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
