Outline of disease process- pt.2 invasive cancer

Question 1

What is basement membrane made up of?

Answer 1

extracellular matrix proteins (laminins , collagen and proteoglycans)

Question 2

What are the theories about mechanism of cancer metastasis?

Answer 2

enroute theory- spread of cancer following blood flow
seed and soil- refers to mols spreading via cell surface and providing an ideal micro environment
pre-metastatic niche- primary tumour prepares the site by secreting factors to make new site optimal for cancer cells

Question 3

Give characteristics of extracellular matrix?

Answer 3

Extracellular Matrix (ECM) - complex meshwork of proteins and carbohydrates
* Major component of ecm is collagen/proteoglycans - gives structural integrity to tissues
* ECM is directly connected to the cells it surrounds- it is the interface between the cell
and other surrounding structures like blood vessels

Question 4

How can cancer cells move into blood stream and ultimately around body?

Answer 4

It is by penetration of this matrix

Question 5

What are cadherins and their role in this?

Answer 5

Cells bind together and to extracellular matrix
Cadherins are a type of cell adhesion molecule (cam) - these bind cells to each other and
the ECM
* E -cadherin is involved in cell-cell adhesion of epithelial cells
studied due to role in tumour suppression
* Epithelial cancers frequently show downregulation and mutation of e-cahderin

Question 6

Describe the mechanism of metastasis?

Answer 6

• Spread of tumour cells from the primary tumour is not clonal
• Primary tumour is composed of cells that are subclonal (genetically identical but differ by mutations)
• 2 different mechanisms
  monoclonal
  polyclonal
• 2 different patterns
  linear
  branched

thus giving different mutations

Question 7

Describe Epithelial Mesenchymal Transition (EMT)?

Answer 7

• Cells must acquire migratory characteristics
• EMT is the conversion of closely connected epithelial cells becoming
  independent mesenchymal cells with the ability to move and invade their
  local environment 2
• This is a reversible process
• EMT usually occurs in embryogenesis however this also occurs in cancer
  metastasis

Question 7

What are the steps to metastasis?

Answer 7

invasion
to
intravasation
to
transport
to
extravasation
to
colonisation

Question 8

Describe invasion?

Answer 8

• EMT begins with signals from tumour stroma (HGF, TGF-beta)
  stimulate kinase receptors (EFGR) & trigger MAPK pathway (controls genes needed to start off EMT)

Question 8

What is function of cell adhesion molecules?

Answer 8

Cadherins ( calcium dependent transmembrane
proteins) & Catenins (protein inducing gene expression)

Question 9

What is function of integrins?

Answer 9

enable cells to “break free” becoming mobile

Question 10

What is function of proteases?

Answer 10

make the pathway through ECM, Matrix Metalloproteins
contribute to loss of cell junctions

Question 11

Describe intravasation?

Answer 11

• Intravasation = entry into blood or lymphatics
• Tumour cell attaches to stromal side of basement membrane
• MMPs and serin proteases help to degrade basement membrane
• Tumour cell passes between the endothelial cells and off into the
  bloodstream (transendothelial migration)

Question 12

Describe transport?

Answer 12

• Tumour cells in bloodstream = circulating tumour cells (CTCs)
• Solo travellers vs. Clumps - unidirectional
• Certain cancers have favoured metastatic sites - first pass organ (first organ on route that lies downstream from primary)

Question 13

Describe extravasation?

Answer 13

Exit of tumour cells from bloods vessels into distant tissues
* Tumour cells become trapped in capillaries
* Reverse of intravasation
* Endothelial side of blood vessel - degrade basement membrane -migrate into stroma
* E- Selectin is a calcium dependent receptor which enables
attachment of the cancer cell to the endothelium surface of blood
vessels and passage through the endothelium (transendothelial migration)

Question 14

Describe colonisation?

Answer 14

• Site of metastasis is determined by the point of extravasation but
  also the microenvironment
• Environment must be favourable - for the tumour to grow it must
  create new blood vessels (angiogenesis) for nutrients and oxygen
• Cells can spread but not colonise - dormant (micrometastases)

Question 15

What is angiogenesis?

Answer 15

formation of new blood vessels

Question 16

What is angiogenic switch dependent on?

Answer 16

inhibitors and inducers

Question 17

What are anti-angiogenic factors?

Answer 17

Angiostatin
Endostatin
Prolactin
Protein 53 (p53)
Thrombospondin 1 & 2

Question 18

What are pro angiogenic factors?

Answer 18

VEGF
Fibroblast growth factor
Hepatocyte growth factor
Epidermal growth factor
Platelet derived growth factor

Question 19

Describe VEGF as an angiogenic inducer?

Answer 19

• VEGF is the Star player ** (vascular endothelial growth factor)
• VEGF family = A -D and placental growth factor
• Signals are transmitted via VEGF Receptors 1-3
• VEGFR must be phosphorylated to be become activated
• Tumour cells can also stimulate nearby cells to produce VEGF and
  in turn promote angiogenesis

Question 20

What is plasminogen cleaved to form?

Answer 20

angiostatin (angiogenic inhibitor)

Question 21

What blocks the MAPK pathway?

Answer 21

endostatin (component of collagen) and thus inhibits gene expression

Question 22

What does concomitant resistance enable?

Answer 22

occassionally when a tumour is released by surgery or radiation , there can be a growth metastasis that were previously dormant

theory is that certain tumours fast producing pro antiogenic factors also produce anti angiogenic factors (which controls growth of distant metastasis)

When the primary tumour is resected, inhibitors also removed and metastasis switched on

Question 23

What controls angiogenic switch?

Answer 23

hypoxia

Question 24

How do tumours trigger VEGF?

Answer 24

Tumours create a hypoxic environment activating HIF1 alpha & beta
subunit triggering VEGF.

Question 25

What is an example of a drug that inhibits angiogenesis?

Answer 25

TKI afatantib

Question 26

Describe the process of EMT?

Answer 26

loss of cell polarity
leading to destruction of cell-cell junctions
giving rise to changes in cell shape
then there is down regulation of e-cadherin and up regulation of n-adherin
secreting of specific proteases and increasing in cell protusion
leading to cell motility