Q

What is the function of hepatocyte growth factor (HGF)?

A

HGF is a mitogen (a motility factor)
This induces epithelial cells to dissociate and scatter in culture
Causes migration of limb buds in development

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14
Q

Which cells produce HGF?

A

Stromal cells of a tumour

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15
Q

Describe the action of HGF.

A

example
Activates c-met (a receptor tyrosine kinase).
This increases tyrosine phosphorylation of beta-catenin, which in turn distrupts E-cadherin mediated adhesion
Causes scattering of tumour cells

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16
Q

What are some examples of serine proteases?

A

Urokinase plasminogen activator
Plasmin
- these bind to receptors on tumour cell surfaces

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17
Q

What are MMPs?

A

They are endopeptidases that degrade various components of the extracellular matrix.
Allows cancer metastases if up-regulated too much

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18
Q

Give some examples of MMPs?

A

Collagenases
Gelatinases
Stromelysins
MT-MMPs

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19
Q

When are MMPs used normally in the human body?

A

Only during tissues remodelling

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20
Q

How can tumour cells cause release of more MMPs?

A

Tumour-stromal interactions leads to TNF-alpha expression by the tumour.
This acts on the host stromal cells, which in turn produces an MMP

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21
Q

Describe the molecular sequence that leads from hypoxia to VEGF release.

A

When a tumour become hypoxic, it releases hypoxia-inducible factor, which begins the release of VEGF.

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22
Q

What is the action of VEGF?

A

Attaches to receptors on nearby endothelial cells, which begin to migrate towards the tumour
This drags blood vessels over towards the tumour

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23
Q

Describe lymphocyte homing

A

Certain genes on lymphocytes are switched on, letting the cell know to travel to the peripheral endothelium and lymph node endothelium and back.
This also happens to neutrophils and macrophages in inflammation

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24
Q

How do tumour cells intravasate and extravasate?

A

They hijack the lymphocyte honing mechanism.

This allows them to move all over the body before arriving at sticking to a new place.

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25
Q

What is the seed and soil hypothesis of tumour metastases?

A

The organ which the cancer metastasises to, must have an appropriate environment for survival

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26
Q

What is the mechanical hypothesis of tumour metastasis?

A

The tumour metastasises ‘downstream’ of where the primary tumour is

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27
Q

What are the 6 hallmarks of cancer?

A 
Self-sufficiency in growth signals 
Insensitivity to growth inhibitors
Evasion of apoptosis 
Limitless replicative potential
Sustained angiogenesis 
Tissue invasion and metastasis
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28
Q

What do human cells normally do in response to growth inhibitors?

A

They halt the cell cycle

- process orchestrated by proteins called tumour suppressor genes

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29
Q

Mutation of what causes cancer cells to become insensitive to growth inhibitors?

A

Tumour supressor genes

- cell is no longer responding to external and internal cues to exit the cell cycle

30
Q

What is contact inhibition, and how is it related to tumour cells?

A

This is when cells of a tissue replicated until they can sense they have reached another structure/more cells, and then they stop replicating.
Tumour cells lose this and push all other tissues out of the way in order to keep on growing

31
Q

Name the three ways cancer cells can become self-sufficient in growth signals.

A

Autocrine signalling
Permanent activation of the signalling pathways that respond the growth signals
Destroys ‘off-switches’ that prevents excessive from normal signals

32
Q

How do cancer cells avoid apoptosis?

A

Alter the mechanism that detects damage or abnormalities and thus preventing apoptosis signalling

33
Q

What is the Hayflick limit?

A

The amount of times a non-cancer cell can divide before dying
(60-70 times)

34
Q

What is the normal mechanism of cell destruction once a cell has reached its Hayflick limit?

A

Each cell division causes the telomere to become shorter.

Once the telomere is too short, chromosomes in the cells start fusing and the cell dies

35
Q

What is the fucntion of a telomere?

A

Telomers are sequences of DNA on the end of chromosomes that prevent the ends of chromosomes from fusing to each other

36
Q

How do cancer cells bypass this telomere barrier?

