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Cancer Biology > Invasion and Metastasis > Flashcards

Invasion and Metastasis Flashcards

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1
Q

What is TGF-beta?

A

A potent tumour promoter

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2
Q

What does TGF-beta promote?

A

Intravasation
Extravasation
Invasion
Metastatic colonisation

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3
Q

What is metastasis?

A

Where a tumour cell leaves the primary tumour and travels to a distant site via the blood stream and establishes a secondary tumour

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4
Q

How many cancer related mortalities does metastasis account for?

A

~90%

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5
Q

What are the common distal sites for breast adenocarcinoma?

A

Bone
Brain
Adrenal

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6
Q

What are the two theories for organ selectivity?

A

Mechanistic theory

Seed and soil theory

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7
Q

What is the mechanistic theory?

A

Determined by the pattern of blood flow

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8
Q

What is the seed and soil theory?

A

Provision of a fertile environment which compatible tumour cells could grow

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9
Q

What are the determining factors of metastasis?

A

Appropriate growth factors or extracellular matrix environment
Compatible adhesion sites on the endothelial lumen surface
Selective chemotaxis - soluble attraction to bring the tumour in

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10
Q

What are the 5 steps of metastasis?

A

1) invasion and infiltration of surrounding host tissue
2) release of neoplastic cells (single cells or small clumps) into the circulation
3) Survival in the circulation
4) Arrest in the capillary bed of distant organs
5) Penetration of the lymphatic or blood vessel walls followed by growth of disseminated tumour cells

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11
Q

How are the blood vessels in tumours different from normal blood vessels?

A

They have different adhesion junctions so they are often leaky, allowing tumour cells to enter the blood stream easier

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12
Q

What is intravasation?

A

Leaving the tumour tissue into the blood stream

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13
Q

What is extravasation?

A

Moving from the blood stream into the tissue

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14
Q

Why is the liver and bones easier to migrate to?

A

They have a natural fenestrated epithelium, meaning they have natural gaps for the lymphocytes to enter and leave the bone marrow and liver

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15
Q

What are the 3 phases of invasion?

A

1) Translocation of cells across extracellular matrix barriers
2) Lysis of matrix proteins by specific proteinases
3) Cell migration

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16
Q

How do cells respond to a chemotactic que?

A

Sticks out an lallelopodium
Makes new attachments to pull itself towards the lallepodium
Lets go of the back so it can move forward without stretching

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17
Q

What is a transwell invasion system?

A

Mimic the basement membrane to see which tumour cells get through
Put the tumour on top of the basement membrane and add a chemotactic que at the bottom to see if they can get through

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18
Q

How do you mimic the basement membrane?

A

Produce a fibrillar collagen and matrigel mix

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19
Q

What is incucyte zoom?

A

Real-time imaging of migration and invasion

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20
Q

How much does incucyte zoom cost?

A

£120,000

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21
Q

In breast cancer, what gene is required for invasion?

A

CSF2

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22
Q

In terms of CSF2, what is the issue in breast cancer?

A

Patients are given CSF2 to prevent other side effects but is evoking metastasis

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23
Q

How have assays been developed to investigate intravasation and extravasation?

A

Put an endothelial layer underneath the basement membrane

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24
Q

What is amoeboid invasion?

A

Move through the membrane, not by eating it, by pushing their way through the fibres of collagen

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25
Q

What is mesenchymal invasion?

A

Going through the extracellular matrix

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26
Q

What is matrix degrading enzymes required for?

A

Controlled degradation of components of the extracellular matrix

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27
Q

What are proteases are involved in degradation the ECM classified into?

A

serine-, cysteine-, aspartyl-, and metalloproteases

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28
Q

How many members of matrix metalloproteases are there?

A

16

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29
Q

How many subgroups of matrix metalloproteases are there?

A

4

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30
Q

What matrix metalloproteases are soluble and secreted?

A

Collagenase
Gelatinase
Stromelysins

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31
Q

What matrix metalloproteases are membrane-type? And what are these?

