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CELLULAR PATHOLOGY > Tumour angiogenesis > Flashcards

Tumour angiogenesis Flashcards

1
Q

what are the 3 main characteristics of malignant tumours?

A

unlimited growth (as long as there is adequate blood supply)

invasiveness (spread of tumour to surrounding tissue AND to distant organs)

metastasis (spread of tumour from primary to secondary site)

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2
Q

briefly describe the steps from when a cell is transformed to its metastatic process

A
  1. transformation + proliferation
  2. tumour angiogenesis
  3. motility and invasion
    (via blood and lymphatic vessels)
  4. multicell aggregates
  5. tumour will embolise (lodge)
  6. arrest in capillary bed
  7. extravasation
    (movement of tumour out of vessel and proliferating at a different site
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3
Q

What is angiogenesis?

A

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

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4
Q

What is vasculogenesis?

A

Vasculogenesis is the formation of new blood vessels from progenitors (de novo)

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5
Q

name the 3 different types of angiogenesis

A
  1. Developmental/vasculogenesis
  2. Normal angiogenesis
  3. pathological angiogenesis
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6
Q

when does developmental angiogenesis occur

A

organ growth

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7
Q

when does normal angiogenesis occur (3)

A

wound repair

placenta during pregnancy

cycling ovary

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8
Q

when does pathological angiogenesis occur

A

tumour angiogenesis

ocular and inflammatory disorders

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9
Q

what is the difference between in situ and invasive breast cancer

A

in situ

  • not vascularised
  • contained, has not spread to nearby breast tissue

invasive

  • vascularised
  • spread to nearby breast tissue
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10
Q

describe tumour angiogenesis steps

from tumour formation to metastasis

A
  • growth of self sustained tumour
  • tumour becomes hypoxic
  • hypoxia = angiogenic switch = tumour secretes angiogenic factor such as VEGF (cytokines)
  • cytokines diffuse out and stimulate endothelial cells within nearby capillaries to proliferate, migrate and form NEW vessels
  • blood vessel network will develop and spread allowing the tumour to further grow
  • cells form growing tumour can travel via capillary network and spread to different areas of the body (metastatic spread)
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11
Q

describe what is meant by tumour hypoxia and what happens as a result of this

A

as tumour grows it gets further away from the capillaries

hypoxia increases with increasing distance of the tumour cells from the capillaries

tumour hypoxia can activate transcription of genes involved in angiogenesis, tumour cell migration and metastasis

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12
Q

tumour hypoxia can activate transcription of genes involved in angiogenesis, tumour cell migration and metastasis.

Name 4 of the target genes that are activated

A

VEGF

GLUT-1

u-PAR

PAI-1

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13
Q

Angiogenic factors are secreted by hypoxic tumour cells. What is the role of these factors and give 4 examples

A

angiogenic factors stimulate directional growth of endothelial cells

  • VEGF
  • FGF-2
  • TGF-B
  • HGF/SF
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14
Q

where CAN angiogenic factors be secreted from?

A

tumour cells

OR

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

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15
Q

some angiogenic factors are bound to components of the extracellular matrix. How are they released from here?

A

these factors may be released by enzymes called MMPs

matrix metalloproteases

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16
Q

describe the release and action of VEGF

  • where is it released from?
  • where does it act?
  • what effect does it have?
A

released by tumour

acts on VEGF-R within the endothelial cells of capillaries

causes proliferation of endothelial cells so that they can from new vessels and surround the tumour to promote its growth and spread

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17
Q

what type of receptor is VEGF-R?

describe the binding of its ligand and the overall outcome of it

A

tyrosine kinase receptor

VEGF binds to VEGF-R (tyrosine kinase receptor)

this causes dimerisation of the receptors

activates certain pathways to promote angiogenesis for the tumour cell

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18
Q

Binding of VEGF to VEGF-R can go on to activate 3 different pathways. Name all of these pathways.

What is the end outcome of all these pathways?

A
  1. Ras-MEK and MAPK pathway
  2. PKB pathway
  3. PLC pathway

THE END OUTCOME OF ALL PATHWAYS IS ANGIOGENESIS

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19
Q

describe the role of Ras-MEK and MAPK pathway in angiogenesis

A

stimulates gene expression and cell proliferation

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20
Q

Describe the role of PKB pathway in angiogenesis

A

stimulates cell survival

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21
Q

describe all 3 PLC pathways and their role in angiogenesis

A

THEY ALL START OFF WITH PLC –> PIP2 AND THEN…

  1. DAG -> PKC
    - stimulates cell proliferation and vasopermeability
  2. IP3 -> Ca2+
    - stimulates cell proliferation and vasopermeability
  3. IP3 -> Ca2+ -> NOS -> NO

THESE ALL LEAD TO STIMULATION OF ANGIOGENESIS IN THE ENDOTHELIAL CELL

22
Q

what is the process of EMT

A

Epithelial to mesenchymal transition

  • this increases the motility of the malignant cells
  • EMT enables the primary tumour cells to acquire migratory characteristics needed for invasion of their local environment
  • it is a reversible process
    (reverse = MET)
23
Q

EMT

results in the loss of what?

A

LOSS OF:

  • epithelial shape and cell polarity

-cytokeratin intermediate filament expression
(what gives it its shape)

-E-caherins

24
Q

EMT

results in the acquisition of what?
5

A

GAIN OF:

  • fibroblast like shape and motility
  • invasiveness (loss of ECM via MMP)
  • vimentin intermediate filament expression
  • mesenchymal gene expression
  • protease secretion
25
Q

EMT

mesenchymal gene expression - examples?

