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Year 2 - Cancer > Cancer 8 > Flashcards

Cancer 8 Flashcards

1
Q

where are most human tumors derived from?

A
  • 80-90% of human tumours are derived from epithelial tissues
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2
Q

what is the structure of human tumors?

A
  • They have tight junctions and are polarised
  • They are based on top of a basement membrane
  • the basement membrane separates them from stromal cells and other tissue
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3
Q

what are the stages of conversion of benign cells to a tumour?

A
  • genetic alterations
  • hyper proliferation
  • de differentiation
  • invasion
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4
Q

what does genetic alteration to the tumour cell do?

A
  • this results in hyper-proliferation
  • this results in the cells losing their identity
  • this leads to a de-differentiation process
  • after this has occurred the tumor will not bare any resemblance to the characteristics of the original tissue
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5
Q

what occurs to the cells at hyper-proliferation?

A
  • this causes cells to lose their identity
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6
Q

what happens to the cells at de-differentiation?

A
  • disassembly of cell-cell contacts
  • causes loss of polarity
  • (polarity is essential for function)
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7
Q

what does invasion do to the tumour?

A
  • Cells secrete proteases to clip the basement membrane
  • Cells make protrusions and invade surrounding tissue by cleaving ECM proteins.
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8
Q

at what stage does metastasis take place?

A
  • Normally, hyper-proliferation leads to a BULK of cells (solid tumor)
  • at this point, the cells are still connected to each other and bound within the tissue
  • as soon as the cells de-differentiate, they break away from the basement membrane
  • at this point, metastasis can take place
  • Once tumor cells exit the venous/lymphatic systems, they can COLONISE and METASTASISE at long distances from the site of origin.
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9
Q

what are the two types of tumour cell migration?

A
  • individual (single cell migration)
  • collective (group of cells)
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10
Q

what do both types of tumour cell motility require?

what does collective migration specifically require?

A
  • integrins and proteases
  • collective migration specifically requires modulation of cell-cell contacts and communication between cells (gap junctions)
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11
Q

how do different tumour types prefer to migrate?

what are the 4 subgroups of migration ?

A
  • Amoeboid (rapid induvidual) : lymphoma, leukaemia, SCLC
  • Mesenchymal (single cells/chains): fibrosarcoma, glioblastoma, anaplastic tumours
  • Cluster/cohorts: epithelial cancer, melanoma
  • Multicellular strands/sheets): epithelial cancer, vascular tumours
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12
Q

where else does collective migration occur?

A

eg. vascular sprouting

  • Whenever vessels need to be remodelled, cells must invade the surrounding areas as a STRUCTURE
  • they cannot travel induvidually

eg. breast feeding

  • When tissue has to grow, cells bud to grow and branch in order to form the mammary glands
  • . The whole tissue will invade its surroundings and grow around.
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13
Q

what is a scratch wound assay?

A
  • If a confluent monolayer is scraped the cells sense spaces between them
  • Immediately, they will migrate together to close the gap
  • healing works using collective migration
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14
Q

how do tumor cells demonstrate migration?

A
  • Tumour cells demonstrate collective migration but it is not organised
  • cells migrate EVERYWHERE
  • this is because Contact inhibition of migration is ineffective in tumour cells.
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15
Q

what happened when tumour cells and EGF were injected into a mouse?

A
  • Tumour cells were inserted into a mouse
  • EGF (a growth factor) was injected into the mouse
  • when the proteins of the mouse were collected it was shown many of them were up-regulated cytoskeletal proteins and signaling proteins
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16
Q

what are examples of stimuli to make cells move?

A
  • Organogenesis and morphogenesis
  • Wounding
  • Growth factors/chemoattractants
  • De-differentiation (tumours)
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17
Q

what happens to the cell shape when they move?

A
  • they become polarised
  • they develop a head which leads the motion
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18
Q

how do cells know when to stop moving?

A

CONTACT-INHIBITION MOTILITY

this is achieved when cells interact with surrounding cells which tell them to stop

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19
Q

what specialised cell structures help with cell motility?

A
  • focal adhesion
  • lamellae
  • filopodia (slender cytoplasmic projections )
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20
Q

how do cells attach to the substratum?

A
  • the cells must attach in order to migrate
  • Focal adhesions hook onto the ECM matrix, and grab it to provide points where the cells can attach
  • the cells then generate traction forces so they an move
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21
Q

how is the hooking controlled?

A
  • the hooking is controlled by dimer integrin receptors
  • They are transmembrane proteins (one transmembrane domain) with a short cytoplasmic tail
  • the tail has no enzymic activity
  • Integrins just have docking places for cytoskeletal proteins
  • they form complexes of proteins
22
Q

what is filapodia?

