Tumour Angiogenesis, Invasion and Metastasis Flashcards Preview

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Flashcards in Tumour Angiogenesis, Invasion and Metastasis Deck (33)
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1

What are three characteristics of malignant tumours? 

  • Growth 
  • Invasiveness 
  • Metastasis 

2

Describe growth of malignant tumours 

Growth of malignant tumours (not self limited as benign tumours) as long as an adequate blood supply is present 

3

Describe the invasiveness of malignant tumours? 

Malignant tumours can migrate into the surrounding stroma where they are free to disseminate via vascular or lymphatic channels to distant organs 

4

Describe mestastasis of malignant tumours 

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

5

Describe the sequential process of metastasis 

  1. Transformation (mutagenic and epigenetic changes) of normal cells and starts proliferating 
  2. After cells get to a certain size, tumour angiogenesis is initiated (new blood vessels will migrate and develop around the growing tumour) 
  3. Tumour cells will become motile and invade into capillaries, venules and lymphatic vessels (intravasation) after epithelial-mesenchymal transition spread to other regions/ organs 
  4. In order for them to form micrometastasis, they need to move out of the vessel via extravasation into organ parenchyma 
  5. Will eventually lodge and proliferate/colonise in a distant organ 

6

What is angiogenesis? 

 

The formation of blood vessels from pre-existing vessels 

7

How is vasculogenesis different from angiogenesis? 

 

This is the formation of blood vessels from progenitors (not pre-existing vessels) 

  • This can occur in embryogenesis 

8

List the different types of angiogenesis 

  • Developmental/ vasculogenesis 
    • Organ growth 
  • Normal angiogenesis 
    • Wound repair, placenta during pregnancy, cycling ovary 
  • Pathological angiogenesis 
    • Tumours, ocular and inflammatory disorders 

9

Explain how angiogenesis is triggered? 

  • Tumours will generally not grow beyond a size of 1-2mm3 without their own blood supply
  • This is because they will become hypoxic hence the blood vessel density will be increased to support further growth 

10

What will stimulate tumour angiogenesis? 

HYPOXIA will activate transcription of genes involved in angiogenesis, tumour cell migration and metastasis  

11

Describe the process of tumour angiogenesis? 

  1. Tumour is at first small and self-sustaining 
  2. Tumour will become hypoxic when it reaches a certain size and starts to secrete angiogenic growth factors e.g VEGF
  3. Angiogenic growth factors will initiate endothelial cells within nearby capillaries to proliferate and migrate 
  4. When enough endothelial cells are being stimulated new vessels will form from the nearby capillary and develop around the tumour 
  5. This will allow the tumour to grow in different angles 
  6. Cells can also escape from primary tumours through vascular network to other regions of the body = METASTATIC SPREAD 

12

List some tumour angiogenic factors 

 

Some tumour cells will produce factors following hypoxia resulting in transcription of certain genes for angiogenesis 

  • Vascular Endothelial Growth Factor (VEGF)
  • Fibroblast Growth Factor-2 (FGF-2)
  • Transforming Growth Factor-β (TGF- β)
  • Hepatocyte growth factor/scatter factor (HGF/SF)

13

Describe the fate of angiogenic tumour factors 

  1. They will be secreted by tumour cells 
    1. VEGF will act on receptors within the endothelial cells of the capillary 
    2. Causes a sprout to be initiated from the capillary network 
  2. Stored bound to components of the extracellular matrix and may be released by enzymes called matrix metalloproteinases 

14

In what type of signalling is VEGF (vascular endothelial growth factor) involved in? 

The VEGF receptor is a tyrosine kinase receptor which will dimerise upon ligand binding and activate a number of pathways including 

  • Ras/Raf/MEK pathway 
  • PI3 kinase/AKT pathway 
  • PLC pathway 

15

How can tumour cells become motile and start invasion? 

