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Cellular Pathology > Tumour Angiogenesis, Invasion & Metastasis > Flashcards

Tumour Angiogenesis, Invasion & Metastasis Flashcards

1
Q

Describe the growth of malignant tumours

A

Unlimited growth (not self-limited as in benign tumours) - as long as an adequate blood supply is available

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2
Q

Outline the invasiveness of malignant tumours

A

Migration of tumour cells into the surrounding stroma where they are free to disseminate via vascular or lymphatic channels to distant organs

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3
Q

What is metastasis?

A

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

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4
Q

What is involved in cancer metastasis?

A

Cancer metastasis consists of sequential, interlinked, and selective steps with some stochastic elements

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5
Q

Describe the influence of each metastatic cascade step in cancer

A

Each step is potentially rate limiting; failure of tumor cell completing any step effectively impedes that portion of the process

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6
Q

Outline the key steps of cancer progression

A
  1. Extensive mutagenic and epigenetic changes followed
    by clonal selection
  2. Angiogenesis (overcomes limitations imposed by
    hypoxia)
  3. Epithelial -> mesenchymal transition (invasive properties
    allowing intravasation and extravasation)
  4. Colonisation of target organs (ability to expand from
    micrometastases)
  5. Release of metastatic cells that acquire ability to
    colonise
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7
Q

What is angiogenesis?

A

Angiogenesis is the formation of new blood vessels from pre-existing vessels

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8
Q

What is vasculogenesis?

A

Vasculogenesis is the formation of new blood vessels from progenitors

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9
Q

What is the role of developmental vasculogenesi?

A

organ growth

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10
Q

What is the function of normal angiogenesis?

A
  • wound repair
  • placenta during pregnancy
  • cycling ovary
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11
Q

What is the consequence of tumour angiogenesis?

A

tumour angiogenesis

ocular and inflammatory disorders

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12
Q

How long can tumours survive without a blood supply?

A

Tumours will generally not grow beyond a size of about 1-2mm3 without their own blood supply before they become hypoxic

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13
Q

Describe a tumour in situ (beningn)

A

Cancers in situ remain differentiated

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14
Q

Describe the structure of an invasive cancer

A

Invasive cancers have a loss of their rigid structure and have an increase in blood vessel density within the tumour

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15
Q

Outline the stimulus of tumour angiogenic factor release

A
  1. Small tumour (not yet 1-2mm^3) is self sustaining
  2. Tumour become hypoxic as when it grows, areas of
    tissue move away from nearest capillary
  3. Angiogenic switch occurs stimulating production of
    vascular growth factors e.g. (VEGF)
  4. VEGF diffuses out as it’s a cytokine, to initiate
    endothelial cells in nearby capillaries to proliferate and
    form vessels around the tumour
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16
Q

Describe the role of hypoxia in tumour angiogenesis

A

Hypoxia is a strong stimulus for tumour angiogenesis

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17
Q

What is hypoxia?

A

Hypoxia – low oxygen tension <1% O2

Increases with increasing distance from capillaries

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18
Q

What is the consequence of hypoxia?

A

Activates transcription of genes involved in angiogenesis, tumour cell migration and metastasis

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19
Q

What are angiogenic factors?

A

Some tumour cells produce factors that stimulate the directional growth of endothelial cells

20
Q

Name some angiogenic factors

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)

21
Q

How are angiogenic factors stored and released?

A

These factors are secreted by tumour cells or are stored bound to components of the extracellular matrix and may be released by enzymes called matrix metalloproteinases

22
Q

Outline the process of tumour angiogenesis

A
  1. Tumour releases VEGF; acts on receptors within capillary
    endothelial cells
  2. Endothelial cells begin proliferating causing sprouts of
    new vessels surrounding the tumour
  3. Other factors FGF-2, PGF and matrix metalloproteinases
    (MMPs) which are enzymes that facilitate invasion
  4. In order for sprouting vessels to invade the ECM and
    migrate they require enzymatic capacity mediated by
    the upregulation of MMPs
23
Q

Describe the structure of VEGFR

A

VEGFR is a tyrosine-kinase receptor that dimerises upon ligand binding

24
Q

What is the effect of VEGF binding?

