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Y3 Biology Of Cancer > Week 6 > Flashcards

Week 6 Flashcards

1
Q

What is the tumour microenvironment?

A

A tumour includes a range of tumour cells and stromal cells alongside resident cancer cells. These make up the tumour microenvironment.

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2
Q

What makes up the majority of a tumour?

A

The stroma

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3
Q

Name the main components of the tumour microenvironment.

A

Cancer-associated fibroblasts (CAFs)

Extracellular matrix (ECM)

Infiltrating immune cells

Blood vessels

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4
Q

What is the main function of CAFs in terms of a tumour?

A

Regulate the ECM

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5
Q

What is the main function of the ECM in terms of a tumour?

A

Supports the tumour

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6
Q

What produces the ECM in terms of a tumour?

A

CAFs

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7
Q

Name some features of the TME and explain which hallmarks of cancer they contribute to.

A

CAFs = sustained proliferative signalling, evade growth signals, avoid immune destruction, activate invasion and metastasis, induce angiogenesis, resist cell death and deregulate cellular energetics.

Infiltrating immune cells = aid sustained proliferative growth signals, evade growth signals, avoid immune destruction, activate invasion and metastasis, induce angiogenesis, resist cell death.

Angiogenic vascular cells = aid sustained proliferative signalling, avoid immune destruciton, activate invasion and metastasis, resist cell death.

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7
Q

Name some features of the TME and explain which hallmarks of cancer they contribute to.

A

CAFs = sustained proliferative signalling, evade growth signals, avoid immune destruction, activate invasion and metastasis, induce angiogenesis, resist cell death and deregulate cellular energetics.

Infiltrating immune cells = aid sustained proliferative growth signals, evade growth signals, avoid immun destruction, activate invasion and metastasis, induce angiogenesis, resist cell death.

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8
Q

What are the main roles of CAFs when they are not tumorigenic? How do these abilities come about?

A

They play a wound healing role when they acquire a myofibroblast phenotype and coordinate tissue repair.
The myofibroblasts express high levels of alpha smooth muscle actin (aSMA) which confers a contractile. phenotype.

Myofibroblasts also produce numerous cytokines which allows them to contribute to homeostasis and modulate the immune system. They achieve this by structural means.

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9
Q

How does the functioning of CAFs alter from normal to tumour regions of the body.

A

The myofibroblasts would be reduced to a normal fibroblast once a wound has healed. However, in cancer; the myofibroblasts remain chronically activated and contribute to an environment when a cancer is able to full-fill hallmarks and evade checkpoints.

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10
Q

When cancer cells metastasise, what happens to normal fibroblasts?

A

They care converted and become CAFs.

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11
Q

What physically happens once CAFs are activated?

A

They become more contractile and produce cytokines and proteins which they release to affect cells in the surrounding environment.

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12
Q

Where do CAFs originate?

A

Most CAFs originate in resident fibroblasts, but some evidence shows that they could also originate from other cell types such as the mesenchymal stem cells from the bone marrow.

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13
Q

Name a way in which CAFs are activated.

A

Via radio/chemo therapy.

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14
Q

What process can drive CAF formation and how is this a positive feedback loop?

A

Inflammation

Inflammation causes CAF formation and CAFs drive inflammation.

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15
Q

How can targetting tumours with DNA damage affect CAFs?

What effect does this have on treating tumours?

A

Targeting tumours with DNA damage may cause activation of CAFs within tumour cells and help the tumour evade the drugs.

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16
Q

Name the ways the CAFs assist tumorigenesis.

A

Remodelling of the ECM

Cell-cell communication in the TME

Immune cell modulation and dampening of the immune response

Metabolite exchange in pancreatic cancer via autophagy of CAFs

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17
Q

How do CAFs remodel the ECM and what effect does this have?

A

MMPs are used to degrade the ECM by burrowing and making pores through it. This degraded ECM can then be remodelled. This is how cancer cells can remove themselves from the TME (via the tunnels made by MMPs) and can metastasise around the body.

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18
Q

How do CAFs aid cell-cell communication in tumorigenesis?

