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Cellular Pathology > Tumour Angiogenesis ,Invasion and Metastasis > Flashcards

Tumour Angiogenesis ,Invasion and Metastasis Flashcards

1
Q

1.What are the three main characteristics of malignant tumours?

A

Growth: ( unlimited growth as long as adequate blood supply)

Invasivness: Migration of- tumour cells —> surrounding stroma–> Distant Organs ( via vascular or lymphatic channels)

Metastasis: Spread of tumour from primary tumour ->Secondary tumours

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2
Q

2.What is the sequential process of metastasis?

7 steps

A
  1. One clonal cell -> GROWTH
  2. New BLOOD VESSELS surround tumour ( o2 and nutrients)
  3. Cells LOOSE CHARACTERISTICS. (less epithelial and change to become more motile)
  4. INVADE the blood vessels surrounding tumours
  5. AGGREGATION of circulating cells will lodge at distant sites
  6. MOVE OUT of capillary
  7. Aggregate of cells –> Proliferate –> Metastasise –> Cycle Repeats
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3
Q
  1. Fill in the blank:

“Process of cancer metastasis consists of sequential, *** and selective steps with some *** elements.

A

Interlinked

Stochastic

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4
Q
  1. What is the outcome of each stage of metastasis influenced by?
A

interaction of metastatic cellular subpopulations with homeostatic factors

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5
Q
  1. Each step of metastatic cascade is potentially rate limiting, what does this mean?
A

That if a step is not completed effectively, it will have consequences on further steps

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6
Q
  1. What are the 5 key steps in cancer progression?
A
  1. Extensive mutagenic and epigenetic changes followed by clonal selection
  2. To overcome hypoxia –> Angiogenesis
  3. EMT ( epithelial –> mesenchymal transition)= intravasation and extravasation
  4. Micrometastases –> Expand –> Colonisation of target organs
  5. Release of metastatic cells that have ability to colonise
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7
Q
  1. What is the difference between Angiogenesis and Vasculogensis?
A

Angiogenesis = The formation of new blood vessels from pre-existing vessels whereas vasculogenesis is the formation of new blood vessels from new progenitors

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8
Q

8.What are the the three types of Angiogenesis?Give examples of each

A
  1. Developmental/Vasculogenesis (Organ Growth)
  2. Normal Angiogenesis (Wound repair,Placenta during pregnancy , cycling ovary)
  3. Pathological Angiogenesis (Tumour angiogenesis, Ocular and inflammatory disorders)
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9
Q
  1. How does tumour angiogenesis occur?
A
  • > Tumour divides loads before it gets to a capillary
  • > Outgrows existing nutrients
  • > Tumour becomes hypoxic
  • > This is a stimulus for tumour to secrete angiogenic factors (act on nearby capillaries)
  • Nearby capillaries starts to have tip formation in the vessel - they’re own proliferation is upgregulated so new blood vessels form around the tumour
  • > Cells shed off - escape through local blood supply - develop into micro-metastases
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10
Q
  1. What the max size a tumour will grow to without their own blood size due to hypoxia?
A

2mm

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11
Q
  1. What is Angiogenesis promoted by?
A

Hypoxia

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12
Q

12.What is Hypoxia?

A

Low oxygen tension

<1% O2

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13
Q
  1. Fill in the blank:

“ Hypoxia increases with increasing distance **’

A

Capillaries

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14
Q
  1. What does hypoxia activate?
A

Transcription of genes involved in:

  • angiogenesis
  • tumour cell migration
  • metastasis
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15
Q

15.Some tumour cell produce angiogenic factors (stimulate directional growth of endothelial cells)
List 4:

A

-Vascular Endothelial Growth Factor (VEGF)

Fibroblast Growth Factor-2 (FGF-2)

Transforming Growth Factor-β (TGF- β)

Hepatocyte growth factor/scatter factor (HGF/SF)

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16
Q
  1. The following questions refer to angiogenic factors:
    - What are they secreted by?
    - How are they stored?
    - How are they released from storage?
A
  • Secreted by tumour cells
  • Stored bound to components of the extracellular matrix
  • May be released by enzymes called matrix metalloproteinases
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17
Q
  1. Briefly explain the process of Vascular Endothelial growth factor (VEGF) signalling?
A

Cancer becomes hypoxic –> VEGF (GF for blood vessels) secretion out of tumour –> VEGF binds to VEGF receptor in endothelial cells–>Switches on downstream signalling–>Pathways are upgregulated in tumour cels –>Growth of endothelial cells–>Activate PKB/AKT pathway–> Gene transcription switched on–>Vessels become leaky/permeable = allows cells to move between tumour and endothelial cell.

18
Q

18.What are three consequences of tumour cell Motility and Invasion?

