Outline of disease process- pt.2 invasive cancer Flashcards
What is basement membrane made up of?
extracellular matrix proteins (laminins , collagen and proteoglycans)
What are the theories about mechanism of cancer metastasis?
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
Give characteristics of extracellular matrix?
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
How can cancer cells move into blood stream and ultimately around body?
It is by penetration of this matrix
What are cadherins and their role in this?
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
Describe the mechanism of metastasis?
- 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
Describe Epithelial Mesenchymal Transition (EMT)?
- 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
What are the steps to metastasis?
invasion
to
intravasation
to
transport
to
extravasation
to
colonisation
Describe invasion?
- EMT begins with signals from tumour stroma (HGF, TGF-beta)
stimulate kinase receptors (EFGR) & trigger MAPK pathway (controls genes needed to start off EMT)
What is function of cell adhesion molecules?
Cadherins ( calcium dependent transmembrane
proteins) & Catenins (protein inducing gene expression)
What is function of integrins?
enable cells to “break free” becoming mobile
What is function of proteases?
make the pathway through ECM, Matrix Metalloproteins
contribute to loss of cell junctions
Describe intravasation?
- 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)
Describe transport?
- 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)
Describe extravasation?
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)
Describe colonisation?
- 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)
What is angiogenesis?
formation of new blood vessels
What is angiogenic switch dependent on?
inhibitors and inducers
What are anti-angiogenic factors?
Angiostatin
Endostatin
Prolactin
Protein 53 (p53)
Thrombospondin 1 & 2
What are pro angiogenic factors?
VEGF
Fibroblast growth factor
Hepatocyte growth factor
Epidermal growth factor
Platelet derived growth factor
Describe VEGF as an angiogenic inducer?
- 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
What is plasminogen cleaved to form?
angiostatin (angiogenic inhibitor)
What blocks the MAPK pathway?
endostatin (component of collagen) and thus inhibits gene expression
What does concomitant resistance enable?
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
What controls angiogenic switch?
hypoxia
How do tumours trigger VEGF?
Tumours create a hypoxic environment activating HIF1 alpha & beta
subunit triggering VEGF.
What is an example of a drug that inhibits angiogenesis?
TKI afatantib
Describe the process of EMT?
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
