Cancer Cell Biology 2 - angiogenesis and metastasis

Question 1

What percent of tumor cells go on to form metastases after they enter circulation?

Answer 1

0.01% survive to form metastases - but it only takes one cell

Question 2

What are the rules for metastatic development?

Answer 2

1. metastasis can occur on the basis of size- larger tumours have a higher chance of metastasis i.e) breast and colon cancer
2. emtastasis can occur before the cancer has grown to a detectable size (soon after initiation)
3. metastasis can be extremely infrequent or does not happen at all

*there are no rules - metastases can happen under any circumstance*

Question 3

Where do breast tumors metastasize?

Answer 3

bone/brain

Question 4

Where do prostate tumors metastasize?

Answer 4

Bone

Question 5

Where do stomach tumors metastasize?

Answer 5

liver/ovary

Question 6

Where do colon tumors metastasize?

Answer 6

liver, lungs

Question 7

Where do melanoma tumors metastasize?

Answer 7

brain, liver and bowel

Question 8

what is the ‘seed and soil theory’ for metastases?

Answer 8

cells are dispersed randomly but only grow in organs which provide the correct factors necessary for growth of that particular tumor (fertile soil)

Question 9

What is the ‘mechanistic theory ‘ of metastases?

Answer 9

the first site to which a cancer emtastasises is the closest one in which there are small blood vessels

Question 10

What are the key steps involved in metastasis?

Answer 10

1. disruption of cell-cell and cell/matrix interactions and degradation of ECM
2. invasion and migration through stroma
3. intravasation into blood or lymph vessel
4. survival in circulation
5. extravasation out of blood or lymph vessel and micration into new tissue
6. survival in new tissue
7. once tumour reaches certai size, develops new blood vessels (angiogenesis)

*these cells need to survive in order to metastasis - if they do survive they are micrometastices which are undetectable - once they develop their own blood supply they are full blown metastatic tumours

Question 12

what are the steps of invasion of metastasis?

Answer 12

1) attachment - cell adhesion molecules/integrins
2) proteolysis - enzymes MMPs and uPA
3) migration- motility factors

Question 13

what is angiogensis ?

Answer 13

new blood vessel formation from pre-existing vasculature -

Question 14

what is vasculogenesis?

Answer 14

new vessel synthesis from endothelial progenitor cells - from scratch

Question 15

what are the steps in angiogenesis?

Answer 15

1. secretion of angiogenic factors by tumour cells (VEGF)
2. release of proteases from activated endothelial cells
3. permeabilisation of blood vessel wall and release of vascular endothelial cells
4. migration of the endothelial cells into the interstitial space and into the tumour
5. endothelial cell proliferation
6. lumen formation
7. fustion of newly formed vessles
8. initiation of blood flow

Question 16

What are ‘Pro-Angiogenic’ factors?

Answer 16

VEGF

Epidermal growth factor (EGF)

platelet derived growth factor (PDGF)

transforming growth factor alpha (TGFalpha)

hypoxia

oncogene activation

loss of tumour suppressor genes p53 or VHL

Question 17

how does hypoxia induce angiogensis and aggressive tumor proliferation?

Answer 17

hypoxia stimulates angiogensis to get more oxygen to the tissue- it impairs drug delivery and selects for more aggressive cells

*since hypoxic cells are not actively proliferating, they are resistant to chemo which targets dividing cells

Question 18

What are angiogensis inhibitors?

Answer 18

• angiostatin - cleavage fragment of plasminogen
• endostatin- cleavage fragment of collagen
• interferons
• platelet factor 4
• TIMPS- tissue inhibitor of metalloproteinases

*it’s about finding a balance between these inhibitors and the proangiogenic factors release by tumours the tumor cells have an inbalance of these*

Question 19

what is the ‘angiogenic switch hypothesis’?

Answer 19

this hypothesis states that regulation of angiogensis is a balance between pro- and anti- angiogenic factors

Question 20

what is VEGF?

Answer 20

vascular endothelial growth factor

-stimulates angiogensis and vasculogenesis

it increases vascular permability, facilitating metastasis (often why tumors bleed however )

regulated by p53 and VHL tumour supressors - however, these are often lost in cancer

VEGF receptors are often over-expresed by tumour endothelium

Question 21

what is the HIF1 pathway in hypoxia induced angiogensis?

Answer 21

HIF1 is a transcription factor that regulates many genes that are controlled via oxygen levles - when the tumor increases in size we reduce amount of oxygen available and HIF1 expression increases as well as VEGF- which is controlled by HIF 1

HIF1= hypoxia inducible factor 1

Question 22

what is the HIF1 pathway in hypoxia induced angiogensis?

Answer 22

HIF1 is regulated by hypoxic conditions because it is stabilized by hypoxia and VHL cannot regulate it under hypoxic conditions

VHL= part of complex with ubiquitin ligase activity which degrades HIF1

Question 23

what is the difference between tumour associated blood vessels and non-tumour associated blood vessels?

Answer 23

tumour associated= leaky allowing cells to spread easily into vasculature

non-tumour associated = regularly patterned and functioning - normal vessel wall and endothelium

Question 24

describe the effect of the tumour microenvironment on cancer research/treatment

Answer 24

research in the past focused on experimenting with just tumour cells in a la condition - but tumours are not isolated in the body.

now we know there is an interplay between tumour cells and healhty cells, so we need to model these interactions to understand the real implications of cancer treatment

*we also know that a metastatic tumour and the primary tumour grow indifferent microenvironments, so a ‘one size fits all’ treatment might not even work in one person with multiple tumours