A

VEGF production

Extracellular vesicles

Exosomes

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19
Q

How do CAFs use immune-cell modulation and dampening to assist tumorigenesis?

A

Tumour promoting CAFs dampen the immune system and mean that the immune system doesn’t target cancer cells.

Directly inhibits the action of tumour killing cells such as cytotoxic T cells.
Promotes the activation of immune cells which dampen the immune system such as T reg’s.

This causes a net effect where immune inhibition of the tumour doesn’t occur.

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20
Q

How do CAFs cause metabolite exchange which aids tumorigenesis?

A

They use autophagy.

CAFs are broken down into constituent parts which are required by cancer cells to allow them to proliferate and grow.

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21
Q

Are CAFs pro or anti-tumorigenic?

A

Different types of CAFs can have different effects. Both are possible.

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22
Q

Are CAFs pro or anti-tumorigenic?

A

Different types of CAFs can have different effects. Both are possible.

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23
Q

What is the main function and purpose of myoCAFs and describe the chemicals that allow this.

A

Their main purpose is contraction to provide the tumour with rigidity.
Can also remodel the ECM.

High levels of alpha SMA.
Low levels of IL-6

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24
Q

What is the main function of ICAFs and what chemicals allow this?

A

Immunosuppression - modulate the immune system and create an environment where cancer can grow.

High levels of IL-6
Low levels of alpha SMA

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25
Q

In terms of CAFs and cancer, what is the purpose of IL-6

A

Aids regulation of the immune system

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26
Q

In terms of CAFs and tumours, what is the purpose of alpha SMA?

A

Forms part of the cytoskeleton of the cell and gives rigidity.

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27
Q

How are fibroblasts defined?

A

By the absence of cell specific markers. Seen by the absence of endothelial, exothelial and leukocyte cell markers.

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28
Q

Why is removal of stromal fibroblasts infrequently used to treat cancer?

A

This has limited impact because specific CAF subtypes need to be targetted.

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29
Q

What are the possible treatment targets against CAFs?

A
  • Prevent CAF functioning. (Could use small molecular inhibitors such as TGFbeta or inhibitors of CXCR4).
  • Reduce CAF production/ Kill CAFs
  • Alter functioning of CAFs. Reprogramme activated CAFs into resident CAFs.
  • Remove the ability of CAFs to make ECM proteins.
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30
Q

What is the most important way in which CAFs help achieve cancer hallmarks ?

A

By remodelling the ECM and modulation of the immune response.

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31
Q

What % of a solid tumour is ECM?

A

60%

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32
Q

What is the purpose of the ECM in terms of a tumour?

A

Gives the tumour the ability to form a solid tumour mass

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33
Q

By what produce do CAFs produce ECM?

A

Desmoplasia

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34
Q

How does the ECM of cancer cells differ to healthy, normal cells?

A

The ratio of ECM components such as ratio of collagen differs.

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35
Q

How is the ECM of patients with breast cancer tumours altered?

A

There is an increased collagen V to collagen I ratio which results in a gel-like ECM which aids metastasis.

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36
Q

Name some changes to the ECM that physically influence disease progression

A

Increased solid stress

Increased interstitial fluid

Increased stiffness/ elastic modulus

Altered tissue microarchitecture

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37
Q

What causes solid stress in a tumour?

A

 This is usually caused by proliferation of the cancer. The proliferation puts solid state pressure on other cells within the tumour.
 Some proteins within the ECM absorb water. This then swells and causes an outward pressure – solid state pressure.

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38
Q

What are the effects of solid state pressure on a tumour and how does this cause disease progression?

A

Outward pressure on the tumour may cause collapse of the vasculature. This drives hypoxia and cancer metastasis given there is no longer delivery of nutrients to the cancer.This hypoxic state allows cancer to recruit mutations which evade epithelial growth but gain mesenchymal growth which further aids metastasis.
o Compression of the mechanosensitive nucleus leads to activation of transcription factors such as YAP and TAZ which in turn contribute to numerous cancer hallmarks; cell cycle regulation, proliferation, inhibition of apoptosis etc.
 These factors sense when the nucleus is under mechanical stress. Yap TAZ signalling is then turned on and allows. This signalling pathway allows cancer to metastasise.