A

fibronectin

PDGF-R

26
Q

EMT

protease secretion - examples?

A

MMP-2

MMP-9

27
Q

what is the function of E-cadherins?

A

E-cadherins are important for a process called contact inhibition

E-cadherins recognise if there is another cell nearby and will then stop proliferating/moving

28
Q

what type of molecule is E-cadherins

A
  • E-cadherins are homotypic adhesion molecules

* E-cadherins are calcium dependent transmembrane glycoproteins that interact, via B-catenin, with the cytoskeleton

29
Q

compare and contrast what happens in a cells with normal functioning E-cadherin compared to a cell with loss of E-cadherin

A

NORMAL CELL
• Cells proliferate
• E-cadherins presence = cell to cell adhesion = contact inhibition = stops proliferation and monolayer of normal cells

LOSS OF/MUTATION OF E-cadherins
• Mutation/loss of E-cadherins = disrupted cell to cell adhesion = loss of contact inhibition = cells grow on top of each other instead

Cancer cells don’t recognise each other and start to grow on top of each other = formation of tumour

30
Q

what is the role of integrins?

A
  • adhesion to ECM via collagen, fibronectin, laminin

- cell migration through matrix

31
Q

what type of molecule is integrin

A

heterodimers (alpha and beta)

heterotypic adhesion molecule

32
Q

What are examples of stromal cells that release things such as angiogenic factors

A

macrophages

mast cells

fibroblasts

33
Q

what are some of the factors that can be released by stromal cells

A
  • angiogenic factors
  • growth factors
  • cytokines
  • proteases (eg- MMP)
34
Q

what is uPA

A

urokinase type plasminogen activator

35
Q

How does uPA contribute to tumour progression

A
  1. stroma cells release inactive pro-uPA
  2. pro-uPA binds to uPA-R on cancer cell = activation of uPA
  3. uPA converts plasminogen –> plasmin
  4. plasmin activates MMP
  5. MMP degrades the ECM = invasion AND release of matrix bound angiogenic factors
36
Q

What are the steps involved in cancer dissemination?
(cancer spread)

put these in order:

  1. extravasation
  2. primary tumour formation
  3. transport through circulation
  4. arrest in microvessels of various organs
  5. formation of micrometastasis
  6. intravasation
  7. localised invasion
  8. colonisation: formation of a macrometastasis
A
  1. primary tumour formation
  2. localised invasion
  3. intravasation
  4. transport through circulation
  5. arrest in microvessels of various organs
  6. extravasation
  7. formation of micrometastasis
  8. colonisation: formation of a macrometastasis

2, 7, 6, 3, 4, 1, 5, 8

37
Q

from breast cancer, what are the 4 common sites of tumour metastasis

A

brain

lung

liver

bone

38
Q

from colorectal cancer, what are the 2 common sites of tumour metastasis

A

liver

lung

39
Q

from gastric cancer, what are the 3 common sites of tumour metastasis

A

liver

oesophagus

lung

40
Q

from lung cancer, what are the 4 common sites of tumour metastasis

A

brain

bone

liver

adrenal gland

41
Q

from pancreatic cancer, what are the 2 common sites of tumour metastasis

A

liver

lung

42
Q

from prostatic cancer, what is the 1 common sites of tumour metastasis

A

bone

43
Q

what is the 1 site of metastasis that breast, colorectal, gastric and pancreatic cancer all have in common?

A

LUNG CANCER

44
Q

What are the 2 different hypotheses for determining the pattern of tumour spread

A

mechanical hypothesis

seed and soil hypothesis

45
Q

what is the difference between the:

  • mechanical hypothesis
  • seed and soil hypothesis
A

mechanical hypothesis:
- tumour spreads due to the anatomy of the vasculature

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

46
Q

kidney cancer/renal cell carcinoma is a highly angiogenic and metastatic tumour. What is it treated using?

A

angiogenic drugs

47
Q

potential cancer treatments target 3 different things. State the 3 things.

A

TREATMENT TARGETS…

  1. tumour angiogenesis
  2. cell motility
  3. invasion
48
Q

what was Judah folkman’s angiogenesis hypothesis?

A

tumour growth dependent on new blood vessel formation (angiogenesis)

lead to a shift in cancer therapy:
- both he tumour and microvascular compartment are valid therapeutic targets

  • targets the ENVIRONMENT of the cancer rather than the cancer itself
49
Q

what type of drug is avastin and what specific cancers does it target?

(LOCK)

A

the first ever specific anti-angiogenesis drug

```
it was approved for the following cancers:
- colorectal
- lung
- kidney
- ovarian
and for eye diseases
~~~

50
Q

mechanims of action of avastin

A
  • it’s a monoclonal antibody
  • it binds to VEGF
  • it prevents VEGF binding to VEGF receptors on endothelial cells

therefore, no angiogenesis

51
Q

what is EMT characterised by?

7

A
  • Loss in cell polarity
    • Deconstruction of epithelial cell-cell junction
    • Changes in cell shape
    • Downregulation of epithelial markers such as E-cadherins
    • Upregulation of mesenchymal proteins such as N-cadherin
    • Secretion of specific proteases
  • Increased cell protrusion and motility

CELLULAR PATHOLOGY (10 decks)

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