Invasive Cancer Flashcards
How are organs defined?
By basement membranes.
What are basement membranes made up of?
Extracellular matrix proteins- laminins, collagen and proteoglycans
What is the extracellular matrix?
Complete meshwork of proteins and carbohydrates
What does collagen/ proteoglycans provide the ECM with?
Structural integrity to tissues.
How is the ECM connected to other cells?
Directly connected to cells it surrounds- acts as an interface between cells and other structures like blood vessels.
How can cancer cells move into the bloodstream and then around the body>T
By penetration of the ECM
What are cadherins?
Type of cell adhesion molecule which bind to each other and the ECM
What is E-cadherin involved in?
Cell-cell adhesion of epithelial cells.
What do epithelial cancers often show?
Downregulation and mutation of E-cadherin.
What is the mechanisms of metasisis?
Tumour cells spread from the primary tumour.
This is subclonal meaning that the cells are genetically identical but differ by mutations.
Name the two different mechanisms used by metastasis.
Monoclonal
Polyclonal
Name the two different patterns used by metastasis.
Linear
Branched
->this gives different mutations
In order for cancer cell to spread, what must they beomce?
Must become mobile
What is epithelial mesenchymal transition (EMT)?
Conversion of closely connect epithelium cells to independent mesenchymal cells with the ability to move and invade their local environemnt.
Is the process of EMT reversible?
Yes
Where does EMT occur?
-Usually in embryogenesis but also occurs in cancer metastasis.
What are the five major steps that cells undergo in order to reach metastasis>
- Invasion
- Intravasation
- Transport
- Extravasation
- Colonisation
Do all cells found it the primary tumour have the ability to metasisise?
No
Describe the process of invasion.
EMT begins with signals from tumour stroma (HGF, TGF-beta) which stimulates kinase receptors (EFGR) & triggers MAPK pathway
Name two cell adhesion molecules which help w invasion.
Cadherins ( calcium dependent transmembrane proteins) & Catenins (protein inducing gene expression)
What do integrins do?
Enable cells to “break free” becoming mobile by modifying the membrane distribution.
What do proteases do?
Make the pathway through ECM by the destruction of tissues.
Matrix Metalloproteins contribute to loss of cell junctions
What can mutation within E-cadherin lead to?
Inadequate cell-cell adhesion and distortion of cell shape.
Describe 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.
Circulating tumour cells travelling in a way one system around the body.
They can travel as a single cell or within a group of platelets (emboli).
Certain cancer cells have favoured metastatic sites.
What are tumours in the bloodstream referred to as?
Circulating tumour cells (CTC’s).
What is the first pass organ?
The first organ on route which lies downstream from the primary tumour.
For example, lungs are the first organ down the pathway from the breast.
Describe extravasation.
- Exit of tumour cells from bloods vessels into distant tissues
- Tumour cells become trapped in capillaries
- Reverse of intravasation
What is E-selectin and what does it do?
->Calcium dependent receptor
-> enables attachment of the cancer cell to the endothelium surface of blood vessels and passage through the endothelium (transendothelial migration).
How is the point of metastasis determined?
By the point of extravasation but also the microenvironment.
What must the environment be like to allow tumours to grow?
Environment must be favourable and create new blood vessels (angiogenesis) for nutrients and oxygen.
What form do dormant cancer cells take up?
Micrometastases
What is angiogenetic switch dependant on?
Inhibitors and inducors.
List some anti - angiogenic factors
Angiostatin
Endostatin
Prolactin
Protein 53 (p53)
Thrombospondin 1 & 2
Name some pro-angiogenic factors.
VEGF
Fibroblast growth factor
Hepatocyte growth factor
Epidermal growth factor
Platelet derived growth factor
What are the majority of angiogenetic inducers?
Grwoth Fcators
What are the majority of angiogenetic inducers?
Growth Factors
Which angiogenetic inducer is the most important and induces angiogenesis?
VEGF
Name the five members of the VEGF family
A
B
C
D
Placental growth factor
Which member of the VEGF family is secreted by a large number of tumour cells?
VEGF-A
How do the members of the VEGF family transmit their signals?
Via three VEGF receptors.
How is VEGFR activated?
Must be phosphorylated.
How can tumour cells promote angiogenesis?
They stimulate nearby cells to produce VEGF and in turn promote angiogenesis
What is VEGFR1?
Inhibitory and regulates the mito VEGF-A available.
What does VEGFR2 do?
Enables angiogenesis.
What is VEGFR3 required for?
The formation of lymphatic vessels.
What do angiogenic inhibitors do?
Help to regulate angiogenesis.
What can plasminogen can be cleaved to release?
Angiostatin- angiogenic inhibitor
What does endostatin do?
Blocks the MAPK pathway thus inhibiting gene expression.
What is Concomitant resistance?
Enabling growth in distant metastases
->can be as a result of surgery which activates previously dormant cells.,
What is the angiogenic switch controlled by?
Hypoxia
How do tumours create a hypoxic environment?
By activating HIF1 alpha & beta subunit triggering VEGF.
Name one drug which inhibits angiogenesis.
TKI Afatanib