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39
Q

What causes increased interstitial fluid pressure in tumours.

A

Tumours tend to have high interstitial pressure given the vasculature is often collapsed, not properly formed etc. This means the vasculature is leaking into the tumour and causing increased interstitial fluid pressure.

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40
Q

What are the effects of increased interstitial fluid pressure in tumours and how does this allow disease progression?

A

CAF formation can be caused.

Drugs efflux away from the tumour towards the periphery making it harder to treat them with drugs.

Modulation of EC sprouting induction of MMPs can also occur.

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41
Q

What causes increased stiffness of a tumour?

A

o Driven by ECM deposition and cross-lining of collagen fibres by lysyl oxidase and transglutaminase 2 (in pancreatic cancer).
 This causes increased TGFbeta signalling and CAF activation.
o Focal adhesion kinase (FAK) pathway increased
o YAP/TAZ pathway increased

42
Q

What effects does increased stiffness of a tumour have and how does this aid disease progression?

A

 Activates CAFs
 Drives a viscous cycle which causes further ECM disposition
Attempts to target tumour ECM stiffness focus on modulating CAF ECM deposition via angiotensin.

43
Q

How does altered tissue microarchitecture aid disease progression in a tumour?

A

o These changes can impact nuclear programming of the cell via YAP/TAZ.
 Uses focal adhesion proteins to do this.
 This drives the cancer EMC phenotype and makes them more migratory and metastatic.

44
Q

Does the ECM directly or indirectly contribute to cancer progression?

A

The ECM provides a framework for a tumour to develop but also directly and indirectly contributes to cancer progression

45
Q

What mediates cell-cell communication in tumours

A

Cytokine secretion via extra cellular vesicles.

46
Q

How are extra-cellular vesicles used to allow cell-cell communication in tumours and what effect may this have?

A
  • Evs are membranous structure shed by most cells in the body.
  • They contain an array of cellular components; proteins, nucleic acids etc.
  • EVs shed by one cell type can be taken up by a distal cell and regulated directly by the EV contents, opening a new area of cell-cell communication within the tumour microenvironment.
  • Help cells communicate using non-coding mRNA, proteins etc
    o These can affect the DNA of other proteins within the cell
47
Q

What is Micro-rNA and what are it’s functions?

A

short RNA molecules which are transcribed within the cell and help regulate transcription and gene expression. They do this by fine tuning.

  • They can regulate gene expression in multiple genes at one time.
  • They can travel throughout the TME without being degraded.
48
Q

What do exosomes derive from?

A
  • Derived from the fusion of multivesicular bodies with the plasma membrane and subsequent release into the extracellular space via exocytosis.
49
Q

What characterises small EVs?

A
  • Can be detected and characterised by proteins present at the membrane which include common markers such as CD63 and cell-type specific markers depending on the cell of origin (e.g. L1CAM for neurons).
50
Q

Explain the difference in EV production/ shed in activated fibroblasts compared with those that are not activated.

A

Tumours shed higher numbers of eVs.

Activated fibroblasts produce EVs at a higher rate.

51
Q

What are the functions of TEVs?

A
  • Used to reprogramme fibroblasts into CAFs which shed more EVs.
  • Transfer a range of molecules that activate resident fibroblasts and drive CAF reprogramming.
  • Play a role in modulation of the TME immune cell function, which is immunosuppresive/tumorigenic.
52
Q

How do TEVs reprogramme fibroblasts to CAFs?

A

o Components within the EVS are taken up within the cancer cells and drive aggressive changes within the cancer cells.

53
Q

How are MSCs reprogrammed to myofibroblasts?

A
  • MSC can be reprogrammed to myofibroblast like cells by TEV-mediated activation of SMAD signalling pathways.
54
Q

What are Treg cells and how does cancer use them?

A

(Treg’s dampen the immune system. Without them the immune system would kill us).
- Cancer can take advantage of these, hyperactivating them within the tumour and reducing any kind of immune response.

