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Cellular pathology > Tumour angiogenesis > Flashcards

Tumour angiogenesis Flashcards

1
Q

What are the characteristics of malignant tumours?

A
  1. Growth
  2. Invasiveness
  3. Metastasis
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2
Q

What happens in the growth of malignant tumours?

A

• Unlimited growth (not self-limited as in benign tumours)
• Relies on adequate blood supply to prevent hypoxia and nutrients
-Hypoxia drives new blood vessel growth around tumour

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3
Q

What is invasiveness?

A

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

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4
Q

What is metastasis?

A

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

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5
Q

Steps involved in metastasis

A
  1. Increased growth from one originating clonal cell
  2. Tumour needs nutrients and oxygen so induces new blood vessels to surround tumour
  3. Cells start to lose their characteristics
    ○ Become less epithelial like and change morphology/shape/mobility to become more motile
  4. Invade into new blood vessels that have formed around tumour
  5. Circulating cells (aggregates/multiple cells) will lodge into distant sites
  6. Move out of capillary
  7. Aggregate of cells start to proliferate again and metastasise and so cycle begins again
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6
Q

What does the process of . cancer metastasis consist of?

A

• Process of cancer metastasis consists of sequential, interlinked and selective steps with some stochastic elements

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7
Q

What is the outcome of each step in metastasis influenced by?

A

• Outcome of each step is influenced by interation of metstatic cellular subpopulations with homeostatic factors

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8
Q

What is each of the metastatic cascade potentially?

A

Each step of the metastatic cascade is potentially rate limiting such that failure of a tumor cell to complete any step effectively impedes that portion of the process

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9
Q

What are key steps in cancer progression?

A
  • Extensive mutagenic and epigenetic changes followed by clonal selection
  • Angiogenesis (overcomes limitations imposed by hypoxia)
  • Epithelial to mesenchymal transition (invasive properties allowing intravasation and extravasation)
  • Colonisation of target organs (ability to expand from micrometastases)
  • Release of metastatic cells that have acquired the ability to colonise
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10
Q

What is angiogenesis?

A

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

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11
Q

What is vasculogenesis?

A

Vasculogenesis is the formation of new blood vessels form new progenitors

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12
Q

What are the types of angiogenesis?

A
  • Developmental/vasculogenesis
  • Organ growth
  • Normal angiogenesis
  • Pathological angiogenesis
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13
Q

What happens in normal angiogenesis?

A

○ Wound repair
○ Placenta during pregnancy
○ Cycling ovary

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14
Q

What happens in pathological angiogenesis?

A

○ Tumour angiogenesis

○ Ocular and inflammatory disorders

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15
Q

Steps involved in tumour angiogenesis

A

• Tumour divides a number of times before it gets to a certain size
• Outgrows existing nutrients
○ Tumour becomes hypoxic
• Hypoxia is a stimulus for tumour to start secreting angiogenic factors
• Factors released by tumours that act on nearby capillaries
• Nearby capillary starts to have tip formation in the vessel (own proliferation get upregulated) so new blood vessels form around tumour
• When cells shed off they can escape through local blood supply and develop micro-metastases

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16
Q

Neovascularization of tumours

A
  • Tumours will not grow beyond a size of about 2mm without their own blood supply as cells cannot survive the lack of oxygen (hypoxia)
  • Angiogenesis (development of a new blood supply) is promoted by hypoxia
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17
Q

What is a strong stimulus for tumour angiogenesis?

A

• Hypoxia is a strong stimulus for tumour angiogenesis

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18
Q

What is hypoxia?

A

• Hypoxia – low oxygen tension <1% O2

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19
Q

How does hypoxia increase?

A

• Increases with increasing distance from capillaries

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20
Q

What does hypoxia activate?

A

• Activates transcription of genes involved in angiogenesis, tumour cell migration and metastasis
-TF gets stabilised

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21
Q

Examples of angiogenic factors

A

• Some tumour cells produce factors that stimulate the directional growth of endothelial cells:
○ Vascular Endothelial Growth Factor (VEGF)
○ Fibroblast Growth Factor-2 (FGF-2)
○ Transforming Growth Factor-β (TGF- β)
○ Hepatocyte growth factor/scatter factor (HGF/SF)

22
Q

How are angiogenic factors mainly stored and released by what enzyme?

