Metastatic Cascade Flashcards
What cancer cell properties offer an advantage for tumour growth and will be favoured as the disease progresses?
Phenotypic drivers
Cancer stem cell properties
Ability to invade
Ability to metastasise
What leads to the development of primary tumour?
A loss of growth control
What leads to the process of tumour dissemination?
A loss of positional control
What are the mechanistic steps in invasion (i.e the metastatic cascade)?
Breakdown of the epithelial basement membrane and invasion of the underlying stroma
Breakdown of a vessel wall and intravasation
Dissemination with blood vessles
Arrest on a vessel wall (adhesion or proliferation) and extravasation
Formation of micro-metastases
Formation of macro-metastases through colonization
What does epithelial integrity require?
Cells to adhere tightly to each other and the basement membrane
If the tumour is to become invasive then this must be lost through either a loss of adhesion or degradation
How does the loss of epithelial adhesion proteins occur?
There is a loss of E-cadherin and cytokeratin
How can a gain of new adhesion proteins and acquisition of the ability to move occur?
There is a gain of contractile fibres: vimentin, alph-smooth muscle actin to enable movement and fibronectin
Acquisition of adhesion molecules (N-cadherin and integrins) to facilitate interactions with the stroma
What are the steps involved in the process of invasion in a cancer cell?
Detachment from the primary tumour (via the down regulation of E-Cadherin expression)
Attachement to matrix components through gain of N-cadherin expression
Degradation of the extracellular matrix through secretion of proteolytic enzymes such as MMPs
Migration
What are the features of normal epithelium?
Well-organized Apico-basal polarity Adherens junctions with regular E-cadherins Regular actin bundles Cytokeratin
What are the consequences of an epithelial to mesenchymal transition?
This leads to a change in cell shape and motility
What are the molecular features of an epithelial to mesenchymal transition?
There is a loss of Cytokeratin expression, epithelial adherens junction protein (E-cadherin) and epithelial polarity
There is also a gain of fibroblast like shape, motility, invasiveness, mesenchymal gene expression, mesenchymal adherens junction protein (N-Cadherin), protease secretion, vimentin (intermediate filament) expression, Fibronectin secretion, PDGF receptor expression, alphavbeta6 integrin expression
What are the transcription factors which reactivate the mesenchymal gene expression programme?
Slug Snail Twist Beta-catenin E2A Forkhead Goosecoid SIP1
What are the genetic and epigenetic changes and stromal factors which assist EMT?
TGFalpha TGFbeta TNFalpha EGF FGF HGF microRNAs
What are motogens?
These are proteins like growth factors which are sensed by cytoplasmic protrusions to cause positive chemotaxis
The movement induced by these factors requires energy from Rad-like GTPases that involve members of rhe Rho family ofG proteins
Rho proper
Rac and Cdc42
How does cell motility occur?
This is a co-ordinated process which involves a series of changes in the cytoskeleton as well as process of making and breaking contact with the matrix
The initial process of movement involves the formation of a leading edge
The cell then deploys integrins to create a new point of contact between the lamellipodium and the ECM
At the same time adhesion contact is broken at the trailing edge which liberates the cytoplasm and plasma membrane to redeployment to the leading edge as if the cell rolled forward