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MBD > Tumour Angiogenesis, Invasion And Metastasis > Flashcards

Tumour Angiogenesis, Invasion And Metastasis Flashcards

1
Q

What are the characteristics of malignant tumours?

A
  • Growth
  • Invasiveness
  • Metastasis
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2
Q

What is the growth potential of a malignant tumour?

A

Unlimited as long as adequate blood supply is available

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3
Q

What is a malignant tumour? How does it differ to a benign cancer?

A

Malignant tumour has unlimited growth potential

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4
Q

What is the invasiveness characteristic of a malignant tumour?

A

Migration of tumour cells into the surrounding stroma (ECM) where they are free to disseminate via the circulatory or lymphatic system to metastasise

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5
Q

What is the metastatic characteristic of a malignant tumour?

A

Spread of tumour cells from the primary site to form secondary tumours at other sites in the body

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6
Q

What are the key steps in cancer progression?

A
  1. Transformation
  2. Angiogenesis
  3. Motility and invasion
  4. Metastasis
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7
Q

What is transformation of a cancer?

A

Extensive mutagenic and epigenetic changes followed by clonal selection

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8
Q

Define exactly what angiogenesis is

A

Formation of new blood vessels from pre-existing capillaries

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9
Q

Why do tumours undergo angiogenesis?

A

As it grows it will be limited by hypoxia - angiogenesis overcomes this

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10
Q

What is vasculogenesis?

A

This is the formation of a primitive vascular network (so new blood vessels) from progenitor cells, so can be thought of as a step before angiogenesis

  • usually only in organ growth during development
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11
Q

What are the types of angiogenesis?

A
  • Developmental (vasculogenesis)
  • Normal angiogenesis
  • Pathological angiogenesis
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12
Q

What is pathological angiogenesis?

A
  • Tumour angiogenesis
  • Seen in ocular and inflammatory disorders
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13
Q

When does normal angiogenesis occur?

A
  • Wound repair
  • Placenta during pregnancy
  • Cycling ovary
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14
Q

Roughly how big (mm3) does a tumour not grow further than without its own blood supply?

A

1-2mm3 without their own organ blood supply

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15
Q

What type of molecules are angiogenic factors - describe their properties?

A
  • Cytokines and proteins
  • Are growth factors that allow for vascular endothelial cell growth and are also chemotactic (meaning that cells grow towards them)
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16
Q

What is meant by the angiogenic switch of the tumour?

A

This is where a stimulus causes an upregulation of angiogenic factor and their secretion

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17
Q

What are the steps in tumour angiogenesis?

A
  • Small tumour gets big enough to need its own blood supply
  • Tumour switches on expression of angiogenic genes/factors
  • New blood vessels grow in and around the tumour, increasing the delivery of oxygen
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18
Q

Name the stimulus that causes the turning on of the angiogenic switch (what is it that causes a tumour to suddenly express angiogenic factors?)

A
  • Hypoxia! (below 1% oxygen tension)
  • Increases with growing distance from the capillaries.
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19
Q

Explain how this stimulus causes angiogenesis

A

Hypoxia in the cells farthest away from the blood supply will cause activation of transcription of genes involved in angiogenesis, cell migration and metastasis

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20
Q

What 4 genes are involved in angiogenesis?

A
  • VEGF: Vascular endothelial growth (most important)
  • GLUT-1: Glucose transporter 1
  • u-PAR: Urokinase plasminogen activator receptor
  • PAI-1: Plasminogen activator inhibitor 1
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21
Q

Why is the one of these genes upregulated by a glucose transporter?

A

As hypoxic cells need a high glucose uptake to sustain themselves by non-oxidative phosphorylation

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22
Q

What does plasminogen activator 1 cause?

A

Invasion and metastasis

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23
Q

What factors stimulate the directional growth of endothelial cells (angiogenic factors)?

A
  • Vascular endothelial growth factor (VEGF)
  • Fibroblast growth factor 2 (FGF2)
  • Placental growth factor (PIGF)
  • Angiopoetin 2 (Ang2)
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24
Q

What is the role of matrix metalloproteases in this mechanism of angiogenesis?

A

Angiogenic factors are secreted by tumour cells or are stored bound to components of the ECM and may be released by matrix metalloproteases

