Kate Angel 3 Flashcards
Why was MET originally suggested to play in a role in cancer?
The Mesenchymal to epithelial transition was suggested to play a role as many metastasis resemble the primary tumour suggesting the cells may reverse the EMT process once the reach a new tissue
Why do many cancer cells undergo MET?
The founding cells of micrometastasis have usually gone through an EMT which can often be induced by stromal and immune cells
If there are n reactive immune cells in the tissue the stroma will be normal and lack the EMT signals required for the founder cell to maintain its mesenchymal phenotype
The mesenchymal phenotype is also poorly growing and therefore it may be that in order to develop into a macrometastasis MET is required
How can TGF-Beta regulate an EMT?
This signals epithelial cells to activate their latent EMT programs as seen with its ability to induce ANGPTL4 which has been implicated in the metastatic cascade as it disrupts endothelial junctions facilitating extravasation
How can stromal factors play a role in EMT?
Signals such as TGF-Beta, Wnt, TNFalpha, EGF,HGF and PGE2 can cause cells to activate their latent EMT programmes as seen by mesenchymal cells undergoing MET in vitro if TGF-Beta is removed from the culture medium
What stromal factors can assist TGF-Beta in causing an EMT?
TNFalpha which is produced by macrophages
PGE2 which is produced by stromal cells in inflamed tissues
What are the three classes of signalling proteins which play a role in maintaining the mesenchymal state?
Cannonical Wnts, Non canonical Wnts, TGFBeta these are produced by all epithelial cells but prevented from operating in an autocrine manner through the expression of 3 inhibitors
These inhibitors are shut down under an EMT but the signalling proteins must be continually expressed to maintain a mesenchymal phenotype as disruption will result in MET
How can macrophages influence invasion and metastasis?
If tumours produce CSF-1 (Colony stimulating factor-1) to recruit macrophages (tumour associated macrophages) the tumour is invasive, lack of this recruitment results in a tumour retaining a benign phenotype
How does a self-reciprocating feedback loop form between TAMs and cancer cells?
Activation of the EGF receptor on carcinoma cells causes them to proliferate, become invasive and express CSF-1 to attract macrophages
CSF-1 induces the macrophages to produce EGF to further activate the cancer cells
What other stromal factors have been shown to cause EMT cellular attributes?
Epithelial cells have been shown to become invasive when they encounter HGF
What are the key transcription factors that regulate an EMT?
Slug and snail which repress transcription of the Ecadherin gene
TGF-beta and Wnts can induce Slug, Sanil and goosecoid expression
What is the role of cancer stem cells in metastasis?
In order for disseminated cancer cell to seed a metastasis it must have the ability to initiate the formation of a new tumour essentially acting as a progenitor cell
This is further evidenced by the fact that mammary cells which go through EMT acquire many mammary stem cell characteristics
Why do proteases play a key role in invasiveness of extracellular proteases?
Cancer cells need to remodel their environment through excavating pathways through the extracellular matrix which is achieved through the use of matrix metalloproteases
This is evident through the high levels of proteolysis detected around tumour edges
They are also capable of mobilising growth factors which were tethered in inactive form to ECM or cell surfaces
Where do most of the MMPs in cancer come from?
They are largely secreted by stromal cells
However some such as MT1-MMP is membrane bound and attached to the cancer cell concentrated on the leading edge
How does MT1-MMP and MMP-2 collaborate in cancer cell invasion?
MT1-MMP can break down the basement membrane through cleavage of collagen in a process essential for invasion
Once in the stroma MT1-MMP can activate pro-MMP-2 which can cleave the collagen fragments produced by MT1-MMP into smaller fragments and create a tunnel infront of the cancer cell for deeper invasion of the stroma
What is the effect of MMP9 on cancer cell invasion?
It is secreted by macrophages and neutrophils which are located at the invasive front of the tumour
It plays a role in extravasation, intravasation and local stromal invasion
It can degrade many types of collagen and laminin as well as activating TGF-Beta
