External factors controlling division and behaviour of normal and cancerous cells Flashcards
How do external growth factors control cell division?
GFs trigger ERK cascade and cause cell division
Cross-talk between ECM (anchorage dependence) and GF (density dependence) signalling produces proliferation
GF receptors and integrin signalling complexes can each activate identical signalling pathways (e.g. MAPK)
Individually, activation is weak and transient
Together, activation is strong and sustained
Give some examples of external growth factors
Hepatocyte growth factor
Vascular endothelial GF
Fibroblast GF
Epidermal GF
Why are signalling pathways involving growth factors often implicated in the uncontrolled division of cancerous cells?
If a gene coding for a component of a signalling pathway is mutated so protein is constitutively active, that pathway will be permanently turned on (e.g. Ras)
Receptors, signalling intermediates and signalling targets (e.g. transcription factors) are proto-oncogenes
This is the mechanism of short-circuiting leading to uncontrolled proliferation as a result of loss of density dependence (GF)
Loss of density dependence + loss of anchorage dependence in cancer
What external factors are required for proliferation?
External growth factors
Cell-cell adhesion
Cell-ECM adhesion
What factors restrain cells within their normal tissue boundaries?
Cell-cell adhesion (contact inhibition)
Cell-ECM adhesion (anchorage dependence)
How does anchorage dependence limit the division of normal cells within their tissues?
Cells need adhesion and to be able to spread in order to respond to GFs and proliferate
If cell loses either one of these –> can’t proliferate
How is mechanical continuity between the cell interior and ECM established?
Via cell-ECM adhesion molecules - receptors on cell surface which bind specifically to ECM molecules
E.g. integrins
How do specific integrins only bind to specific ECM molecules?
Heterodimer complexes of alpha and beta subunits that associate extracellularly by their head regions
Tail region spans plasma membrane
10 alpha and 8 beta subunits - 20+ combinations
Specific combination only binds specific short aa sequence on ECM molecule
How do integrins establish mechanical continuity between the cell and the ECM?
Integrin (w/specific alpha and beta subunits) specifically binds a short, specific aa sequence
Such peptide sequences are often found in more than one ECM molecule
Intracellularly, integrins are linked, via actin-binding proteins, to actin cytoskeleton
How does contact inhibition limit the division on normal cells within their tissues?
Epithelial cells in high density:
No cell-cell junctions –> activated MAPK –> decreased p27KIP1 –> high proliferation
Cell-cell junctions form –> inactive MAPK –> increased P27 –> low proliferation
Bc in adherens junctions, beta-catenin bound to cadherin at the membrane is unavailable for LEF-1 binding and nuclear effects (if unbound, B-catenin/LEF-1 complexes increase proliferation)
Cadherins clustered together –> changes in activation of some small GTPases (Rac, Rho) - affected by GTP and act as switches in signalling - can influence proliferation
Association of many GF receptors into cell-cell contacts can prevent their activation - established cell-cell contacts might prevent GF receptors from being able to respond to soluble GFs
What is “inside-out” signalling?
Integrin complexes can be switched on or off - not always ready/capable of binding to matrix
When bent over - low affinity
Extended - adhesion switched on - can bind matrix strongly
Signal generated inside cell (e.g. as a result of hormone binding to R) can act on integrin complex to alter affinity
What is “outside-in” signalling?
Matrix ligand binding to integrin opens the legs of the complex allowing cytoplasmic signalling molecules to bind
Explain the significance of metastasis in cancer development
- In order to metastasise, cells must break away from primary tumour, travel in blood or lymph vessel, enter vessel, lodge at distant site, leave vessel, establish secondary tumour
What are the cellular and molecular changes necessary for cancer to develop?
- Loss of anchorage dependence (ECM binding)
- Loss of density dependence (growth factor)
- Normal cell wouldn’t be able to proliferate if it lost both signals
- However, cancer cell doesn’t need either bc one signal further downstream has been permanently turned on
- Pathways are ‘short-circuited’
- There are mutant gene products that are constitutively turned on so upstream signals not required