A

Invadapodia

They are anchored into the plasma membrane

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32
Q

What matrix metalloproteases cleave type IV collagen of the basement membrane?

A

MMP2 and MMP9

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33
Q

What is collective invasion?

A

Tumours made up of tumour cells and other cells and move together

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34
Q

Name a cancer type which fibroblasts are important for invasion?

A

Squamous cell carcinoma

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35
Q

How do squamous cell carcinomas migrate?

A

Via collective invasion

36
Q

What GTPase effects tumour cell migration and how?

A

RhoGTPases

Through changing their cytoskeletal structure

37
Q

Describe lamellipodia

A

High Rac activity

Polymerisation of the actin cytoskeleton and forms the F-actin which pushes the membrane forward

38
Q

Describe filopodia

A

High CDC42 activity

F-actin filaments make fine protutions in the membrane and this’ll push the activity

39
Q

Describe invadopia

A

High CDC42 activity
Still has filopodia
Positions the matrix metalloproteases at the end of the membrane and degrades the matrix

40
Q

Describe membrane blebs

A

High RhoA activity
Pushes your way through the fibres
Pulls the membrane apart and allows the interstitial pressure to push the membrane up

41
Q

What is EMT?

A

Changing from a more epithelial phenotype to a more mesenchymal phenotype

42
Q

How does EMT occur?

A

Dissolve the hemidesmosomes which epithelial cells are attached to the plasma membrane by
Downregulate tight junctions and adhesion junctions such as E cadherin - switch to N cadherin
Lose basal polarity through downregulating polarity proteins including Crumbs, PATJ and LGL
Increase plasticity
Increase MMP

43
Q

How is E cadherin downregulated?

A

Upregulate transcriptional repressors, ZEB, Snail and/or slug and Twist1 -> bind to E cadherin promoter -> downregulate it

44
Q

How is ZED1, TWIST and SNAIL upregulated?

A

TGF-beta activates SMAD -> SMAD translocates to the nucleus -> SMAD binds to their promoters -> increased transcription

45
Q

What signalling pathway does cytokine receptors stimulate?

A

JAK/STAT

46
Q

How does WNT signalling promoter migration?

A

Produce beta-catenin -> increased EMT

47
Q

How do integrins induce EMT?

A

Through interacting with the ECM

48
Q

How does hypoxia induce EMT?

A

Induce HIF-1alpha -> interact with Notch intracellular domain -> upregulate TGF-beta expression -> SMAD pathway

49
Q

How do tumour-associated fibroblasts induce EMT?

A

Make TGF-beta and IL-6 -> push EMT forward

50
Q

How do tumour-associated macrophages induce EMT?

A

Make TGF-beta and cytokines

51
Q

How do myeloid derived suppressor cells induce EMT?

A

make TGF-beta and EGF

52
Q

Effect of CD4 T cells on migration?

A

Promote EMT

53
Q

Effect of CD8 T cells on migration?

A

block EMT but tumour cells can manipulate them to induce EMT through changing their behaviour

54
Q

How do Tregs induce EMT?

A

Produce TGF-beta

55
Q

Why is the point nature of tumour cells important in migration?

A

When they get into the blood stream, important in making sure they can withstand the severity of the blood flow

56
Q

Why is EMT important?

A

Promotes a cancer stem cell-like phenotype
Produces survival signals to avoid anoikis
Increasing drug resistance

57
Q

How does EMT modulate the immune response?

A

Downregulate HLA molecules so it doesn’t present as many antigens
Increased checkpoint molecules
Promote Treg differentiation instead of CD4’s and CD8’s
M2 phenotype macrophages (tumour-promoting phenotype)

58
Q

What part of EMT modules the immune response?

A

The production of TGF-beta

59
Q

How can macrophages be tumour-promoting?

A

They guide tumour cells in the process of intravasation since they naturally move in and out of the circulatory and lymphatic system

60
Q

How do tumour cells interact with platelets?

A

Via platelet adhesion receptors and their ligands

61
Q

How do tumour cells induce platelet activation?