A

• These factors are mainly stored bound to components of the extracellular matrix and may be released by enzymes called matrix metalloproteinases

23
Q

Steps involved in vascular endothelial growth factor(VEGF) signalling

A

• Cancer becomes hypoxic
• Hypoxia results in VEGF secretion out of tumour
• VEGF is not an autocrine GF for the tumour, it is a GF for blood vessels
• VEGF binds to VGEF receptor (tyrosine kinase receptor) in endothelial cells
○ Switches on downstream signalling
○ These pathways are upregulated in tumour cells and drive growth of endothelial cells
○ Binding results in increased survival of endothelial cells (do not apoptose) – activate PKB/AKT pathway, gene transcription is also switched on, vessels become leaky and permeable to allow cells to move in between tumour and endothelial cell compartment

24
Q

What are mechanisms of tumour cell invasion?

A

• Tumour has closely packed cells
○ Cells move away through downregulation of adhesion molecules
○ Cells break away from nearby network of cells and upregulate other proteases that allow cells to move away from where it has been proliferating
• 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

25
Q

What is the epithelial-mesenchymal transition?

A

• Go from epithelial shaped cell to more mesenchymal

26
Q

What is there a loss of in the epithelial-mesenchymal transition?

A

• Loss of
○ Epithelial shape and cell polarity
○ Cytokeratin intermediate filament expression
○ Epithelial adherens junction protein (E-cadherin)
§ No more tight junctions
§ Allows cells to break off

27
Q

What is there an acquisition of in epithelial-mesenchymal transition?

A

○ Fibroblast-like shape and motility
§ Cell is more elongated
○ Invasiveness
○ Vimentin intermediate filament expression
○ Mesenchymal gene expression (fibronectin, PDGF receptor, αvβ6 integrin)
○ Protease secretion (MMP-2, MMP-9)
○ Important for degradation of extracellular matrix and move in

28
Q

What do E-Cadherins allow?

A

○ Allows cell adhesion (Cell-cell contact)

29
Q

What do E-cadherins form?

A

Formation of tight junctions

30
Q

Why do we get rid of tight junctions?

A

§ Need to get rid of these for cells to break off

31
Q

What type of dimers are E-cadherins?

A

Homodimers

32
Q

What are E-Cadherins dependent on?

A

Calcium dependent

33
Q

What does E-Cadherin inhibit?

A

Inhibits invasiveness

34
Q

What do E-Cadherins bind?

A

Bind beta-Catenin

35
Q

Normal cell adhesion vs Disrupted cell adhesion?

A

○ Normal cell = tight junction and these adhesion molecules are responsible for this
○ Disrupted cell-cell adhesion = cells grow on top of each other whereas before there would be a monolayer of normal cells

36
Q

What are integrins?

A

Cell-matrix adhesion molecules

37
Q

What type of dimers are integrins?

A

○ Heterodimers (α and β subunits)

38
Q

What are integrins involved in?

A
  • Adhesion to extracellular matrix

- Cell migration

39
Q

What do factors released from stromal cells include and contribute to?

A

• Factors released by stromal cells (macrophages, mast cells, fibroblasts) include angiogenic factors, growth factors, cytokines, proteases and contribute to tumour progression

40
Q

What do stromal proteins release?

A

• Stromal cells release proteases

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

41
Q

Where are specific receptors for UPA found?

A

On tumour cells

42
Q

What is activated when UPAr complex becomes activated?

A

• UPA and UPAr complex become activated and activate plasminogen

43
Q

What does plasmin activated by UPAr complex activate and what does this lead to ?

A

• Plasmin activates downstream proteins i.e. matrix metalloproteinases (MMPs)
○ Permitting invasion by degrading extracellular matrix (ECM) thus releasing matrix-bound angiogenic factors
○ MMPs go on to degrade ECM
○ Increased plasmin also activates latent GFs

44
Q

Steps involved in cancer dissemination?

A
  1. Primary tumour formation
  2. Localised invasion
  3. Intravasation
  4. Transport through circulation
  5. Arrest in microvessels of various organs
  6. Extravasion
  7. Formation of a micrometastasis
  8. Colonisation – formation of a macrometastasis
45
Q

Comment on efficiency of cancer dissemination

A

Overall process is highly inefficient

46
Q

What is the mechanical hypothesis in tumour spread?

A

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

47
Q

What is the seed and oil hypothesis of tumour spread?

A

○ 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.

48
Q

What is tumour growth dependent on?

A

• Tumour growth dependent on new blood vessel growth

49
Q

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

50
Q

What is Avastin?

A

First specific anti-angiogenesis drug

51
Q

Mechanism of Avastin

A

○ Monoclonal antibody
○ Binds to VEGF
○ Prevents VEGF binding to receptors on endothelial cells
○ Prevent intracellular phosphorylation of receptor so no dimerization and therefore no downstream signalling

Cellular pathology (12 decks)

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