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๐˜พ๐™š๐™ก๐™ก๐™ช๐™ก๐™–๐™ง ๐™‹๐™–๐™ฉ๐™๐™ค๐™ก๐™ค๐™œ๐™ฎ ๐Ÿงซ COPY COPY > Tumour Angiogenesis, Invasion & Metastasis > Flashcards

Tumour Angiogenesis, Invasion & Metastasis Flashcards

1
Q

What are the 3 main features of Malignant Tumours?

A

โ€œ1. Growth:

  • Unlimited growth.
  • Not self-limited as in benign tumours.
  • As long as an adequate blood supply is available.
  1. Invasiveness:
    - Migration of tumour cells into the surrounding stroma.
    - Where they are free to disseminated via vascular or lymphatic channels to distant organs.
  2. Metastasis:
    - Spread of tumour cells from the primary site.
    - To form secondary tumours at other sites in the body.โ€
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2
Q

Describe the Sequential steps of Metastasis:

A

โ€œ1. Extensive Mutagenic & Epigenetic Changes.
Followed by Clonal Selection.

  1. Angiogenesis:
    - Overcomes limitations imposed by Hypoxia.
  2. Epithelial to Mesenchymal Transition:
    - Invasive properties allowing Intravasation and Extravasation.
  3. Colonisation of Target Organs:
    - Ability to expand from Micrometastases.
  4. Release of Metastatic Cells:
    - That have acquired the ability to colonise.โ€
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3
Q

Angiogenesis:

A

Formation of New Blood Vessels from Pre-existing Vessels.

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4
Q

Vasculogenesis:

A

Formation of New Blood Vessels from Progenitors.

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5
Q

What are the 3 main types of Angiogenesis?

A

โ€œ1. Developmental/Vasculogenesis:
- Organ Growth.

  1. Normal Angiogenesis:
    • Wound Repair
    • Placenta during Pregnancy.
    • Cycling Ovary.
  2. Pathological Angiogenesis:
    • Tumour Angiogenesis
    • Ocular and Inflammatory Disordersโ€
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6
Q

Why is Neovascularisation of Tumours important for their Growth?

A

โ€œTumours will generally not grow beyond the size of 1-2 mm3.

Without their own Blood Supply.โ€

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7
Q

What changes in Invasive Cancer?

A

There is Loss of the Rigid Structure.

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8
Q

How is the Angiogenic Switch Turned On?

A

โ€œ1. Small Tumour is self sustaining as long as it is small.

  1. It becomes Hypoxic when it grows because it grows away from nearby capillaries.
  2. Once it doesnโ€™t have enough nutrients.
  3. The Angiogenic Switch is Turned On. โ€œ
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9
Q

How does the Tumour make New Blood Vessels?

A

โ€œThe tumour secretes Angiogenic Factors.
These are Growth Factors that stimulate new blood vessel growth.
- VEGF is one growth factor released.
- VEGF initiates endothelial cells within the Capillaries to Proliferate and Migrate.
- New vessels start to form from the nearby capillary that develop around the Tumour.
- The Tumour can Escape through the new vessels and Spread.โ€

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10
Q

What is Hypoxia and what are its affects?

A

โ€œ1. Hypoxia is defined as: Low Oxygen Tension <1% O2.

  1. A Strong Stimulus for Tumour Angiogenesis.
  2. Increases with increasing distance from capillaries.
  3. Activates the Transcription of Genes involved in:
    • Angiogenesis
    • Tumour Cell Migration
    • Metastasis.โ€
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11
Q

What do Angiogenic Factors do?

A

Stimulate the Directional Growth of Endothelial Cells.

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12
Q

Where do Angiogenic Factors come from?

A

โ€œ1. Secreted by some Tumour Cells.

  1. Stored bound to components of the Extracellular Matrix.
    May be released by enzymes called Matrix Metalloproteases.โ€
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13
Q

Give Examples of some Angiogenic Factors:

A

โ€œ1. Vascular Endothelial Growth Factor (VEGF).