A
  1. Increased mechanical pressure ( because of cell prolif)
  2. Increased Motility (EMT)
  3. Increased production of degradative enzymes (by tumour and stromal cells)
19
Q
  1. During the EMT , we have gene down regulation. What does this cause the LOSS of?
A
  • Epithelial Shape
  • Cell Polarity
  • Cytokeratin intermediate filament expression
  • Epithelial Adherence junction protein E-Cadherin
20
Q
  1. During EMT, we have gene up regulation. What do we GAIN from this?
A
  • Fibroblast shape and motility
  • Invasivness
  • Vimentin intermediate filament expression
  • Mesenchymal gene expression
  • Protease Secretion(MMP-2, MMP-9)
21
Q
  1. Give three examples of mesenchymal genes that would be expressed during EMT
A
  • Fibronectin
  • PDGF receptor
  • avbeta6 integrin
22
Q
  1. The following questions are about E-Cadherins:
    - What type of adhesion molecules are they?
    - What do they bind to in cells?
    - What are they dependant on?
    - Do they inhibitor or promote invasivness?
A
  • Homotypic Adhesion molecules (adhesion to cells with same cadherin)
  • Bind to beta-catenin in cells
  • Calcium dependant?
  • Inhibit invasivness
23
Q
  1. How do E-Cadherins inhibit invasiveness?
A

Okay so in a normal cell , there are tight junctions due to the adhesion molecules, when they proliferate they remain as a monolayer of normal cells (with tight junctions between) and so contact inhibition-they arent touching``````

24
Q
  1. When there is a loss of E-Cadherin or a mutation in E-cadherin what would happen to cell-cell adhesion?
A

So when there is a loss of E-cadherin, there is disrupted cell-cell adhesion, rather than having a monolayer of normal cells,the cells grow on top of each other and so there is contact
Therefore contact inhibition is LOST

25
Q
  1. What are integrins?
    - heterotypic or homotypic?
    - what do they bind to? Via what 3 things?
    - What does this allow for?
A

They are cell-matrix heterotypic adhesion molecules , they bind to the extracellular matrix (via collagen, fibronectin and laminin) to allow cell migration

26
Q

26.Are integrins heterodimers or homodimers?Give their subunits

A

Heterodimers with alpha and beta sub units

27
Q
  1. In what way does the stromal cell contribute to tumour progression?
A

The stromal cell releases factors ( eg macrophages, fibroblasts and mast cells) these factors induce :

  • Angiogenic factors
  • Growth Factors
  • Cytokines
  • Proteases
28
Q
  1. Give a specific example of how the stromal cell can contribute to tumour progression?
A

The stromal cell releases uPA (Urokinase-type plasminogen activator), this is activated by tumour cells
-This increases plasmin production and cell movement
-The plasmin production–>Activated matrix metalloproteinases (MMPs)
> MMPs allow invasion by degrading extracellular matrix (ECM) –> releases matrix-bound angiogenic factors

29
Q
  1. List the appropriate site of tumour metastasis for the following cancers:
    - Breast Cancer
    - Colorectal Cancer
    - Pancreatic Cancer
A

Breast Cancer= Brain, lungs, liver

Colorectal Cancer= Lungs

Prostatic Cancer = Arm(bone)

Pancreatic Cancer = Lungs

30
Q
  1. List the steps involved in Cancer Metastasis?
A
  1. Primary tumour formation
  2. Localised Invasion
  3. intravasation ( tumour cell INTO blood vessel)
  4. Transport through circulation
  5. Arrest in microvessels of various organs
  6. Extravasation (Tumour OUT of blood vessel , into target tissue)
  7. Formation Micrometastasis
  8. Formation of Macrometastasis
31
Q
  1. In the process of cancer dissemination, which steps are successful, which are inefficient. USE figures
A

Tumour cells can extravasate successfully (>80%) but the last two steps are very inefficient (<0.02% of cells actually form micrometastases).

32
Q
  1. What are the names of two hypothesis to determine the pattern of tumour spread?
A
  1. Mechanical Hypothesis

2. Seed and soil Hypothesis

33
Q
  1. What is the mechanical hypothesis to what determines the patterns of how tumours spread?
A

Basically it depends on anatomical considerations so whats near the tumour eg blood and lymphatic vessels, it will then get entrapped by capillary beds

34
Q
  1. What is the size of a carcinoma cell in comparison to a capillary?
A

Carcinoma Cell = 20-30um

Capillary = 8um

35
Q

What is the seed and soil hypothesis for what determines the pattern of tumours spread?

A
  • Specific adhesions between tumour cells and endothelial cells in the target organ create a favourable environment in the target organ for colonisation.
  • Genetic alterations acquired during progression allow tumour cells to metastasize.
36
Q
  1. In 1971 Judah Folkman came up with the angiogenesis hypothesis. What is this?
A

Tumour growth dependent on new blood vessel growth

“If a tumor could be held indefinitely in the vascularised dormant state….it is possible that metastases will not arise”

37
Q
  1. There has been a paradigm shift (big change) in cancer therapy. How?
A

Now both the tumour and microvascular compartment are valid therapeutic targets

38
Q
  1. What cancer is highly angiogenic
A

Kidney cancer/renal cell carcinoma

39
Q
  1. How can highly angiogenic tumours be targeted?
A

Highly angiogenic tumours can be targeted by blocking blood vessels of the tumour causing regression to an extent.

40
Q
  1. What is Avastin?

What cancers can it treat?

A

First specific anti-angiogenesis drug
in 2013 was the second biggest selling oncology product
Approved for colorectal, lung, kidney and ovarian cancers and eye diseases

41
Q
  1. What is the mechanism of action of Avastin/Bevacizumb?
A

oAvastin is a monoclonal antibody that binds to VEGF to prevent VEGF binding to receptors on endothelial cells
oThis prevents intracellular phosphorylation of receptor so no dimerisation and therefore no downstream signalling.

Cellular Pathology (13 decks)

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