55
Q

Why don’t NK cells kill tumours?

A
  • Not usually active within the cells so don’t kill tumours.
  • This is the case because tumour EVs produce ligands (NKG2D-L) which coat the NK cells and makes them titrated and absorbed. This means they can never become coated and kill the cancer cells. EVs act as a decoy to NK cells.
56
Q

What are the methods by which a lot of tumours have gained resistance to chemotherapy?

A
  • Impaired drug uptake
  • Decreased apoptosis
  • Enhanced DNA repair
  • Widely reported TEV mechanism involves the efflux pump, ABCB1.
57
Q

In short, what is the basis of immunotherapy?

A

CD8+ T-cell killing impaired by PD-L1 (basis of immunotherapy).
TEVs can deactivate CD+ T-cells via surface expression of PD-L1 in a range of cancers.

58
Q

What happens if cells dont have sufficient oxygen?

A

They are in a hypoxic state and necrosis occurs.

59
Q

What is angiogenesis?

A

The formation of new blood vessels from existing ones requiring the migration and growth of other endothelial cells.

60
Q

Name some differences in the blood vessels of healthy and tumour bodies.

A

Recognisable hierarchy Vs lack of arteriole-capillary-vessel hierarchy in tumours.

Pericytes closely associated with ECs whereas loose association in tumours.

Smooth lumen with single layer endothelium, precisely distributed ECM and organised pericytes Vs abnormal basement membrane in tumours.

61
Q

Why must cancers be treated with different/ multiple treatment types?

A

Cancers are heterozygous so must be treated with multiple treatment types. If they are only treated with one treatment, this may only target some of the cells and not the ones who could be resistant to it. Resistant cells will survive and re-populate.

62
Q

What does VEGF stand for?

A

Vesicular endothelial growth factor

63
Q

why is targetting VEGF not enough to stop tumour growth?

A
  • Not known to be successful given that there are many other growth factors. If you knock out one growth factor, the tumour will just over produce other growth factors.
64
Q

What happens to VEGF in tumour cells?

A

Normal endothelial cells have receptors for these growth factors.
If these receptors receive excessive growth factors, ECM degradation occurs and so the blood vessel becomes leaky. Endothelial cells also migrate and go towards the high concentration of growth factor (tumour).
Endothelial cells also proliferate. This means that other endothelial cells are formed. Not all of them migrate.

65
Q

What is the angiogenic switch?

A

Refers to a time-restricted event during tumour progression where the balance between pro and anti-angiogenic factors tilts towards pro-angiogenic outcomes. This results in the transition from dormant avascularised hyperplasia to outgrowing vascularised tumour and eventually to a malignant tumour.

66
Q

What is the key-angiogenic factor?

A

VEGF

67
Q

What is the key anti-angiogenic agent ?

A

Thrombospondin 1

68
Q

Where does VEG A primarily act? And what is its main function.

A

On endothelial cells.

Can bind to receptors on cancer cells and make them more active and proliferative.

69
Q

What is VEGF receptor 1 and what does binding to this do in cancer cells?
What does it do in normal, healthy cells?

A

 This is soluble
 Normally mops up free VEGF and removes it from the system
 Body naturally produces this to remove excess VEGF
 Cancer cells can alter this system
• Cancer cells sometimes have VEGF receptor 1
• If VEGF then binds to these receptors, it can cause growth of the cancer cells

70
Q

What are the main purpose of the VEGFR2 and VEGF-A receptors?

A

They are the key deliverers of angiogenesis

71
Q

What cells express VEGF2 receptos?

A

Endothelial cells

72
Q

What is the VEGFR3 mainly involved in?

A

The development of the lymphatic sutem.

73
Q

What does a lack of VEGF cause?

A

Lack of angiogenesis occurring.

74
Q

What receptor does VEGF-A bind to?

A

VEGFR2

75
Q

By what cells are VEGFs produced?

A

Many cancers secrete VEGFs, but they can also be produced by infiltrating immune cells.

76
Q

What are the effects of VEGF-A and how does this cause disease progression?

