Metastasis-adhesion molecules Flashcards
What is the go vs.grow hypothesis
That proliferation and cell migration are mutually exclusive.
What is intraversion and extraversion?
intraversion-it is the cells entering the blood stream
extraversion-cells entering the paranchymal tissue
What are the cell adhesison moleculeS?
dystroglycan
integrin
CD44
DDR
What are the characteristics of integrin?
Hetrodimer transmembrane
mg and calcium dependent
cystine flooded rich domain
What do the ecm-cell adhesion depend on? How about cell to cell adhesion?
fibronectin, laminin,collagen
V-CAM, ICAM, E-cadherin
What are the binding domains in the integrin? What are the ligands?
RGD-fibronectin
DGEA-collagen
What is the most optimal adhesion for migration?
Intermediate adhesion
FAK overexpression is associated with metastasis and i invasion
True
What is the role of FAC in cell migration?What signalling inhibits FAK?
It turnovers and remodels, it detaches from ECM to attach to it again to move, it does this by PDGF activating the pI3K pathway which inhibits FAC
What does the phosphorylation of src induce
metabolism, cytoskeletal changes
What proteins are involved in the migration of cells, forwar pseudopod formation and focal adhesion assembly? How does it do that?
rho,rac,cdc42.
It polymerizes actin and and creates stress fiber which allows it to move
What proteins are involved in focal adhesion disassembly? and how is done?
V-SRC is activated it will phosphorylate p190 which will increase p120(rho gtpase) prevents formation of stress fibre and new focal adhesion assembly.
Calpain woiuld cleave FAK which is an adaptor protein which is responsible for keeping FAC intact and mediates downstream signalling from src, integrin and growth factors, it will cause he disassembly of focal adhesion and impair src, integrin, growth factor signalling
What ‘s the role of ECM in metastatic cancer cells?
It provides structural support and biochemical signalling
What is the role of integrin in providing biochemical signallig to metastaic cells?
It can be inside out or outside in signalling through them respond to changes and can mediate changes
Overall what is the main steps that cells migrate? What is the importance of FAK
Cells have focal adhesion disassembly at the end but at the leading edge focal adhesion assembly at the leading edge, and FAK plays an important role in this procesS and upregulated in cancer
What signalling is involved in focal adhesion disassembly?
PDGF activates PI3K which activates PIP3 which dissociates the alpha and beta integrin which will then dissociate vinculin and a-actinin
What part of the cell is calpain used?
The end of the cell
What are the charecteristics of calpain? What is the difference between calpain 1,2, n-calpain? What protein regulates it’s actvity?
It’s intracellular cysteine rproteases, conserved non lysosomal, calcium dependent.
1,2-ubiquitously expressed
n-calpain- tissue specific
calpastatin
What are the calpain substrates? What is it’s role in proliferation? What would counteract this effect?
Focal adhesion proteins, and cell cycle regulators such as p27,p53,cyclinD.
It promotes proliferation
Calpastatin
What oncogene mediates calpain activity?
v-src
How does increased EGF or any growth factor activity increase metastasis? specific mechanism
MAPK signalling pathway activated it can phosphorylate FAK which will mediate calpain activity and cleave FAK leading to the disassmebly of the FAC. the other indirect way is the dephosphorylation of FAK which will cause the disassmbly of FAC leading the cells to be detached from ECM leading to metastasis
What are some integrins receptors that are overexpressed during metastasis? How are they related to metastasis
a6b1 and a6b4. They can be changed via inside out signalling of rho,growth factors, src, calpain
How does a6b4 induce metastasis?
By being expressed in the leading edge and binding to actin instead of intermediate filament
Where is a6b4 normally found and what does it bind to normally? what is it’s function normally?
It’s found in eoithelial cells binds to laminin and intermediate filament. cell adhesion
How does DDR2 promote metastasis? Is DDR1 upregulated in breast, ovarian, pedriatic cancers?
By binding to collagen type 1 &3 and activating MMP which will degrade the matrix and promote invasion
yes
What are the 3 different tissue invasions? And what are they characterized by?
collective multicellular intraversion- ECm remdelling
mesenchymal invasion-actin remodelling and protrusion
Both of these are proteolysis based
amoeboid invasion-Rock based cycles of contraction and expansion
What are the differences between mesenchymal and amoeboid invasion?
1.rock independent but MMP, src,calpain,integrin dependeny
It has stronger matrix adhesion and more expression of a2b1 and ore autophosphorylation of FAK
While amoeboid has the opposite of those
What does EMT transition depend on?
actin polymerization creating a protrusion
What are the consequences of distrupting cell polarity? and what is cell polarity important for? How does it work
dysregulation of proliferation and apoptosis but it will promote invasion.
It’s important in downregulating signalling of the microenvironment
It works as adaptor and scaffolding proteins
What are some potential therapeutic targets? What are the effects of these drugs on cells? What is an example of a drug that reduced invasion in anmal models?
MMP inhibitors, integrin inhibitors , growth factor inhibitors, src inhibitors
cytostatic
warfarin or sunitinib(non specific)
How does tamoxifen work?
By acting on the e-cadherin and increasing cell cell adhesion
Why is multi-agent therapy a good idea when treating cancer?
It’s able to treat the heterogenity of cancer, if you just treat the common subtypes of tumour population the uniques subpopulation will persist and colonize and take over
Are there any ant-migratory drugs in clinical trials?
No