A

Finger-like protrusions rich in actin filaments

23
Q

what is the function of filopodia?

A
  • filopodia are protrusions that are actin-rich
  • Vinculin is an ACTIN-BINDING PROTEIN
  • the filopodia sense the surrounding environment to see where the cell should attach
  • they are required in coordination of movement
24
Q

what are lamellipodia?

A
  • sheet like protrusions that are rich in actin filaments
25
Q

what is the function of lamellipodia?

A
  • The cell migrates in a certain direction, and the sheets of membrane project to the front of the cell (in the same direction).
  • The sheets then ruffle back, so that the cell can move.
26
Q

why is control required in cell movement?

A
  • Within a cell, control is needed to coordinate what is happening in different parts
  • Control is needed to regulate adhesion/release of cell-extracellular matrix receptors
  • From outside to respond to external influences – sensors and directionality
27
Q

what is hapoptatic motility?

what is chemotactic motility?

A
  • HAPOPTATIC MOTILITY: directional motility or outgrowth of cells with no purpose (eg. going for a walk in the park)
  • CHEMOTACTIC MOTILITY: movement in response to a chemical stimulus (this is a purposeful response like going to buy bread)
28
Q

how do the focal adhesions and lamellipodia work together to allow the cell to move?

A
  • the focal adhesions act like feet
  • they allow the cell to attach and protrude
  • the lamellipod extends and attach to the ECM
  • once the focal adhesion has been made the back of the cell must contract using energy to push the cell forward
  • the cell moves one step at a time
  • the old adhesions are left behind as the cell moves forward
29
Q

how does actin filament polarity help migration direction?

A
  • Actin is a fundamental monomer in cells
  • Actin can polymerise in the cells
  • Actin monomers are polarised
  • when a signal reaches a cell to migrate in a certain direction there is a rapid disassembly of the filaments
  • then there is rapid diffusion of monomers of actin to the new head of the cell
  • repolarisation of the cell.
30
Q

show a migrating cell:

A
31
Q

what allows the cells to contract during migration?

A
  • In the filapodium, actin is in its filamentous form, in a parallel arrangement
  • Stress fibres have an anti-parallel organisation of the filaments
  • in combination they are able to contract to make movement
32
Q

in what ways can actin molecules remodel?

A
  • There are different classes of cytoskeletal proteins that control each of these steps.
  • nucleation
  • elongation
  • capping
  • severing
33
Q

explain nucleation :

A
  • The nucleation step is the rate-limiting step in the organisation of the cytoskeleton
  • it requires a lot of energy
  • Arp = actin-related proteins. They have similar structures to actin, but they are NOT actin
  • they help the monomers form a trimer
  • after this happens the filaments can form
  • Arp-2,3 complex is the main protein involved
34
Q

explain elongation:

A
  • After trimer formation, elongation must occur
  • Different classes of proteins assists the process
  • profilin is a protein that binds to G-actin and drags it over to the actin filament
  • Thymosin protein binds to actin monomers and acts as a brake to inhibit the polymerisation process
35
Q

explain capping?

A
  • Capping proteins regulate the elongation process of the filament.
  • The capping protein binds the end of the filament and prevent monomers from being added on.
  • Once adding is blocked, there is a disassembly process that results in the shortening of the filament.
36
Q

how are the actin filaments generated into filaments?

A
  • once the filament has been broken down into small pieces there is the option to glue the pieces of filament back together again
  • This process involved the re-annealing of the filaments.
  • Alternatively, short filaments may be used to grow a separate fibre.
37
Q

explain severing:

A
  • The filament size can be regulated by severing
  • Severing proteins chop the filament up, which counter-intuitively generates more ends so that filaments can grow more rapidly.
  • Gelsolin has two functions – it is a capping and severing protein
38
Q

what is crosslinking and bundling?

A
  • Filaments can take different shapes. Cross-linking and bundling proteins do this.
  • Fascin will bind filaments together at a particular distance
  • Fimbrin binds long-distance filaments together
  • Alpha-actinin is a dimer, which binds filaments.
  • Spectrin, filamin, and dystrophin will cross-link the filaments in particular angles. Each particular protein will make a specific angle with the filaments.
39
Q

how does bundling occur?

why are motor proteins useful in bundles ?

A
  • From the filament formed, bundling may occur
  • depending on the way the proteins bundle motor proteins may come in
  • if the filaments are too close together then motor proteins will not be able to come in
  • Motor proteins include myosin – this comes in to promote sliding, enabling the cell and filaments to contract.
40
Q

how does the branching process take place?

