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Pharm Decks > Lecture 6 - Angiogenesis and Metastasis > Flashcards

Lecture 6 - Angiogenesis and Metastasis Flashcards

1
Q

What is Metastasis?

A

The ability of cancer cells to escape from the primary tumour via the blood and lymphatic system and to grow in a secondary site

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2
Q

What are the 4 clinical stages of cancer? (lung)

A

Stage I: Tumour 1-4cm. Disease has not spread outside of the lung

Stage II: Tumour is 3-7cm. Disease may be in lymph nodes or nearby tissues, but not in distant parts of the body

Stage III: Tumour is 3 cm to >7cm. Disease can be in >1 lymph nodes or nearby tissue, but not in distant parts of the body

Stage IV: Cancer has spear to distant parts of the body

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3
Q

What is the % of cancer mortality related to advanced metastatic disease?

A

90%

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4
Q

What percentage of cancers are diagnosed at stage III or IV?

A

45-46%

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5
Q

What are the stages in the metastatic cascade? (8)

A
  1. Primary tumour growth (proliferation)
  2. Angiogenesis
  3. Detachment and invasion into the surrounding tissue towards the vessels
  4. Intravasation into lymphatics/ capillaries
  5. Survival in the circulation
  6. Arrest in new/ secondary organ (small capillaries, adhesion to vessel wall)
  7. Extravasation into the secondary tissue
  8. Establishment of microenvironment
    - death
    - dormant
    - proliferating
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6
Q

How do tumours overcome outgrowing their source of oxygen and nutrients?

A
  • Change their metabolism (e.g. use fatty acids)
  • Attract new blood vessels
  • Co-opt existing blood vessels
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7
Q

What is angiogenesis?

A

The growth of new blood vessels
- formation, maturation and differentiation of blood vessels from pre-existing vessels.

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8
Q

What is an example of a time we would use angiogenesis not related to cancer in the body?

A

If you are wounded

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9
Q

What is tumour neo-angiogenesis?

A

the specific type of angiogenesis that occurs during tumour formation
- not programmed and depends on local signals

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10
Q

What condition drives neo-angiogenesis?

A

Hypoxia

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11
Q

What is HIF-1alpha?

A

hypoxia inducible factor 1 alpha is turned on by tumours in hypoxic conditions and is a transcription factor which leads to expression of VEGF (vascular endothelial growth factor)

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12
Q

Overview of MAPK cascade

A

Ras –> Raf –> MEK –> ERK –> Gene expression –> Cell Proliferation

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13
Q

What is VEGF and what does it do?

A
  • vascular endothelial growth factor
  • VEGF drives the growth of blood vessels
  • VEGFR sits on endothelial cells
  • tumour cells secrete the VEGF so that endothelial cells attracted towards the tumour
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14
Q

What are the receptors and ligands of the VEGF family?

A

Receptors - VEGFR 1,2,3

Ligands - VEGF A,B,C,D

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15
Q

What are the common pathways which VEGF signals through?

A
  • MAPK
  • PI3K/AKT
  • PLC/PKC
  • FAKL
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16
Q

What do the common pathways which VEGF induce lead to?

A

Proliferation, cell survival, migration

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17
Q

How is angiogenesis controlled normally?

A
  • By an angiogenesis switch, as normally this process would be switched off when not needed in the body.
  • Endogenous inhibitors inhibit the growth of blood vessels
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18
Q

What are the main characteristics of tumour angiogenesis?

A
  • Disorganised vascular structure
  • Low inter-endothelial cell junctions
  • Low pericyte coverage
  • Increased microvasculature permeability (leakiness)
  • High interstitial fluid (IFP)
  • High pressure, collapsing
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19
Q

What are some of the therapeutic strategies to inhibit angiogenesis?

A
  • Inhibit production of angiogenic proteins
  • Neutralise activators
  • Stop blood vessels growing at the receptor stage
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20
Q

Name a small molecule inhibitor for anti-angiogenic therapy

A

Sorafenib
- inhibits MAPK but also inhibits VEGF receptors
- tyrosine kinase inhibitor

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21
Q

Name a monoclonal Ab for anti-angiogenic therapy and its mechanism of action

A

Bevacizumab
- antibodies against VEGFA so ligand can’t bind, neutralises VEGF-A

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22
Q

Why might some cancers respond better than others to Bevacizumab?

A
  • If VEGF is the main cause of angiogenesis it will respond better than cancers where there are other contributing factors
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23
Q

What cancers typically respond better to Bevacizumab and what respond worse?

A

Better - Colorectal and Renal carcinoma

Worse - Malignant melanoma, pancreatic, breast, prostate

24
Q

What are the resistant mechanisms cancer use against angiogenic therapies?

A
  • Metabolic adaptation
  • Re-vascularization by the expression of alternative angiogenic factors (e.g. bFGF, PDGF)
  • Co-option of normal peritumoural blood vessels and vascular mimicry
  • Blood flow alterations owing to vessel pruning and normalization can improve blood flow
25
Q

What might your anti-angiogenic therapy actually end up doing to the cancer which you don’t want?

A
  • May induces vascular regression
  • which leads to intratumoral hypoxia
  • selection of more invasive cancer cells
  • which resistant to anti-angiogenic therapy.
26
Q

What is it which tumours do to get into the surrounding tissues towards the vessels?