A

Through tumour-induced platelet aggregation

62
Q

What effect does activated platelets and platelet microparticles have on tumour cells?

A

Produce growth factors such as VEGF, insulin-like growth factor, platelet derived growth factor and TGF-beta1
Promotes angiogenesis and tumour growth

63
Q

Why do platelets express so much TGF-beta?

A

Since TGF-beta is involved in wound healing

64
Q

What stages of metastasis do platelets aid?

A

Intravasation and extravasation

65
Q

How do platelets help tumour cells move throughout the blood stream?

A

Single tumour cells can roll on the endothelium with the aid of platelet P-selectin to prevent sheer force damage
Platelet tumour aggregates circulate in the blood stream with the tumour cells shielded by platelets, which release growth factors to inhibit NK cells

66
Q

How do platelets aid with extravasation?

A

Due to clot formation abilities

TGF-beta helps paracellular extravasation

67
Q

How does TGF-beta promote metastasis to the lung from a breast tumour?

A

Upregulates ANGPTL4 -> loosens epithelial junctions in the lung endothelium
Induces Id1 -> drives tumour reinitiation

68
Q

How does TGF-beta promote metastasis to the bone from a breast tumour?

A

TGF-beta activates osteoclasts -> osteoclasts degrade the bone matrix -> releases more TGF-beta -> stimulate PTHrP and IL-11 -> stimulate oestblasts -> release RANKL to mobilise osteoclasts

69
Q

What can ID-1 induce?

A

Tumour reinitiation

Stem cell-like phenotype

70
Q

Why to osteoclasts need to be activated for metastasis?

A

there is no room in the bond for tumours to metastasis too unless some is eaten

71
Q

How do tumours make microenvironments before they migrate?

A

They produce exosomes which bud off and are full of proteases, microRNA etc. to a pre-metastatic niche and release growth factors, chemokines etc.

72
Q

What kind of niche are glioblastoma cells in?

A

Perivascular niche

73
Q

What is a perivascular niche?

A

Where the tumour cells attach at the top of the epithelium

74
Q

What is a ad hoc niche?

A

Coordination between the tumour cells, myeloid cells and fibroblasts
Make moelcules which will make a supportive extracellular environment and provides survival signals for the tumour cells

75
Q

What is a native stem cell niche?

A

the normal stem cell provides a stem cell environment for the cancer cell to invade

76
Q

How are cadherin junctions loosened in the lung?

A

Exosomes release GLIO105 which downregulates ZO1
Release of chemokines will produce more chemokines and activate monocytes which will stimulate VEGF to losen the junctions

77
Q

How do alveloar cells support the production of the pre-metastatic niche in the lungs?

A

They produce chemokines which release neutrophils - act as a chemoattractant signal

78
Q

How long can clinical dormancy last in breast cancer?

A

10 years

79
Q

How are dormant cells reactivated?

A

Growth factor stimulation
Activation of self renewal stem cell transcription factors
MET

80
Q

What are three approaches being investigated for dormant cells?

A

Keep them dormant since they aren’t doing any harm
Turn the dormant cells on so they can be targeted for chemotherapy
Kill the dormant cells

81
Q

What is the issue with keeping the dormant cells?

A

They could eventually stop being dormant

82
Q

What is the issue with turning the dormant cells on?

A

They could be more aggressive so chemotherapy doesn’t work

83
Q

What is the issue with killing dormant cells?

A

Do not know what is keeping them dormant, need to know this to be able to target it

84
Q

What is being diagnosed with lymph node positive associated with?

A

Worse prognosis

Indicates the tumour cells are moving

85
Q

Why do most cells spread via the lymphatic instead of the blood?

A

The lymphatics has a fenestrated membrane so it is easier for the tumour cells

86
Q

How can tumour cells and their associated macrophages manipulate the lymph system?

A

They can induce lymph angiogenesis (enlargement of the lymph nodes) - those which are closest to the tumour are enlarged
Could allow them to access the circulatory system

Cancer Biology (13 decks)

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