Invasion- regulation of cell migration Flashcards
What are the steps in tumour progression?
Homeostasis
Genetic alterations
Hyperproliferation
Dedifferentiation (disassembly of cell-cell contacts; loss of polarity)
Invasion (increased motility; cleavage of ECM proteins)
What are the 2 broad types of tumour cell migration?
Individual
Collective
What is required in individual tumour cell migration?
Integrins and proteases
What is required in collective tumour cell migration?
Cadherins and gap junctions
Give 2 individual tumour cell migration strategies.
Ameoboid
Mesenchymal (single cells)
Give 3 collective tumour cell migration strategies.
Mesenchymal (chains)
Clusters/cohorts
Multicellular strands/sheets
What tumour types adopt an ameoboid migration strategy?
Lymphoma
Leukaemia
SCLC
What tumour cell types adopt a mesenchymal (single cell) migration strategy?
Fibrosarcoma
Glioblastoma
Anaplastic tumours
What tumour cell types adopt a cluster/cohort migration strategy?
Epithelial cancer
Melanoma
What tumour cell types adopt a multicellular strand/sheet migration strategy?
Epithelial cancer
Vascular tumours
What can stimulate cells to move?
Organogenesis and morphogenesis
Wounding
Growth factors/chemoattractants
Dedifferentiation (tumours)
How do cells know where to move to?
Directionality (polarity)
How do cell know when to stop moving?
Contact inhibition motility
How do cells move?
Engage into specialised structures, e.g. focal adhesions, lamellae, filopodium.
What are filopodia?
Structures used for cell motility.
Finger-like protrusions rich in actin filaments.
Bundle of parallel filaments.
What are lamellipodia?
Structures used for cell motility.
Sheet-like protrusions rich in actin filaments.
Branched and cross-linked filaments.
Why is control of cell movement necessary?
Needed within a cell to coordinate what is happening in different parts.
Regulate adhesion/release of cell-ECM receptors.
Needed from outside to respond to external influences- sensors, directionality.
What are the 2 types of cell motility?
Hapoptatic
Chemotatic
What are the stages in cell motility?
Extension
Adhesion
Translocation
Deadhesion
What are stress fibres?
Antiparallel contractile structures.
What are the 2 types of actin?
G-actin (small soluble subunits)
F-actin (large filamentous polymer)
How can G-actin be remodelled?
Sequestering
Nucleating
Into F-actin
How can F-actin be remodelled?
Bundling Motor proteins Side-binding Capping Cross-linking Severing Into G-actin
What is nucleation (in cell motility)?
Rate-limiting step in actin dynamics.
Formation of trimers to initiate polymerisation.
What is elongation (in cell motility)?
Profilin competes with thymosin for binding to actin monomers and promotes assembly.
List capping proteins that cap the + end.
Cap Z
Gelsolin
Fragmin/severin
List capping proteins that cap the - end.
Tropomodulin
Arp complex
What is the role of capping proteins in cell motility?
Regulate elongation.
List severing proteins.
Gelsolin
ADF/cofilin
Fragmin/severin
What is the role of severing in cell motility?
In a severed population, actin filaments grow and shrink more rapidly than in an unsevered population.
List proteins involved in cross-linking and bundling of actin filaments.
Alpha-actinin Fimbrin Filamin Spectrin Villin Vinculin
What is the main branching protein involved in cell motility?
Arp complex
Creates 70 degree angle between actin filaments.
What is gel-sol transition in cell motility?
Transition from gel (rigid) to sol (can flow) by actin filament severing.
What actions are required in regulation of filopodia extension?
Actin polymerisation
Bundling
Cross-linking
What are the signalling mechanisms that regulate the actin cytoskeleton?
Ion flux changes (i.e. intracellular calcium).
Phosphoinositide signalling (phospholipid binding).
Kinases/phosphatases (phosphorylation cytoskeletal proteins).
Signalling cascades via small GTPases.
How is the actin cytoskeleton controlled by small G proteins?
Rho subfamily of small GTPases belongs to Ras super-family.
Participate in a variety of cytoskeletal processes.
G proteins activated by receptor tyrosine kinase, adhesion receptors and signal transduction pathways.
Expression levels up-regulated in different human tumours.
What are the roles of Rac in cell motility?
Involved in actin polymerisation and branching of the lamellipodium (extension).
Involved in focal adhesion assembly with Rho (adhesion).
What are the roles of Rho in cell motility?
Involved in focal adhesion assembly with Rac (adhesion).
Involved in stress fibres, tension and contraction (translocation).
Deadhesion.
What are the role of Cdc42 in cell motility?
Exploratory processes of filopodia
Polarised motility
Actin polymerisation
