Cancer 8: invasion

Question 1

What are cacinomas?

Answer 1

Cancer invasive of epithelial cell
80% of himan cells
epithilialcell are polar with their nucleus at the bottom

Question 2

What are the 5 steps leading to carcinoma?

Answer 2

Homeostasis, gemetic alterations
hyperproliferation
de-differetiation-dissassembly of layer and/or lose polarity –form a mass
invassion-increased motility or cleavage of ECM (necessary for migration to lymph of blood vessels)-become metastatic as cleave through stromal cells)

need proteases
can reacquire their characteristics once invaded other tissues-unsure how

Question 3

What are the different cell migrations of cancer? What allows this?

Answer 3

Either as individual or as clusters
Clusters are more potent-will cause more metastasis than equivalent number of individual -can happen even through blood -called collective migration
Differentr tumours can migrate differently-ameboid (round)-lymphoma/leukemia-individual
Mesenchymal single chains (individual) or chains-fibro/glio
Clusters-epithelial
Multicellular sheets-epithelial

allowed by coordination through gap junctions-cadherins
integrins and proteases are generally found in any metastatic
i

Question 4

Do normal cells also migrate like cancer cells? exemples?

Answer 4

Called collective migration
In cell cultures it happens a lot
vascular sprouting-invasive of the tissue
mammary gland proliferation during pregnancy-branching morphogenesis

clusters also have leader cells-like the tip cell

Question 5

What growth factor can induce cell migration, especially in cancer?

Answer 5

EGF has this effect-when injected into carcinoma, cells will proliferate up the needle
these cells are the one more likely to metastase

RNAseq of these cells found high expression of cytoskeletal proteins and motility machinery
EGFR also highly upregulated

Question 6

summary: How do cells move and how do they do it? what for?

Answer 6

Will happen in organogensis, wound repair, tumours
Often in response to growth factor or chemoattractants

Cells become polarised-cone shape with tip towards chemoattractant-
Stop when contact another cells-called contact inhbition motility

Moves using structures (focal adherstion,)

Question 7

How do focal adhesions help cells move? And filamentous actin?

Answer 7

Focal adhesion create attachement to the subtratum and the actin form a sort of hook that drags the cell to the place-like a step
Integrins-bind cytoskeletal actin with a bundle of cytosolic proteins-signalling+connection to cytoskeleton
Outside portion is for the signalling

Question 8

What are filopodia? When do they appear and how do they help the cell migrate? What are lamellipodia?

Answer 8

Filopodia-fingerlike protusion ruch in actin filament
appear after a cell has been signalled to migrate

Used to sense the sourrounding of the cell by connecting to integrins

Lamellopedia-large sheets of protruding actin-throw membrane to form attachements to substratum

These 2 are the main studies migration parts

Question 9

What are the 2 types of motility?

Answer 9

Hapotactic-random “walk in the park”

Chemotactic-following chemoattractant-with purpose

Question 10

Describe the process which allows a cell to drag itself across substatum

Answer 10

Cell is attacheched to substatum via focal adhesion
Uses filopodia to sense where the next “step” is
When it moves, itll throw out lamellipodium forward wich will attatch to the substatum (via new focal adhesion)
Then contract the back end-translocate the cell body towards the new adhesion, removing the oldest/futher away adhesion

rinse and repeat

Question 11

How do cell contract and cause translocation for movement?

Answer 11

G and F actin- (g form togetther to make F (filament actin)
form actin filaments (plus and minus end)
When following a chemoattractant, the actin will be opposite pushing forwards
When change direction, make F actin to g actin then quickly reform the filaments opposite from the new direction

Question 12

What are filopodium made of? what about lamellipodium?

Answer 12

Parrallel filaments of actin with membrane in front-like a tough rod
Lamellipodim-cross and branched actin filaments under membrane
Focal adhesion complexes have anti-parrallel thich bundles

Question 13

What is the main limitation for the transition of G actin to F actin?