  • MMPs have a role in allowing for invasion of blood vessels into the ECM
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25
What are the angiogenic factors secreted by?
Tumour cells or components of the extracellular matrix
26
What receptor does VEGF bind to on endothelial cells, what type of receptor is it?
VEGF-R2 (one of a few in a family) * **Tyrosine kinase**
27
Explain what happens when VEGF binds to its receptor here
VEGF-R2 dimerises at the membrane and recruits cofactors that subsequently activate 3 major signal transduction pathways
28
Name the 3 major signal transduction pathways that this binding of VEGF uses
* Phospholipase gamma! * Protein kinase B * Ras
29
Describe what the 3 pathways (binding of VEGF uses) achieve for the endothelial cell which ultimately lead to angiogenesis
* Cell survival * Vascular permeability * Gene expression * Cell proliferation
30
Which of the signalling pathways is especially important in promoting cell survival?
Protein kinase B
31
Explain what is meant by the epithelial-mesenchymal transition of the malignant cells
This is a phenotypic switch where the cells lose the epithelial shape and properties and become a fibroblast-like cell
32
Describe the properties of the cells that are lost in this switch? Also **name some epithelial markers that are lost**
Loss of: * epithelial shape and polarity * Cytokeratin intermediate filament expression * Epithelial adherens junction position
33
Describe the properties of what the cells become in this switch and some mesenchymal cell markers
Become fibroblast like in terms of shape and motility * increased invasiveness * express vimentin intermediate filaments * protease secretion (MMP2 and MMP9) * other mesenchymal gene expression (fibronectin, PDGF receptor ...)
34
Describe the differences in shape of these two cells (endothelial cells vs fibroblasts)in culture
Endothelial cells form a nice monolayer of closely associated cells but fibroblasts are long cells that are very motile
35
What proteases are secreted in the epithelial-mesenchymal transition?
MMP-2 and MMP-9
36
What causes the loss of epithelial shape and cell polarity in the epithelial-mesenchymal transition?
Beta-catenin and cloudin-1
37
What is the function of E-Cadherins?
Adhesion of epithelial cells with the same cadherin - loss of E-cadherin or loss of function causes cells to grow on top of each other instead of in a monolayer * allow for maintenance of normal epithelial cell polarity ![]()
38
What causes the loss of epithelial adherens junction position in the epithelial-mesenchymal transition?
E-cadherin
39
What increases the gain of mesenchymal gene expression in the epithelial-mesenchymal transition?
Fibronectin, PDGF receptor, alpha 5 beta 6 integrin
40
What are E-cadherins?
Homotypic adhesion molecules
41
What are E-cadherins dependant on?
Calcium
42
What do E-cadherins inhibit?
Invasiveness
43
What does E-cadherin bind to?
Beta-katenin
44
What is meant by epithelial cell contact inhibition?
* Once epithelial cells are in contact with other epithelial cells with the use of cell-cell adhesion molecules such as E-cadherin, they inhibit migration and proliferation of each other. * So at low density, the cells proliferate until higher density when they inhibit proliferation and motility.
45
If there is loss of E-cadherin in a cancerous cell (from E-M transition) the cell becomes mote motile but what is released by the cell to increase invasiveness?
Release of enzymes like matrix metalloproteases
46
What forms a tumour mass?
When E-cadherin is lost in tumours, so you loose contact inhibition and cells grow on top of each other and proliferate
47
What factors are released by stromal cells?
Angiogenic factors, growth factors, cytokines and proteases
48
Give an example of a molecule released by stromal cells in this process
uPA - urokinase type plasminogen activator
49
Explain the effect of this molecule (uPA) on cancer cells
* uPA will bind to receptor on cancer cells and will result in plasmin production FROM PLASMINOGEN * uPA is not to be confused with tissue plasminogen activator in the blood system
50
What does plasmin activate?
Matrix metalloproteases
51
What do matrix metalloproteases do?
* Degrade extracellular matrix * → Release matrix-bound angiogenic factors → increased invasiveness
52
What is an example of a matrix bound angiogenic factor?
Transforming growth factor-beta1
53
Describe the efficiency of the various steps in cancer metastasis
* The first step of cancer cells moving into the blood is around 80% efficient * But the last two steps (formation of a micrometastasis and a macrometastasis) is very inefficient (less than 0.02%)
54
What are the hypotheses for pattern of tumour spread?
* Mechanical hypothesis * Seed and soil hypothesis * Genetic alterations acquired during disease progression
55
Describe the mechanical hypothesis for why specific cancer sites metastasise in specific organs more regularly than expected
Anatomical considerations like blood and lymphatic systems and entrapment in capillary beds
56
Describe the seed and soil hypothesis for why specific cancer sites metastasise in specific organs more regularly than expected
Specific adhesions between tumour cells and endothelial cells in the target organ, creating a favourable environment in the target organ for colonisation
57
What tumour processes can be targeted to inhibit cancer?
* Tumour angiogenesis * Cell motility * Invasion
58
Have we had any success in targeting cell motility (cell-cell adhesion molecules)? What about invasion (matrix metalloproteases)?
No to both
59
Explain the angiogenesis hypothesis
If we were to be able to keep a tumour indefinitely in the non-vascularised, dormant state, then it is possible that we can keep it from metastasising * both the tumour **and the microvascular compartment** are valid therapeutic targets
60
Name an example of a cancer that is highly angiogenic
* Kidney cancer (renal cell carcinoma) * This helped us to understand the biology of how VEGF is involved in driving angiogenesis and was successfully treated to inhibit angiogenesis
61
What is avastin?
Monoclonal antibody drug that targets anti-angiogenesis
62
What types of cancer is avastin approved for?
* Colorectal, lung, kidney, ovarian
63
How does avastin work?
* Binds to VEGF and prevents it from binding to VEGF receptors on endothelial cells * not a cure but reduces tumour burden
64
What are the common sites of metastasis for breast cancer?
* Lung * Liver * Brain * Bone
65
What are the common sites of metastasis for colorectal cancer?
* Liver * lung
66
What are the common sites of metastasis for stomach cancer?
* Oesophagus * Liver * Lung
67
What are the common sites of metastasis for lung cancer (non small-cell)?
* Adrenal gland * Liver * Bone * Brain
68
What are the common sites of metastasis for pancreatic cancer?
* Liver * Lung
69
What are the common sites of metastasis for prostate cancer?
Bone

MBD (23 decks)

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