invasion- regulation of cell migration Flashcards
DIAGRAM summary of tumour progression
normally there is homeostasis, but genetic mutations cause hyper-proliferation, causing the cells to DE-DIFFERENTIATE: they lose polarity and cell-cell contact invasion then occurs, where cells move more, ECM proteins are broken down, so cells invade basement membrane invasion is where benign becomes malignant
what occurs in metastasis
normally, BM separates epithelial cells from stroma- but these cells invade the MB and enter blood, travel to new location, and invade another organ
types of tumour cell migration- examples of individual and collective with types of cancer
can either migrate individually or collectively individually are ameoboids (occurs in lymphoma/leukemia) or single mesenchymal cells (occurs in glioblastoma) collectively are clusters (occurs in epithelial cancer/melanoma) and multicellular strand (epithelial cancer/vascular tumours)
what molecules are more present in collective vs individual
integrins and proteases are present more in collective tumour cell migration (in clusters, more ECM proteins broken down= more invasion) also more cadherins and gap junctions (cells in clusters need to communicate with each other)
how to analyse migration of primary glial cells vs tumour cells
scratch wound assay- in the middle of glial cells, put a scratch- normal glial cells sense space and migrate there together, and then stop once no more space left tumour cells migrate much more faster and randomly- no organisation, and they KEEP growing
what occurs when growth factor given to invasive cells
invasive cells migrate to the growth factor, thus there’s an upregulation of genes involved in motility and cytoskeleton
stimuli causing cell movement
wounding, growth factors, dedifferentiation ie tumours, and organogenesis
DIAGRAM how cells know where to move, how they move and how they stop
cells change shape and become polarised, with a front and a back: they move using special strucutres they stop by contact-inhibition motility
DIAGRAM how cells begin movement ie attach to substratum
there are integrins which are activated- a plaque of proteins then form which include FOCAL ADHESIONS- they then attach to substratum (proteins in ECM) via FILAMENTOUS ACTIN (ie cytoskeleton)
how cells become MOTILE
FILOPODIA- FINGER-like protrusion rich in actin and VINCULIN: they sense the surrounding environment LAMELLIPODIA- SHEET LIKE protrusion rich in acti
types of motility
hapoptatic- no purpose, movement is random without a sense of direction chemotactic- sense of direction, more of a purpose
DIAGRAM summary of cell motility
cells have focal adhesion which acts like feet- they attach to BM cell then extends via lamellipodium (like a hand reaching out) cells then form a new focal adhesion cells then move via muscle contraction previous adhesion is removed
DIAGRAM actin filaments types- what occurs upon signal
when there is a signal eg nutrient source, F actin (large polymer) break down into G actin (small subunits) so that they can move, and F actin reassembles at new site so that cell can migrate to new site
DIAGRAM actin filament organisation in different structures
lamellipodium has short branched cross linked filaments filopodium has parallel filaments stress fibres are ANTIPARALLEL to allow cell contractio
remodelling of actin filaments
G actin/F actin can become different arrangements of proteins for different purposes
1st stage of polymerisation- nucleation
actin undergoes nucleation with ARP proteins to initiate polymerisation: this is the LIMITING STEP
2nd stage- elongation
once small actin filament formed, PROFILIN helps elongate it, which competes with THYMOSIN, which inhibits elongation
3rd stage- capping with examples
capping proteins either go onto negative or positive end of actin filament, telling it to stop growing CAPZ/tropomodulin and ARP complex (also does capping as well as nucleation)
4th stage- severing with complex
actin filaments are cut into smaller parts by severing proteins eg gelsolin ie depolymerised
what occurs to severed protein
either capped, two severed proteins are reannealed, or further growth occurs
next stage- cross linking/bundling with examples
multiple filaments are connected together by proteins to stabilise them eg fascin, fimbrin, alpha actinin, spectrin, dystrophin
next stage- branching
ARP complex AGAIN is a branching protein- a branch of an actin filament forms at a 70 degree angle
next stage- gel-sol transition by actin filament severing
due to cross linking, a GEL is formed which is rigid when filaments need to go through basement membrane/move, severing occurs to form a SOL, which is not rigid and can flow
DIAGRAM different actin activities during cell migration
polymerisation when lamellipodium is extending- involves all stages including disassembly at start (F to G actin), then gel/sol transition actin then ATTACHES to ECM actin then CONTRACTS actin then DETACHES
DIAGRAM lamellae protrustion
disassembly BEHIND leading edge polymerisation, BRANCHING and capping then occurs assembly occurs at LEADING edge
filopodia
finger like protrusions- polymerisation occurs, cross-linking/bundling then occurs, and capping proteins form at top to prevent further growth
different molecules with different types of organisation of actin
bristle, microvilli have long finger like action stereocilia have actin of increasing order filopodia lamellopodia has actin arranged randomly and in BRANCHES
different mechanisms regulating actin cytoskeleton
ion flux changes ie Ca2+ phospholipid binding kinases signalling cascade via small GTPases
DIAGRAM- control via G proteins, example, and what occurs in tumours
eg Rho, belongs to Ras family Rho has a GDP, which becomes GTP using hydrolysis of ANOTHER GDP elevated in tumours
DIAGRAM main G proteins, and what they produce
RhoGTP produces stress fibres RacGTP produces lamellipodia Cdc42GTP produces filopodia thus they all control actin polymerisation
DIAGRAM effect of small GTPase on cell migration
Rac involved in extension by actin polymerisation Rac and Rho involved in forming new adhesion, Rho mainly needed for contraction and deadhesion Cdc42 not involved in migration directly, but needed for sensing WHERE to migrate