  1. Fibroblast Growth Factor (FGF-2).
  2. Transforming Growth Factor - ฮฒ (TGF-ฮฒ).
  3. Hepatocyte Growth Factor/Scatter Factor (HGF/SF). โ€œ
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14
Q

What does VEGF bind to?

A

โ€œVEGF Receptor is a Tyrosine Kinase Receptor.

Which Dimerises upon Ligand Binding.โ€

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15
Q

Which pathways does VEGF binding stimulate?

A

โ€œ1. RAS-MEK Pathway.

  1. AKT/PKB Pathway.
  2. PLC Pathway. โ€œ
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16
Q

What are the 3 main Mechanisms of Tumour Cell Motility & Invasion?

A

โ€œ1. Increased Mechanical Pressure
Caused by Rapid Cellular Proliferation

  1. Increased Motility of the Malignant Cells
    Epithelial to Mesenchymal Transition.
  2. Increased Production of Degradative Enzymes.
    By both Tumour Cells and Stromal Cells.โ€
17
Q

What happens in the Epithelial Mesechymal Transition (EMT)?

A

โ€œAn Epithelial Cell switches into a different type and becomes de-differentiated.
It becomes more Motile and Invasive.โ€

18
Q

Which Epithelial Proteins are downregulated to facilitate this Transition?

A

โ€- E - Cadherin.

  • Desmoplakin.
  • Cytokeratin.
  • Cortical Actin.โ€
19
Q

What features are lost after EMT?

A

โ€œ1. Epithelial Cell Shape and Polarity.

  1. Cytokeratin Intermediate Filament Expression.
  2. Epithelial Adherens Junction Protein:
    • (E-cadherin).โ€
20
Q

What pathways are Upregulated that stimulate the Transition?

A

โ€œ1. PI3K/AKT/mTOR Pathway

  1. WNT Pathway
  2. Notch Pathway
  3. TGF - ฮฒ Pathway
  4. Smad Pathwayโ€
21
Q

Which Mesenchymal Proteins are upregulated to facilitate this Transition?

A

โ€- N-cadherin.

  • Vimentin.
  • Fibronectin.
  • Matrix Metalloproteinases (MMPs)โ€
22
Q

What features are acquired after EMT?

A

โ€œ1. Fibroblast like Cell Shape and Motility.

  1. Invasiveness.
  2. Vimentin Intermediate Filament Expression.
  3. Mesenchymal Gene Expression:
    • Fibronectin.
    • PDGF Receptor.
    • ฮฑvฮฒ6 integrin.
  4. Protease Secretion:
    • MMP - 2.
    • MMP - 9.โ€
23
Q

What are the two main Cell Adhesion Molecules?

A

โ€œ1. E-Cadherins

  1. Integrins โ€œ
24
Q

What are E-Cadherins and what do they do?

A

โ€œ1. Homotypic Adhesion Molecule.
- Adhesion of Cells to each other with the same Cadherin.

  1. It is Calcium-Dependent.
  2. Inhibits Invasiveness.
  3. Binds ฮฒ-catenin.
  4. Contact Inhibition:
    - In a Monolayer of Normal Cells.
    - If cells recognise that there is a cell nearby they will stop proliferation. โ€œ
25
Q

What would be a consequence of Mutation/Loss of E-Cadherin?

A

โ€œIf there is a Mutation in or a Loss of E - Cadherin:

  • There would be Distrupted Cell - Cell Adhesion.
  • Due to a Loss of Contact Inhibition.
  • And Cells will start to grow on top of each other.โ€
26
Q

What are Integrins and what do they do?

A 
"1. Heterotypic Adhesion Molecule: 
- Adhesion of Cells to the Extracellular Matrix indirectly binding to the Actin Skeleton of the cell.
- This is via Proteins:
  Collagen.
  Fibronectin.
  Laminin.
  1. Found as Heterodimers:
    - They have Alpha ฮฑ Subunits and Beta ฮฒ Subunits.
  2. These Strong Links to the ECM can facilitate Cell Migration.โ€
27
Q

What are Examples of Stromal Cells?