A

Manipulation of telomerase to increase the length of the telomeres
- allows infinite division

37
Q

What is the maximum distance a cell can be away from a blood vessel and still survive?

A

2mm

38
Q

Describe what happens when a tumour is less than 2mm to avoid blood vessel growth.

A

Tumours are constantly expressing HIP-alpha

This binds to pVHL when oxygen is present, and is degraded by proteasomes

39
Q

Describe sustained angiogenesis in tumours.

A

When oxygen isn’t present, HIP-alpha will bind to DNA to transcribe hypoxia-inducible genes.
One of these genes is VEGF - forces nearby blood vessels to grow new arms and supply the tumour

40
Q

What dictates whether a tumour is malignant or not?

A

Whether cancer cells break away from their site/organ to invade surrounding tissues and spread to different body parts

41
Q

What is the immune surveillance theory?

A

Suggests cancer cells constantly arise in the body, but are normally eliminated before they multiply enough to be clinically significant

42
Q

How do NK cells recognise targets?

A 
Via killer activation receptors (KARs) and killer inhibitory receptors (KIRs)
- KRIs recognise MHC class I molecules
43
Q

How does a KAR activate cell death?

A

When a KAR binds to carbohydrate ligands on the target cell, it activates a kill signal that is sent to the NK cell

44
Q

How does a KIR prevent cell death?

A

If the KIR cell receptors are engaged however, then a ‘don’t kill’ signal is received by the NK cell, and the target cell survives.
Failure to engage the KIR will result in NK induced lysis by the target cell

45
Q

How are tumours theoretically destroyed by NK cells?

A

Low expression of MHC class 1 molecules on the surface is particularly low, and KRI doesn’t recognise the ligands, and the cell is allowed to be destroyed

46
Q

Describe lymphokine-activated killer cells (LAKs)

A

NK cells that are generated in the presence of high concentrations of IL-2 and are able to kill fresh tumour cells

47
Q

Describe tumour-infiltrating lymphocytes (TILs).

A

T-lymphocytes that can destroy a tumour when stimulated by IL-2

48
Q

Tumour cells secrete TNF-alpha and beta. What is the function of this?

A

These are cytokines with anti-tumour activity

Stimulate necrosis of tumour cells and TNF-alpha can also inhibit angiogenesis

49
Q

What are the two cytokines that have anti-tumour activity?

A

TNFs - alpha and beta
Interferons - alpha, beta and gamma
- directly inhibits proliferation of tumour cells

50
Q

What are the three reactions of the adaptive immune system in response to antigens on tumour cells?

A

Antibodies - generated against certain tumour-specific antigens on the malignant cells
CTLs - sometimes kill tumour cell by direct contact
DTH - Th1 cell recruitment and activation of macrophages, which attack and kill tumour cells

51
Q

What is BRAF?

A

BRAF is a human oncogene that makes a protein kinase called B-raf kinase

52
Q

Where is B-raf located?

A

On cells as a receptor tyrosine kinase

53
Q

Describe the MEK/ERK signalling cascade.

A

B-raf gets phosphorylated after receiving signals from growth factors
The tyrosine auto-phosphorylates and the cytoplasmic domain activates RAS
Activated RAS then activates the protein kinase activity of RAF kinase
RAF kinase phosphorylates and activates MEK, which in turn phosphorylates and activates ERK

54
Q

What kind of protein are RAF and ERKs?

A

Serine/theronine-selective protein kinases

55
Q

What kind of protein is MEK?

A

A tyrosine/threonine kinase

56
Q

What does mutation of the BRAF gene cause?

A

Is the gene is mutated, then a faulty protein is created, which leaves the signalling cascade in an always turned on position

57
Q

What are the most common tyrosine kinase inhibitors used that can manipulate the immune system?

