Brainscape's Knowledge GenomeTM


Top Flashcards (Certified)
All Flashcards

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

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

A

90%

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

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

A

45-46%

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What is angiogenesis?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What condition drives neo-angiogenesis?

A

Hypoxia

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Overview of MAPK cascade

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What are the receptors and ligands of the VEGF family?

A

Receptors - VEGFR 1,2,3

Ligands - VEGF A,B,C,D

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What are the common pathways which VEGF signals through?

A
  • MAPK
  • PI3K/AKT
  • PLC/PKC
  • FAKL
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What do the common pathways which VEGF induce lead to?

A

Proliferation, cell survival, migration

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

Name a small molecule inhibitor for anti-angiogenic therapy

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
What might your anti-angiogenic therapy actually end up doing to the cancer which you don't want?
- May induces vascular regression - which leads to intratumoral hypoxia - selection of more invasive cancer cells - which resistant to anti-angiogenic therapy.
26
What is it which tumours do to get into the surrounding tissues towards the vessels?
Change their phenotype via the epithelial to mesenchymal transition (EMT)
27
What are typical markers of epithelial cells?
- adherence junctions (E-cadherin) - epithelial markers: E-cadherin, b-catenin - cytokeratin expression - epithelial cell polarisation
28
What are typical markers of mesenchymal cells?
- fibroblast-like shape - increased motility an invasiveness - secretion of proteases (MMPs) - mesenchymal markers: N-cadherin, vimentin
29
What is MMP?
matrix metallo proteases Secreted during the EMT to help degrade the matrix
30
What is the opposite of EMT which is important once tumours have got to their secondary site?
Mesenchymal to epithelial transitions MET
31
What is the main signalling pathway which activates EMT?
TGFbeta pathway
32
Overview of the TGFbeta pathway
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
What cells can secrete TGFb?
- Cancer cells - Fibroblasts - Epithelial cells - Complex network of cells which contribute
34
What can stimulate the EMT?
Autocrine signalling can stimulate EMT. Sectreted factors from the microenvironment act in a paracrine fashion to induce epithelial–mesenchymal transition (EMT).
35
What is the process of intravasation?
- 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
What is the most important thing cancer cells have to do once they have made it into the blood vessels?
Survive
37
Why is it difficult for cancer cells to survive in the blood vessels?
- will encounter immune cells - platelets - bumping against the wall they will get damaged and die
38
What else can cancer cells die of in circulation?
Anoikis - death due to not being attached to something
39
How do cancer cells overcome Anoikis?
- Adaptation of metabolism to keep ATP production --> protein production - Increase in survival signalling through other pathways - Increase expression of pro-survival factors
40
What happens once cancer reach their secondary site?
- Adhesion molecules will mediate the adhesion of cancer cells to the secondary site
41
What are examples of adhesion molecules used by cancers at the secondary site?
Selectins (P-selectin, L-selectin) CD44 Integrins
42
How might cancer cells die when they have reached their secondary site?
Tumour cells might get stuck trying to get out They might adhere to different sites
43
What are the other ways other than in the blood which cancer cells can metastasis around the body?
- Transcoelomic spread - Lymphatic spread - Hematogenous spread - Canalicular spread
44
What is the seed soil hypothesis?
- 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
What must the secondary site have for the cancer to stop there?
- Compatible adhesion molecules on endothelial cells - Appropriate growth factors and ECM - Selective chemotaxis - Physical features
46
What do some cancers do instead of settling and growing at their new secondary site:?
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
What affects the ways in which cancers metastasise?
- The cancer type - The time of metastasis - the route taken to metastasise
48
Breast cancer most common metastasis
Lung earlier on
49
What therapies are available to target metastatic disease?
- Not many effective ones - But all the usuals may be used
50
What are we looking to do when targeting metastatic disease?
- Control further metastases - Control the growth of both the primary and secondary tumours - Relieve the symptoms experienced by the patient
51
What is Denosumab and what does it do?
- 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
How does cancer metastasise via Transcoelomic spread?
- Through body cavities - e.g. penetrating peritoneal, pleural, pericardial or subarachnoid spaces - ovarian tumours to liver surface
53
How does cancer metastasise via Lymphatic spread?
- via lymphatic system - most common route for initial spread carcinomas - e.g. breast cancer
54
How does cancer metastasise via Hematogenous spread?
- 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
How do cancers metastasise via Canalicular spread?
- favoured by carcinomas through a small passageway - e.g. bile ducts, urinary system, subarachnoid space

Pharm Decks (16 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2025 Bold Learning Solutions. Terms and Conditions