A
  • VEGF-A induces endothelial growth, permeability, and leakage.
    o This destabilises existing vessels to allow sprouting to begin.
77
Q

Outline the process of sprouting angiogenesis initiated by VEGF-A

A

 Sprouting angiogenesis is led by top cells, which can sense their environment and direct the sprouting process.
 Tip cells are followed by stalk cells, which have a more proliferative phenotype.
 The number of tip cells is regulated by lateral inhibition between the tip and stalk cells.
• The tip cells prevent the adjacent cells from becoming tip cells and thereby optimise the number of tip cells.
• The tip cells sends growth signals to other endothelial cells and causes them to keep growing. This causes formation of a new vessel.

78
Q

What type of molecules are VEGF receptors?

A

Tyrosine kinases

78
Q

What type of molecules are VEGF receptors?

A

Tyrosine kinases

79
Q

What signalling pathway does VEGF use?

A

Classical tyrosine kinase pathway

80
Q

What does P13K signalling do?

A

It is anti-apoptotic and increases vessel permability

81
Q

What is HIFa?

A

Hypoxia inducible transcription factor.

82
Q

What happens to HIF under normal conditions?

A

• Under normal conditions, HIF is broken down by hydroxylation quickly. This allows pVHL to bind. Ubiquitin tags can then be added. It is then sent to proteosomes to be broken down.

83
Q

What happens to HIF in tumour hypoxic conditions, and what doe this cause?

A
  • However, in hypoxia, HIF is nitrosylated.
  • Oxygen levels regulate HIF at the protein rather than mRNA level- both HIF components (HIF-1α and HIF-1 β are constitutively expressed
  • Under normoxic (20% oxygen) conditions HIF-1α is is enzymatically hydroxylated andrapidly degraded
  • The von Hippel-Lindau (VHL) tumour suppressor protein binds to hydroxylated HIF-1α enabling ubiquitination (a marker for proteosomal degradation to occur) of HIF-1α
  • In the absence of HIF-1α HIF target genes cannot be switched on, so there is no angiogenic signal
  • Under hypoxia VHL cannot bind HIF-1α, it is stabilised, dimerises and binds to the hypoxia response element in target genes (such as in the VEGF promotor)
84
Q

What is the main target gene of HIF?

A

VEGF

85
Q

Name mechanisms for tumour neo-vascularisation

A

Angiogenesis

Intussusceptive angiogenesis

Vasculogenesis

Endothelial progenitor cells

Vasculogenic mimictry

Transdifferentiation of cancer cells

86
Q

What is intussusceptive angiogenesis and how does it occur?

A

A process whereby a new blood vessel is created by splitting of an existing blood vessel into two.
- Increase in eNOS increases lumen size of the vessel. This allows increased blood flow into the vessel which causes stress. The blood vessel then forms a pillar formation and blood flor through the vessel is significantly reduced.

Uses VEGF and PDGF growth factors

87
Q

What is de-novo vessel formation and how does it occur?

A
  • Induced through differentiation of endothelial progenitor cells (EPCs) in a process called coined vasculogenesis
  • EPCs are mostly unipotent adults stem cells that have the capacity to self-renew, proliferate, take part in neovascularization and repair endothelial tissue.
  • In tumours, vasuculogenesis is initiated by crosstalk between tumour cells and EPCs in the bone marrow. VEGF in the tumour microenvironment mobilizes VEGFR2+ EPCs from the bone marrow. Tumours also secrete other factors well known to mobilise EPCs to the tumour bed.
88
Q

What is vascular mimicry and how does it work?

A

The ability of cancer cells to orginise themselves into vascular-like structures for the obtention of nutrients and oxygen independetly of normal blood vessles or angiogenesis.

  • Extra ECM is laid down. This creates channels which pass through the solid tumour These passages present markers of cancers.
  • Anti-angiogenic therapy does not work on this because endothelial cells are not the issue. Chemotherpay would work.
89
Q

What does anti-angiogenic therapy do?

A

Does not directly target the cancer but is designed to prevent tumours from forming blood vessels to stop their growth

90
Q

Do anti-angiogenic therapies need to be used long term or not?