Answer 13

G actin needs to form a trimer to initiate polymeration
But this isnt very stable-need nucleation
Protein-nucleator (arp proteins) (ressemble actin a lot)-form the trimer but are more stable-facilitate initiation of polymeration
This is the minus end

Question 14

What proteins are neccessary for the elognation of actin?

Answer 14

Once initiatied via nucleation, actin has to grow
Need profilin and thymosin (both form complexes with actin_
actin-profilin bind and helps the filament grow
Thymosin does the opposite-grabs the actin and stops it from being integrated
Need to upregulate Prolifin and down thymosin

Question 15

What proteins helps capping of the actin filaments? How does this relate to severing?

Answer 15

Need to stop filament so it doesnt just grow
-end-tropomodulin, Arp complex
+end-capZ gelsolin, fragmin

When severed, actin filaments dont immediatly become G actin-the filaments could be used as basis for new elongation if not capped
Capping coordinates–gelsolin, fragmin, cofilin

Question 16

What are the 3 fates of severed filaments?

Answer 16

Can be capped and then recycled to monomers
CAn be annealed as a small filament to another acin filament
Or can be a basis for growth from a pre-existing end-add more g actin (via prolifin-actin)-

Question 17

How is the shape of actin filament detemined?

Answer 17

Via cross linking and bindling
Depending cross linking proteins
Fascin, fimbrin and a-actin form cross linking bewteen parallel fibres

sprectin-create angle bewteen parralell fibres
Filamin also
and dystrophin
Myosin also can do the cross link-do the contraction

When bundles no more severing
By having filaments with opposing polarities-buclking via myson helps contract the cell

Question 18

How does actin filaments form branches and bind one another?

Answer 18

Using ARP complex at the minus end-bind each other at exactly 70 degrees
Gel-sol transition-gel-rigid and sol-can flow
the framework is cleaved from the gel form to the sol (but no all is cleaved-just a few cuts here and there)

Question 19

What are the 6 steps of actin assembly? Where does it fit in with cell migration

Answer 19

Nucleationm branching, severting, capping, bundling, dissaseembly

all these steps happen when the cell throwws lamellipodim-

Gel sol transition when new adhesion so cell can start moving-happens when bucling and contraction

Question 20

How do all the actin moving look at the level of the lamellae

Answer 20

Constant elongation, capping, branching, assembly, cross linking of the actin => in the direction of the growth, pusing the membrane away
At the bottom /opposite side-dissassembly and recyling of actin

the actin will then conintue the mash

Question 21

How do filopedia grow?

Answer 21

As any actin-elongate normally and recyling at back
When find adhesion, as they are recylied at back-pulled backed

actin cross linked via fascin

Microvilli are a type of filopodia but better organised

Question 22

What are the 4 main ways that signalling can impact actin cytoskeleton?

Answer 22

Ion flux change-like ca influx (muscle lol)
Phosphoinositde signalling-phospholipid bind
Kinase/phosphatase
Singalling cascades via small GTPase

Question 23

How do small GTPase contoll actin cytoskeleton?

Answer 23

RHo subfamilly-exist as ADP form-activated as RhoGTP
most is inactive and when active, cleaved fast

Master regulators of cytoskeletal processes
Activated by TKR
Uregulated in humain tumour (not like RAS which is mutated)
When injecting some of the small GTPase in cells, froms cspecial shapes
Cdc42- form masses of filopedia-control
Rac-form pancake cells-lamellopedia contol
Rho-form massive amounts of stress fibres-cell shrivel up and super contract

Part of hpw they act-RacGTP activates ARP2/3 downstream (via WAVE)
Cdc42-ARP2/3-via WASP this time
Cdc42 also cativated cofilon, profilin

Question 24

How do smallGTPase fit within the cell migration description?

Answer 24

THe small GTPase are sequestreated to specific parts of the cell to make them act
Extension-Rac
Adhesion-Rac and RHo
Transolcation-RHo
De-adhesion-Rho

Cdc42-filopedia formation before lamellopedia extension