A
  • in lamellar proteins the branches are at 70 degrees exactly
  • The Arp-2 complex is the protein responsible for the branching appearance of the filaments as the cells move forward in the lamellar.
  • The Arp-2 complex can nucleate and branch
  • this allows the filaments to elongate outwards
41
Q

what is gel sol transition by actin filament severing?

A
  • when cells need to move and project the rigid cell cortex must be broken down
  • this will allow the cell membrane to move forwards
  • This is called gel-sol transition
  • gel is a rigid structure of the actin cytoskeleton
  • If the membrane pushes through, this gel mesh must be broken down
  • severing breaks down the gel
  • The actin cross-linking proteins are still present, but the filaments aren’t forming a mesh anymore
  • this means the cytoplasm can move to a new area
42
Q

which of the following diseases is not related to the actin cytoskeleton ?

A
  • High blood pressure
  • Wiskott-Aldrich Syndrome – WAS (immunodeficiency, eczema, autoimmunity) - this means the cell does not know where to migrate to
  • Duchenne Muscular Dystrophy (muscle wasting)
  • Bullous Pemphigoid (an autoimmune disease)
  • Alzheimer’s
43
Q

summarise the actin activities during cell movement:

A
  • Proteins can be integrated in the process of directional motility
  • When the lamellipodium extension takes place, there is a lot of actin polymerization in the lamellipodium.
  • In the focal adhesion formation, there is assembling, nucleation, elongation, capping, severing, branching and bundling
  • At the membrane, there is the gel-sol transition on the cortex.
  • Finally, cells need to contract at the back; otherwise they will be RIPPED APART
44
Q

what is lamellae protrusion?

A
  • When the lamellipod protrudes, the membrane protrudes forwards
  • There is an assembly of filaments.
  • There is branching and capping.
  • At the back of the lamella, there is SEVERING
  • so the filament can be released
  • This allows the G-monomers to move to the point in the cell (at the front), where they are needed to make new assemblies.
  • The net result is new assembly of actin at the leading edge, provided by monomers at the back of the cell
45
Q

how does filopodia grow?

A
  • There are tight filaments with bundling proteins
  • They form by complexes that stimulate the bundling and polymerisation of the filaments.
  • Then they form a bundle, and elongate by adding monomers
  • As a result, there is a very fast elongation from the cell.
  • When the filopodia senses the removal of the stimulus, it collapses
  • This collapsing is done by bring capping proteins, to stop the process
  • the membrane is then pushed down
46
Q

what are the 4 signalling molecules that regulate the actin cytoskeleton?

A
  1. Ion flux changes (i.e. intracellular calcium levels can affect proteins)
  2. Phosphoinositide signalling (phospholipid binding)
  3. Kinases/phosphatases (phosphorylation cytoskeletal proteins)
  4. Signalling cascades via small GTPases – master regulators
47
Q

what does the RHo subfamily of small GTPases belong to?

A
  • Rho subfamily of small GTPases belongs to the Ras super-family
  • there are 20 family members including Rac, Rho, Cdc42
  • When activated, they form the actin cytoskeletal structures
    *
48
Q

what does

CDC42 activation

RAC activation

RHO activation

result in?

A

CDC42 activation = induces filopodia into the cells

RAC activation = huge expansion and flattening of the cell.

RHO activation = stress fibres

49
Q

how is the actin cytoskeleton controlled by small G proteins?

A
  • activated when GDP -> GTP
  • Once activated, small G proteins bind to specific proteins (known as effectors).
  • These effectors are the messengers that carry out actions
  • . Proteins are inactivated by hydrolysis of GTP à GDP.
50
Q

how does signaling from small GTPases regulate actin cytoskeleton and motility?

A
  • Among the effector proteins of the GTPases are many cytoskeletal proteins. Once they are engaged and activated, other proteins are activated.
  • For example, Rac protein activates WAVE and Arp-2/3 à so Rac will induce polymerisation.
  • By just activating single molecule, there will be branching out to activate many proteins
51
Q

what is the participation of small GTP-ases on cell migration?

A
  • The lamellipodia is a classic structure formed by Rac (it is involved in actin branching and polymerisation).
  • Focal adhesion assembly is a RAC AND RHO PROCESS
  • contraction is a RHO process
  • Cdc42 controls the exploratory processes by filopodia, driving polarised motility and actin mobilisation.
52
Q

what happens if RHO is blocked?

A
  • If you block Rho, cells may be ripped apart.
    *

Year 2 - Cancer (15 decks)

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