9: External Control (of devision and behavior) Flashcards
What kind of external influences can the cell detect?
- Chemical
- hormones, Growth factors, ions, nutrinents, dissolved gases etc.
- Physical
- mechanical, temperature, stretch,
What are the main external influcences to the cell are often important in cancerous cell behaviour?
- •Growth factors
- •Cell-cell adhesion
- Cell-ECM adhesion
Next to Growth factors, what is the other importnat part needed for cell proliferation?
Binding to the extracellular matrix
- Achorage dependance!
Explain the concept of Anchorage dependance
Cells need bindin to ECM (+ a degree of spreading of cells) for
- survival
- Protein synthesis and DNA replication
- proliferation
Explain the role of ECM in cell phenotype
The composition of the ECM has a crucial role in determenin the cells organisation and phenotype
How do cells “sense” the composition of the ECM?
Via binding of integrins
- Special ECM receptors that can bind to many different ECM molecules
- Link to cytoplasm
- Contunitnity between cytoplasm and external environment
Explain the structure of Integrins
Are compsed of
- alpha and ß subunit
- have a head binding to ECM molecules
- and a tail/Leg which has the membrane and cytoplasmic domains
How do integrins sense different ECM compositions?
There are different combiations of the alpha and beta subunits
- Each recognises different short AA sequences of ECM molecules
- They can be specific to one ECM molecule or are found in more than one molecule
Explain the intracelluar organisation of integrins
Bind to Actin (exeptino in epithelial cells–> can also bind to intermediate filaments) Intracellularly via actin binding proteins
- induce signal transduction intracellularly
Explain the structure of focal adhesions
Integrins cluster togetheer to then form focal adhesions (sometimes can also form hemidesmosomes)
- involved in signal transduction
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What is “outiside-in” signaling?
- ECM receptors (e.g. integrins) can act to transduce signals
- e.g. ECM binding to an integrin complex can stimulate the complex to produce a signal inside the cell,
- This changes the cells phenotype
Explain ther role of Intrgrins during “outide in” -signal regulation
Integrins can undergo confirmational change and therefore change ability to
- bind ligands
- change the signaling pathway
How can integrins sense the mechanical properties of the surrounding?
Via the amoun of force that is generated at a focal adhesion depends on
- both the force generated by the cytoskeleton (F cell)
- and stiffness of the ECM
What is “inside-out” integrin signalling?
An intracellular signal (e.g. as response to a homone binding etc.) can
- change the integrin affinity for the ECM
- used e.g. in inflammation, blood clotting
Explain the mechanism of anchorage dependance
- growth factor receptors and integrin signalling complexes can each activate identical signalling pathways (e.g. MAPK)
- Alone: this activation is weak and/or transient
- •Both needed for strong proliferative signal!
Explain the concept of density dependance of cell devision
In cell monolayers–> cells compete for GF and therefore proliferate less (not just inhibted by contact inhibition)
Explain the two different types of cell-cell contacts that can occur
- Short term
- normally non-epithelial cells
- transient intercations, don’t form stable junctions
- Long term
- normally epitheilial cells
- stable cell-cell junctions
Explain the concept of contact inhibition of locomotion
Mostly
- collision of non-epithelial cells repells the cells
- paralisation of motiliy at contact side
- promoting formation of otile front at other side and moving to opposide direction
Explain the concept of Contact-induced spreading of epithelial cells
When epitelial cells meet:
- form stable junctions/cell-cell adhesions
- leading to cell spreading to form stable mono-layers
Explain the intracellular mechanism how cell-cell adhesions influence proliferation
Cell-cell junctions are calcium dependant: low Ca2+= low juncitons= high proliferation
- Without cell-cell junction
- high MAPK activity
- low p27KIP1 (CKI)
- promote proliferation
- With cell junctions
- MAPK inhibited
- inhibit proliferation
What is the mediator molecule that might be responeible for the link of cell-cell adhesions and proliferation
Thought to be mediated by ß-cadenin (link between calcium dependant junction and further intracellular signaling)
Explaint the role and regulation of ß-catenin in cell proliferation
ß-catenin is bound to cell-cell junction molecules
- When there is no junction–> ß-catenenin is free in cytoplasms
- Binds to LEF-1 and promotes gene transcription and cell proliferation
- Gets inactivated by APC complex
Explain the formation and Mechanism of Adenomatous polyposis coli (APC)
It is a form of inhierited disease forming uncontrolled colorectal polyps
- Due to a disfunciton of the APC gene that cannot degrade ß-catenin
- No degradation of ß-catenin –> uncontrolled proliferation
Other than ß-catenin mediatied, how can cell-cell jucntions als alter cell proliferation?
- Cadherin clusterin after cell-cell junciton can activate small GTPases (e.g. Rac activation, Rho inhibitiob)–> proliferation
- GF receptors involved in Cell-Cell junctions reduced their ability to respond to extracellular stimmuli
What happens to contact inhibtion in tumor cells?
What does that lead to?
Tumor cell often loose contact-inhibition leading to
- Uncontrolled proliferation
- Multilayering
- Epithelial break down of cell-cell contacts
–> Solid tumor formation and invasion of tissues
What are the different steps in metastisis formation?
- Cells must break away from the primary tumour
- travel to a blood or lymph vessel
- enter the vessel
- lodge at a distant site
- leave the vessel,ultimately
- establish a secondary tumour
What do primary carcinomal cells alter/have to metastisise?
- Reduction of cell-cell adhesions (e.g. cadherin levels reduced)
- Primary cells must be motile
- degradation of ECM must take place; matrix metaloproteinase (MMP) levels increased in order to migrate through basal lamina and interstitial ECM
- the degree of carcinoma cell-cell adhesion is an indicator of how differentiated the primary tumour is, and indicates its invasiveness and the prognosis
What is Blebbing?
Happens when Cells are detached from ECM
- membrane swells into several spherical bubbels
Can end
- apoptotic
- Non-apoptotic = cell locomotion, cell division and stresses