A

โ€œ1. Macrophages.

  1. Mast Cells.
  2. Fibroblasts.โ€
28
Q

What Factors do Stromal Cells Release?

A

โ€- Angiogenic Factors.

  • Growth Factors.
  • Cytokines.
  • Proteases.โ€
29
Q

How is uPA activated?

A

โ€œUrokinase-Type Plasminogen Activator (uPA):

  • Activated by Tumour Cells.
  • It binds to the Urokinase Receptor (uPAR) and becomes activated.
  • uPA activates Plasminogen and converts it into Plasmin.
  • Resulting in Plasmin production.โ€
30
Q

What does Activated uPA do?

A

Activated uPA activates Plasminogen and converts it into Plasmin.

31
Q

What is Plasmin?

A

Plasmin is a Potent Proteolytic Enzyme.

32
Q

What does the Plasmin Activate?

A

โ€œActivates Matrix Metalloproteinases (MMPs):

  • Which permit invasion by degrading extracellular matrix (ECM).
  • Thus releasing matrix-bound angiogenic factors.โ€
33
Q

Outline the Steps involved in Cancer Dissemination:

A

โ€œ1. Primary Tumour Formation.

  1. Localised Invasion.
  2. Intravasation:
    • Invasion of cancer cells through the basement membrane into a blood/lymphatic vessel.
  3. Transport Through Circulation.
  4. Arrest in Microvessels of Various Organs.
  5. Extravasation:
    • Leakage of Cancer Cells from the blood/lymphatic vessel into the surrounding tissues.
  6. Formation of a Micrometastasis.
  7. Colonisation: Formation of a Macrometastasis.โ€
34
Q

How efficient is the process of Cancer Dissemination:

A

โ€œThe overall process is Highly Inefficient:

  • Tumour Cells can Extravasate successfully (>80%)
  • But the last two steps are very inefficient (<0.02% of cells actually form Micrometastases).โ€
35
Q

What determines the pattern of tumour spread?

A

โ€œMechanical Hypothesis:
- Anatomical Considerations:
Whatever is closeby in terms of blood and lymphatic systems.
More likely to affect closer tissues due to entrapment in capillary beds.

Seed and Soil Hypothesis:

  • Specific adhesions between Tumour Cells and Endothelial Cells in the Target Organ.
  • Creating a favourable environment in the Target Organ for Colonisation.
  • Genetic Alterations acquired during progression allow Tumour Cells to metastasize. โ€œ
36
Q

How successful have therapies targetting each process been?

A

โ€œ1. Tumour Angiogenesis:
- Success with targeted therapy to angiogenic factors like Vascular Endothelial Growth Factor (VEGF).

  1. Cell Motility:
    - No success with targeting Cell-Cell Adhesion Molecules or Integrins
  2. Invasion:
    - All clinical trials with Matrix Metalloproteinases have been unsuccessful in reducing tumour burden!โ€
37
Q

What is the basis of targetting Tumour Angiogenesis?

A

โ€œTumour Growth is dependent on New Blood Vessel Growth.
Both the Tumour and the Microvascular Compartment are Valid Therapeutic Targets.
They can be used for many different types of Cancers.โ€

38
Q

What specific type of Cancer is treated with Anti angiogenic Drugs?

A

Renal Cell Carcinoma which is a Highly Angiogenic and Metastatic Tumour.

39
Q

How does Avastin work?

A

โ€œIt is a Monoclonal Antibody.

  • Binds to VEGF.
  • Prevents VEGF Binding to VEGF receptors on Endothelial Cells.โ€

๐˜พ๐™š๐™ก๐™ก๐™ช๐™ก๐™–๐™ง ๐™‹๐™–๐™ฉ๐™๐™ค๐™ก๐™ค๐™œ๐™ฎ ๐Ÿงซ COPY COPY (13 decks)

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