Invasion: Regulation of cell migration Flashcards
What sort of tissue is involved in 80-90% of cancers?
Epithelial
What is beneath the layer of cells that are tightly attached to each other lying on a basement membrane?
The stroma which consists of blood vessels and supportive tissues
What happens if there is an accumulation of genetic alterations in the layer of cells?
There may be some hyper proliferation which will lead to the formation of a benign tumour
How does a benign tumour progress to a malignant tumour?
Cells de-differentiate (losing their identity and function as epithelial cells), cell-cell contacts disassemble and cells lose polarity
What do malignant cells require to invade the basement membrane?
Cleavage of ECM proteins and increased motility
What can occur after invasion of basement membrane by malignant cells?
Metastasis
How does the movement of metastatic cells differ to normal cells?
They migrate much faster than normal
They don’t attach to neighbours
They move haphazardly in every direction (normal cells show oriented movement
They move all over each other and don’t stop when they should by contact inhibition
What stimuli for cell movement are there?
Organogenesis Morphogenesis Wounding Growth factor/chemoattractants De-differentiation
What happens when a cell is stimulated to move?
It will change its shape to achieve polarity and thus have directionality to the movement
What coordinates the change in shape of a cell that has been stimulated to move?
The cytoskeleton
Why is regulation an important aspect of cell movement?
The cell needs to know when to stop (contact-inhibition motility)
How to move- develop specialised structures to allow movement e.g. focal adhesions, lamellae, folipodia
What is responsible for the important aspect of cell movement of attaching to the substratum?
ECM
What are focal adhesions?
The sites at which the cell attaches to proteins which make the ECM
What does filamentous actin that lies beneath the membrane do?
Hooks focal adhesions to cytoskeletons via integrins
What do integrins do on the intracellular side?
They interact with various cytoskeletal proteins to form a plaque
What are filopodia?
Finger-like protrusions rich in actin. These protrude from the cell to sense where they want to attach and direction of movement
What overlies filopodia?
Vinuncilin- a protein
What are lamellipodia?
Sheet-like protrusions rich in actin filaments that attach to the substratum and when they move back, the structures are called ruffles
In what way is cell movement similar to wall climbing?
First the filopodia extend to find support to hold onto (focal adhesions)
Lamellipodia then attach to the substratum to provide support during movement
Movement of the cell body occurs with retraction of the dorsum and movement forward. This is repeated quickly
Why is control of cell movement required?
To coordinate what is happening in different parts of the cell i.e. where to extend and retract
Also needed to regulate adhesion/release of cell-extracellular matrix receptors to prevent cell breaking
Also needed from the outside to respond to external influences. This involves sensors and directionality
What are the two types of cell motility?
Hapoptatic- Movement with no direction
Chemotactic- movement in which the cell senses a stimulus and moves towards it
How can actin be found?
Small soluble globular monomers (G-actin) or large polymerised filamentous polymer (F-actin)
In terms of F-actin, what will happen if there is a signal like a nutrient source at the other end of the cell to the F-actin?
The F-actin will disassemble and subunits will defuse to the side with the signal. There is reassembly of the subunits at the new site and this facilitates movement
Give some examples of structures that are affected by the arrangement of actin filaments?
Cell cortex has a random gel-like arrangement to provide support to the plasma membrane
Stress fibres have anti-parallel arrangement forming contractile bundles
Filopodium have tight parallel bundles
What is the remodelling of actin filaments driven by?
Different actin binding proteins
What is actin dynamics?
Cycle between G-actin monomers and F-actin
Why does the G-actin monomer polymerise very quickly in solution?
The lowest energetic state is as a filament
As the filament is the lowest energetic state of actin, why is there not just lots of filaments in cells?
There are sequestering proteins which store G-actin monomers until they are needed
What are capping proteins?
Stop signals which prevent further growth-
What is the rate limiting step in actin dynamics?
Nucleation- involves formation of trimers to initiate polymerisation
What are ARP 2 and 3 involved in?
They are actin related proteins as they’re similar and they form a complex on which trimers of actin can attach- elongation of the filament can occur from the Arp2/3 complex
What does elongation do?
Brings monomers (usually sequestered) to to the gilament
What does profilin do?
Binds to the monomers and helps to elongate the filament
What does thymosin do?
It is a sequestering protein that prevents polymerisation
What regulates filament growth?
Balance between profilin and thymosin
What angle do branched filaments form?
70 degrees
How does branching of a filament occur?
Arp complex binds to side of filament and provides nucleation at different site
Give some examples of capping proteins?
Plus end: Cap Z Gelsolin Fragmin Severin Minus end: Tropomodulin Arp complex
What are the two types of cross linking and bundling?
One type is actin filaments and alpha-actinin which forms a contractile bundle with a loose packing allowing myosin-II to enter the bundle
Other type is actin filaments and fibrin which forms parallel bundling with tight packing
What is severing used for?
Prevent low rate of growth/shrinking of very long filaments- when severed, they grow and shrink more often
Give some examples of severing proteins?
Gelsolin, AF/colfilin and frogmen/severin
Give an example of when severin is used?
In the gel-sol transition; chicken wire network of filaments holding cell in shape must be broken down in order for filopodia to form
What do membrane connections allow?
They allow the cell to sense surfaces- they are hot spots of signalling and involve sensing suitable environments for protrusion
What do membrane connections involve?
A transmembrane protein and an intracellular plaque which is attached to the cytoskeleton
What mediates membrane connections?
Cell-cell and cell-ECM receptors
What proteins are involved in membrane connections?
Talin Alpha-catenin Spectrin Ezrin All of these are perturbed in cancer
What are the three main signalling mechanisms that regulate the actin cytoskeleton?
Ion flux changes
Control by phosphoinositide signalling
Signalling cascades via small GTPases
Give an example of ion flux changes regulating actin cytoskeleton?
Gelsolin severing is Ca+ dependent as this exposes the fast depolymerising end
Alpha actinin crosslinks actin filaments and this is decreased in high Ca2+
What does the Rho subfamily of small GTPases belong to?
The Ras superfamily (Rac, Rho, Cdc42 etc)
What activates these G proteins?
Tyrosine kinase
Adhesion receptors
Signal transduction pathways- expression levels are unregulated in different tumours
What are filopodia activated by?
Cdc42
What are lamellae activated by?
Rac
What are stress fibres activated by?
Rho
What is Rac an important protein for?
Lamellar protrusion and it controls actin branching
What is Rho an important protein for?
Cell contraction
Retraction of the cell to the rear
What controls how cells form focal adhesions?
Rac, Rho and cdc42
What diseases are caused by deregulation of actin cytoskeleton?
High blood pressure
Wiskott-Aldrich syndrome
Epidermolysis bullosa
Bullous pemphigoid