A

These are cytostatic rather than cytotoxic so may need long-term use.

91
Q

Is resistance against anti-angiogenic drugs likely and why?

A
  • ECs are genetically stable unlike cancer cells, so are less likely to develop resistance.
92
Q

Name some of the successes of anti-angiogenic therapies.

A

Target a variety of tumours.

In glioma, clinical studies show that anti-angiogenic treatment can prolong progression-free survival.

93
Q

Name some of the failures of anti-angiogenic treatments.

A

Some VEGF monotherapies have only provided limited benefits to certain tumour types and have not shown efficacy in some cancers.

Bevacizumab studies shows high incidences of relapse and death due to disease progression suggesting an increased tumour aggressiveness after anti-angiogenic therapy.

Fails to improve overall survival.

Some anti-angiogenic treatments are associated with increased local tumour invasiveness and formation of distant metastasis.

94
Q

What are the different types of resistance to anti-angiogenic drugs.

A

• Resistance can be classified into intrinsic resistance, observed from the outset of the therapy, and acquired resistance

95
Q

Name some of the proposed mechanisms for anti-angiogenic therapies.

A

• Several mechanisms have been proposed for anti-angiogenic therapy resistance, including direct effects of hypoxia such as induction of tumour invasion and metastasis, co-option of normal vessels in the surrounding tissue, vascular mimicry as well as the contribution of stromal cells including recruitment of TAMs, EPC and pro-angiogenic myeloid cells as well as the upregulation of alternative pro-angiogenic factors

96
Q

How may anti-angiogenic drugs promote disease formation?

A

• Anti-angiogenic therapy can promote tumour invasion and metastasis in pre-clinical cancer models, which might be triggered by increased hypoxia due to vessel depletion.

97
Q

Describe and explain the key stages in tumour induced angiogenesis.

A
  • Angiogenesis is the formation of blood vessels from existing ones
  • GFs (such as VEGF and PGF) are produced by cancer cells and released into the local environment where they bind to receptors on endothelial cells
  • This causes EC activation, typified by remodelling of the ECM and detachment of pericytes
  • GF signalling causes tip cell formation, which begin to migrate down the GF gradient
  • Tip cells induce proliferation of nearby ECs to cause tubule growth
  • Vessel maturation and ECM deposition occurs
98
Q

Explain why ERK inhibitors may be used as potential angiogenesis inhibitors

A
  • ERK is the key enzyme activated by VEGF
  • Its activation causes cell cycle progression and cell migration
  • Its removal would stop angiogenesis by stopping tubule growth
99
Q

Explain some of the reasons why anti-angiogenic therapies may have failed.

A
  • There are multiple GFs and receptors so removing one has little effect
  • Hypoxia induces HIF, which greatly increases VEGF and other GFs, allowing escape from the treatment
  • EPCs and vascular mimicry become the major ‘vascularisation’ route
  • Hypoxia induces cancer cell growth and migration
  • Hypoxia induces ROS production, increasing mutagenesis
100
Q

How do blood vessels produced by angiogenesis and vascular mimicry differ?

A
  • ECs vs cancer cells
  • Defined ECM vs no/little ECM
  • Secure, non-leaky vessels (tight junctions and pericytes) vs leaky vessels with little support
  • Highly regulated through GF signalling vs little/ no regulation
101
Q

Explain how hypoxia may result in tumour production of VEGF. Describe some of the additional consequences of tumour hypoxia

A
  • HIF 1a is degraded in normoxia through hydroxylation
  • Hydroxylation allows VHL binding, adding ubiquitin for proteasomal degradation
  • Under hypoxia VHL is nitrosylated so cant bind HIF, HIF levels increase and bind to promotor of VEGF
  • Increased ROS increase mutagenesis
  • Increased ROS increased TAM activation, supporting cancer growth
  • Hypoxia induces GF signalling that directly causes cancer cell growth
  • Drives EPC recruitment and vascular mimicry, enabling tumour oxygenation and a metastatic route

Y3 Biology Of Cancer (8 decks)

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