A

Change their phenotype via the epithelial to mesenchymal transition (EMT)

27
Q

What are typical markers of epithelial cells?

A
  • adherence junctions (E-cadherin)
  • epithelial markers: E-cadherin, b-catenin
  • cytokeratin expression
  • epithelial cell polarisation
28
Q

What are typical markers of mesenchymal cells?

A
  • fibroblast-like shape
  • increased motility an invasiveness
  • secretion of proteases (MMPs)
  • mesenchymal markers: N-cadherin, vimentin
29
Q

What is MMP?

A

matrix metallo proteases
Secreted during the EMT to help degrade the matrix

30
Q

What is the opposite of EMT which is important once tumours have got to their secondary site?

A

Mesenchymal to epithelial transitions MET

31
Q

What is the main signalling pathway which activates EMT?

A

TGFbeta pathway

32
Q

Overview of the TGFbeta pathway

A
  1. TGFbeta binds to the TGFbeta receptor which phosphorylates it
  2. Leads to phosphorylation of SMAD 2 and SMAD 3
  3. SMADs translocate to the nucleus acting as transcription factors leading to expression of ZEB1, SNAIL and TWIST
  4. These factors drive mesenchymal phenotype
33
Q

What cells can secrete TGFb?

A
  • Cancer cells
  • Fibroblasts
  • Epithelial cells
  • Complex network of cells which contribute
34
Q

What can stimulate the EMT?

A

Autocrine signalling can stimulate EMT.
Sectreted factors from the microenvironment act in a paracrine fashion to induce epithelial–mesenchymal transition (EMT).

35
Q

What is the process of intravasation?

A
  • Happens once cancer cells have migrated through to the tissues by blood vessels
  • process of entering the blood vessel
  • enter the circulation by transmigrating paracellularly through the endothelial cell (EC) junctions
  • pass transcellularly through
36
Q

What is the most important thing cancer cells have to do once they have made it into the blood vessels?

A

Survive

37
Q

Why is it difficult for cancer cells to survive in the blood vessels?

A
  • will encounter immune cells
  • platelets
  • bumping against the wall they will get damaged and die
38
Q

What else can cancer cells die of in circulation?

A

Anoikis - death due to not being attached to something

39
Q

How do cancer cells overcome Anoikis?

A
  • Adaptation of metabolism to keep ATP production –> protein production
  • Increase in survival signalling through other pathways
  • Increase expression of pro-survival factors
40
Q

What happens once cancer reach their secondary site?

A
  • Adhesion molecules will mediate the adhesion of cancer cells to the secondary site
41
Q

What are examples of adhesion molecules used by cancers at the secondary site?

A

Selectins (P-selectin, L-selectin)
CD44
Integrins

42
Q

How might cancer cells die when they have reached their secondary site?

A

Tumour cells might get stuck trying to get out
They might adhere to different sites

43
Q

What are the other ways other than in the blood which cancer cells can metastasis around the body?

A
  • Transcoelomic spread
  • Lymphatic spread
  • Hematogenous spread
  • Canalicular spread
44
Q

What is the seed soil hypothesis?

A
  • Most cancers don’t stop at the first environment they come to
  • Provision of a fertile environment which supports the growth of the tumour cells is where they will stop
45
Q

What must the secondary site have for the cancer to stop there?

A
  • Compatible adhesion molecules on endothelial cells
  • Appropriate growth factors and ECM
  • Selective chemotaxis
  • Physical features
46
Q

What do some cancers do instead of settling and growing at their new secondary site:?

A

Establish dormancy - arrest of tumour growth in the primary or at a metastatic sites. Cells stay quiescent and do not divide until a favourable environment is present.

47
Q

What affects the ways in which cancers metastasise?

A
  • The cancer type
  • The time of metastasis
  • the route taken to metastasise
48
Q

Breast cancer most common metastasis

A

Lung earlier on

49
Q

What therapies are available to target metastatic disease?

A
  • Not many effective ones
  • But all the usuals may be used
50
Q

What are we looking to do when targeting metastatic disease?

A
  • Control further metastases
  • Control the growth of both the primary and secondary tumours
  • Relieve the symptoms experienced by the patient
51
Q

What is Denosumab and what does it do?

A
  • monoclonal antibody
  • targets the receptor activator of nuclear factor-kappaB (RANK) ligand (a protein essential for osteoclast differentiation activity and survival)
  • Loss of osteoclasts from the bone surface reduces bone turnover and bone loss in malignant and benign diseases
  • In breast cancer, bone metastases are frequent – cancer treatment-induced bone loss (CTIBL) also occurs
52
Q

How does cancer metastasise via Transcoelomic spread?

A
  • Through body cavities
  • e.g. penetrating peritoneal, pleural, pericardial or subarachnoid spaces
  • ovarian tumours to liver surface
53
Q

How does cancer metastasise via Lymphatic spread?

A
  • via lymphatic system
  • most common route for initial spread carcinomas
  • e.g. breast cancer
54
Q

How does cancer metastasise via Hematogenous spread?

A
  • favoured route of sarcomas
  • certain types of carcinomas tend to follow venous flow due to thinner walls of veins
  • e.g. colorectal to liver via portal vein
55
Q

How do cancers metastasise via Canalicular spread?

A
  • favoured by carcinomas through a small passageway - e.g. bile ducts, urinary system, subarachnoid space

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