A

Raf kinase mutations (commonly melanoma)
MAP kinase mutations (melanoma)
ECG receptor kinase mutations (lung cancer)
ALK kinase mutations (lung cancer)
Kit kinase mutations (GI stomach tumours)
Ret kinase mutations (medullary thyroid cancer)
JAK kinase mutations (myelodysplastic syndrome)
Her2 mutations (breast cancer)

58
Q

How do tyrosine kinase inhibitors work?

A

The acts as a synthetic ATP that binds permanently to the kinase. This prevents the ATP release that causes phosphorylation of the tyrosine kinase, and the protein is permanently switched off.

59
Q

Describe the action of Vemurafenib.

A

A B-raf kinase inhibitor, interrupts the B-raf on the signalling pathway

60
Q

What are the BRAF mutations that can be treated with Vemurafenib, and what happens if a different mutation is treated with this drug?

A

It works best on the most common mutation V600E BRAF mutation, and has some efficacy against the less common V600K BRAF mutation
If this drug is given to someone with a different BRAF mutation, either it has no efficacy, or it even stimulates the protein, and the tumour grows

61
Q

Describe how T-cell activation and proliferation can be inhibited

A

The T-cell has a receptor called CTLA-4
When the body wants to down regulate T-cell proliferation and activation, APCs cells with a B7 ligand, bind to the CTLA-4 receptor on T-cells
Binding of these two receptors shuts down T-cell activity

62
Q

How does Ipilimumab work?

A

This is a CTLA-4 immune checkpoint inhibitor
This is a monoclonal antibody that binds to CTLA-4 and stops the interaction of it with its ligands
If CTLA-4 no longer interacts with its ligands, then T-cell activation and proliferation is no longer suppressed, and there is an increase in tumour-infiltrating T-effector cells

63
Q

Describe normal binding of PD-1 with its ligands, PD-L1 and PD-L2.

A

The PD-1 receptor found on T-cells binds to its ligands to inhibit T-cell activation and proliferation.
The body normally uses this mechanism to regulate the immune system and avoid autoimmune problems

64
Q

Describe how cancer cells inhibit T-cell activation and proliferation in regards to PD-1 receptors.

A

Cancer cells make PD-L1, so that the T-cells can bind to it and turn themselves off
This prevents an immune attack on the tumour

65
Q

How does Nivolumab work?

A

It is a human monoclonal antibody that blocks all interaction between PD-1 and its ligands PD-L1 and L2

66
Q

What are the lines of treatment for a BRAF V600E mutation?

A

1st - BRAF inhibitor (Vermurafenib) and Ipilimumbab

2nd - if the tumour is unresponsive, Nivolumab can be tried instead of Ipilimumab

67
Q

What are the advantages of targeted cancer treatment?

A 
More selective for cancer cells
Less selective for normal cells 
- less side effects
- higher doses
- more anti-cancer effects
68
Q

What are predictive and prognostic markers?

A

Predictive marker - predict which patients will benefit from specific treatment
- helps choose which drug to treat each patient with
Prognostic marker - informs of the outcome regardless of treatment
- helps choose which patients to treat

69
Q

What is the major problems with precision treatment?

A

Most people wouldn’t be suitable for a targeted drugs and would have to continue receiving chemotherapy
Also each cancer in each person has different mutations, and probably more than one that could be the one causing the cancer
Biopsies must be performed (uncomfortable and sometimes not possible)

70
Q

What are the three stages of the AR signalling pathway?

A

1) AR binding
2) Nuclear translocation
3) DNA binding and activation

71
Q

Describe how Enzalatmide (AR signalling inhibitor) directly targets three stages of at AR signalling pathway.

A

1) Blocks AR binding
2) Blocks nuclear translocation
3) Blocks DNA binding and activation

72
Q

What are the three E’s of immunoediting?

A

Elimination - the body detects the cancer cells and bombards it with NK cells and CTLs (4 and 8)
Equilibrium - some cancer cells survive this and enter a stage where they are kept in check by the NK cells and CTLs
Escape - the body can no longer suppress the cancer, and the cancer cells escape into the rest of the body and cause havoc

People and Illness (6 decks)

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