A

Activate RAS/MEK, AKT, PKB and PKC pathways

Ca2+ release and endothelial cell proliferation is also induced by VEGF binding

25
Q

What are the requirements for metastasis to occur?

A
  • Increased mechanical pressure caused by rapid cellular
    proliferation
  • Increased motility of the malignant cells (epithelial to
    mesenchymal transition)
  • Increased production of degradative enzymes by both
    tumour cells and stromal cells
26
Q

What is lost during epithelial-mesenchymal transition?

A

Loss of

  • Epithelial shape and cell polarity
  • Cytokeratin intermediate filament expression
  • Epithelial adherens junction protein (E-cadherin)
27
Q

What is acquired during epithelial-mesenchymal transition?

A

Acquisition of

  • Fibroblast-like shape and motility
  • Invasiveness
  • Vimentin intermediate filament expression
  • Mesenchymal gene expression (fibronectin, PDGF receptor, αvβ6 integrin)
  • Protease secretion (MMP-2, MMP-9)
28
Q

What are the 2 crucial cell adhesion molecules affected during epithelial-mesenchymal transition

A
  • E-cadherins

- Integrins

29
Q

Outline the effect of E-M transition on E-cadherins

A 
E-Cadherins (downregulated)
- Homotypic adhesion molecule (adhesion of cells with the 
  same cadherin)
- Calcium-dependent
- Inhibits invasiveness
- Binds β-catenin
30
Q

What is the effect of E-M transition on integrins?

A 
Integrins (upregulation)
- Heterodimers (α and β subunits)
- Heterotypic adhesion molecule
- Adhesion to extracellular matrix 
  (via collagen, fibronectin, laminin)
- Cell migration
31
Q

What are the angiogenic factors released by stromal cells?

A

Factors released by stromal cells (macrophages, mast cells, fibroblasts) include angiogenic factors, growth factors, cytokines, proteases

32
Q

Name an example of angiogenic factor released by stromal cells

A

Urokinase-type plasminogen activator (uPA); activated by tumour cells - resulting in plasmin production

33
Q

What is the effect of plasmin production on cell invasion?

A

Plasmin activates matrix metalloproteinases (MMPs), which permit invasion by degrading extracellular matrix (ECM) thus releasing matrix-bound angiogenic factors

34
Q

How efficient is metastasis?

A

The 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)

35
Q

What are common sites of metastasis?

A

Lung and brain are common sites of primary tumour metastases

36
Q

What is the mechanical hypothesis of tumour spread pattern?

A

Anatomical considerations: Blood and lymphatic systems, entrapment in capillary beds (20-30µm carcinoma cell, ~8µm capillary)

37
Q

What is the seed and soil hypothesis of metastasis?

A

Specific adhesions between tumour cells and endothelial cells in target organ, create favourable environment in target organ for colonisation

Genetic alterations acquired during progression allow tumour cells to metastasize

38
Q

How is tumour angiogenesis inhibited using treatments?

A

Success with targeted therapy to angiogenic factors like vascular endothelial growth factor

39
Q

How successfully is cell motility targeted in cancer prevention?

A

No success with targeting cell-cell adhesion molecules or integrins

40
Q

What is Judah Folkmans hypothesis on tumour growth?

A

Tumour growth dependent on new blood vessel growth
“If a tumor could be held indefinitely in the non-vascularized dormant state….it is possible that metastases will not arise”

41
Q

What is the significance of Folkmans hypothesis?

A

Paradigm shift in cancer therapy

Both the tumour and microvascular compartment are valid therapeutic targets

42
Q

What is a common pathological angiogenesis?

A

Kidney cancer/renal cell carcinoma is a highly angiogenic and metastatic tumour

43
Q

What is avastin?

A

First specific anti-angiogenesis drug

in 2013 was the second biggest selling oncology produc

44
Q

When is avastin used?

A

Approved for colorectal, lung, kidney and ovarian cancers and eye diseases

45
Q

Outline the mechanism of action of avastin

A

Avastin:

  • monoclonal antibody
  • binds to VEGF
  • prevents VEGF binding to VEGF receptors

Cellular Pathology (13 decks)

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