carcinogenesis 4: regulation of cell migration Flashcards
outline the stages of progression of a tumour:
- homeostasis
- genetic alterations
- hyper-proliferation
- de-differentiation (loss of polarity & disassembly of cell-cell contacts)
`5. invasion (increased motility and cleavage of ECM proteins)
what happens during metastasis?
cells acquire mobile mesenchyme-type cell phenotype -> enter bloodstream -> travel through bloodstream -> exit circulation -> invade new organs (on invasion lose mesenchymal characteristics) - requires integrins for moement & proteases to digest ECM
how can cells travel when they metastasise?
as single cells or as clusters
- clusters may travel as cohorts or multicellular strands/sheets in epithelial cancers (requires cadherins and gap junctions for coordination)
- clusters carry higher risk of malignancy
how is metastasis biomimetic?
metastasis mimics morphogenic events (eg angiogenesis, morphogenesis & ovarial egg cells - use tip cells to move)
what genes are upregulated in invasive cells?
genes involed in cytoskeleton regulation & motility machinery
what are some stimuli for cell movement
- organo/morphogenesis
- wounding
- growth factors
- dedifferentiation
- regulation required to coordinate stages, control adhesion/release of receptors & respond to external influences
cells require attachment to the ECM to allow _____ and _____
response to growth factors & movement across tissue
- filamentous actins terminate at focal adhesions to the ECM substratum -> provides traction for movement
what are filopodia?
finger-like protrusions rich in actin to allow movement
- bundles og parallel filaments
what are lamellipodia?
sheet-like protrusions rich in actin filaments
- branched and crosslinked filaments
what are stress fibres?
antiparallel contractile structures
what are the stages of cell motility?
- extension: lamellipodium extends from cell in direction of movement
- adhesion: tip of lamellipodium attaches to ECM forming new adhesion
- translocation: posterior region of cell contfacts allowing cell body to move forward
- de-adhesion: most posterior cellular attachment is broken
what are the 7 stages of remodelling of actin filaments?
- nucleation: actin monomer joins with Arp 2 & Arp 3 (ARP complex) forming nucleated actin filamet with ARP complex at minus end
- elongation: profilin joins with free actin monomers to promote assembly of filaments
- capping: ends of actin filaments capped to prevent further polymerisation (positive end = gap Z/gelsolin/fragmin, negative end = ARP complex/tropomodulin)
- severing: gelsolin/ADF/fragmin promote severing of strands -> filaments grow and shrink more rapidly
- cross-linking: proteins such as α-actinin/fimbrin allow cross-linking of chains while filamin/spectrin allow more complex shapes to form
- branching: ARP complex causes brancing of actin filaments
- gel-sol transition: actin filament severs -> transtion from rigid ‘gel’ state to ‘sol’ state that can flow and allow for protrusions of membrane
what types of actin is the filament comprised of?
growing end: ATP-actin
behind leading edge: ADP-actin (as there has been dephosphorylation)
what is the limiting step of remodelling of actin filaments?
step 1 (nucleation) - requires trimers to initiate polymerisation
how does actin remodelling differ in filopedia & lamellipodium?
filipodia: actin polymerises -> bundling proteins link strands together to form finger-like protrusion -> filaments capped -> retract due to degradation of base
lamellipodium: extension results from polymerisation of actin before the gel/sol transition occurs
how does actin remodelling happen in lamellae?
polymerisation and assembly at the leading edge feature capping and branching allows for extension, severing and disassembly occurs behind leading edge
what are the signalling mechanisms?
- ion flux changes
- phosphoinositide signalling (PIP2/PIP3)
- kinases/phosphatases
- signalling cascades via small GTPases
how are the G-proteins activated?
by RPTKs, adhesion receptos & signal transduction pathways
- trigger motility eg filipodia, lamellipodia, stress fibres
what are the families of small GTPases that trigger different things?
Cdc42: filopodia
Rac: lamellipodia
Rho: stress fibres