In order for tumour cells to mestastasize they need to start invading, this is carried out by

  • Increased mechanical pressure caused by rapid cellular proliferation 
  • Increased motillity of malignant cells (epithelial → mesenchymal transition) 
  • Increased production of degradative enzymes by both tumour cells and stromal cells 

16

Describe the epithelial → mesenchymal cell transition 

  • For transition into a mesenchymal cells the genes that make an epithelial cell become downregulated 
    • Epithelial cells will lose cell-cell adhesion molecules (E-cadherin) 
    • Lose epithelial shape and cell polarity 
    • Cytokeratin intermediate filament expression 
  • Cell signalling pathways are also upregulated with cause them to become more motile 
    • PI3K/Akt signalling, Wnt pathway 
    • The phenotype of the cell starts to change and transition allows the cell to become more motile and invade 

17

What is lost in the epithelial-mesenchymal transition? 

Loss of 

  • Epithelial shape and cell polarity 
  • Cytokeratin intermediate filament expression 
  • Epithelial adherens junction protein (E-cadherins) 

18

What is gained in epithelial-mesenchymal transition? 

Acquisition of 

  • Fibroblast-like shape and motility 
  • Invasiveness 
  • Vimentin intermediate filament expression 
  • Mesenchymal gene expression (fibronectin, PDGF receptor, avb6 integrin) 
  • Protease secretion (MMP-2, MMP-9) 

19

What are E-cadherins? 

Homotypic adhesion molecules 

20

What is E-cadherin dependant on? 

Calcium

21

What is the function of E-cadherins? 

It will bind to beta-catenin and inhibit invasiveness 

  • Hence it is lost in downregulated cancer cells during epithelial to mesenchymal transition 
  • Important in contact inhibition 

22

What important role does E-cadherin play in the downregulation of cancer cells? 

Facillitate in a process called CONTACT INHIBITION 

  • Occurs when cells come into contact with one another and stop proliferating 

23

What are integrins? 

  • Transmembrane receptor adhesion molecules acquired in cancer cells 
  • (α and β subunits)
  • Integrins will adhere to your extracellular matrix via 
    • Collagen, fibronectin and laminin 

24

What is the role of integrins? 

CELL MIGRATION 

  • Alpha and beta adhesion molecules will bind to extracellular matrix and signal into the cell 
  • The cell can acquire some invasive properties and gets more adhesive moving through the matrix 

25

What are stromal cells? What do they release? 

Macrophages, Fibroblasts, Endothelial cells, Adipocytes 

  • Will form the environment that stem cells are sitting in and surround cancer cells 
  • Will release angiogenic factors, growth factors, cytokines, proteases 
    • uPA activated by tumour cells = plasmin production 

26

What is the significance of plasmin in tumour progression? 

Plasmin will activate matrix metalloproteinases (MMPs) which will permit invasion by degrading extracellular matrix-bound angiogenic factors 

27

What is the role of urokinase-type plasminogen activator (uPA)? 

  • This will result in plasmin production 
  • Plasmin activates MMPs (matrix metalloproteinases) which permits invasion by degrading ECM bound angiogenic factors 

28

What is the activity of uPA? 

  1. Stromal cells will release inactive pro-uPA 
  2. Pro-uPA binds to receptor on cancer cell which activates it 
  3. Active uPA will convert plasminogen to plasmin 
  4. Plasmin is a proteolytic enzyme important for fibrin dissolution and mediating cell migration 
  5. Plasmin can activate pro-MMPs to active MMPs to facilitate ECM degradation 

29

What are the steps involved in cancer dissemination?

(Cancer which has spread from the site of original growth to a secondary site) 

  • The process is highly inefficient 
  • Tumour cells can extravasate succesfully (>80%) but the last two steps are very inefficient (<0.02% of cells actually form micrometastasis) 

30

What will determine the pattern of tumour spread? 

What are the two hypotheses? 

  1. MECHANICAL HYPOTHESIS 
    1. Anatomical considerations: blood and lymphatic systems, entrapment in capillary beds (20-30um carcinoma cells, -8um capillary) 
  2. SOIL AND SEED HYPOTHESIS 
    1. There are specific adhesions between tumour and endothelial cells in the target organ creating a favorable environment in target organ for colonisation 

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