Cancer Cell Biology 2 Flashcards
What are the two main classes of cancer critical genes?
- proto-oncogenes
- tumour suppressor genes
Proto-oncogenes
Normal genes within our cells that:
→ promote cellular proliferation
Mutated or Over-expressed:
→ they become oncogenes
Inappropriate expression or activity of proteins encoded by oncogenes leads to:
→ uncontrolled cell proliferation
Tumour suppressor genes
Normal genes within our cells that:
→ prevent cellular proliferation
Can be deleted or mutated so that the corresponding protein no longer works properly.
This abolishes the control of the cell cycle and:
→ allows proliferation to continue without any restraint
Oncogenes act in a dominant manner
Gain of function converts:
→ proton-oncogene to oncogene
Cells have two copies of a gene:
→ each copy is an allele
Oncogenes are dominant:
→ mutation in only one allele is enough to effect the behaviour of the cell
Oncogenes encode oncoproteins:
→ which provide cells with an advantage to proliferate, enhanced survival or motility
Tumour suppressor genes act recessively
Undergo loss of function mutation:
→ both copies of allele on tumour suppressor gene
→ need to be inactivated
Wnt signalling
Degradation complex:
→ contains adenomatous polyposis coli (APC)
APC:
→ protein that forms part of degradation complex
→ to turn off wnt signalling
Wnt ligands are released by:
→ stromal cells
Activation of wnt signalling causes:
→ degradation complex to become inactive
No phosphorylation of B-catenin:
→ then it is not degraded.
Mutation of APC (4)
→ makes APC non-functional
→ hence WNT signalling remains on
→ allowing cells to continuously proliferate
→ blocking their ability to differentiate and migrate
Activation of WNT signalling (5)
(in the presence of wnt)
1) wnt ligands bind to stem cell receptors
2) to inactivate degradation complex which contains APC
3) hence the degradation complex won’t target beta-catenin
4) hence beta-catenin levels remain high
5) beta-catenin binds to TFs to induce cell proliferation
Deactivation of WNT signalling (5)
(in the absence of wnt)
1) degradation complex becomes active
2) it acts as a ligase
3) to phosphorylate and ubiquinate the beta-catenin
4) causing to be shipped to proteasome to be degraded
5) hence beta-catenin can no longer activate gene expression
ECM
→ Collagen provides ECM its structure
→ ECM also contains fibronectin and laminin. They act as anchors for cells to which they bind with integrins.
→ Proteoglycan fill up the remaining space
Role of the ECM in cell migration
When required cells are able to move along the ECM:
→ for a cell to move, it forms a leading edge; which firmly attaches to the ECM
→ this attachment is between integrins of the cell and fibronectin of the ECM; which allows the cells to move forward
→ collagen fibres can be cross linked; which can be arranged as tracks to facilitate cell migration
To migrate:
→ cancer cells transform themselves to become more mesenchyal
→ through the epithelial-mesechymal transition (EMT) process
Tumour microenvironment (TME) - recruitment of macrophages
The TME is found to be infiltrated with immune cells, especially macrophages.
→ cancer cells use cytokines such as M-CSF and IL-1B to attract macrophages
→ and transform them into tumour-associated macrophages (TAMs)
→ TAMs act to support cancer progression
They release growth factors such as:
→ EGF - helps cancer cells proliferate
→ VEGF - acts on endothelial cells to sustain angiogenesis
Crucially TAMs also secrete proteases:
→ MMPs
→ which degrade the ECM paving way for invasion
TME - activation of fibroblasts
→ cancer activated fibroblasts (CAFs) are the major cell type found within the TME
→ mostly derived from normal fibroblasts and are referred to as being ‘activated’
→ cancer cells release signalling proteins such as Hedgehog (Hh) and PDGF to activate fibroblasts
→ Hh also stimulates the proliferation of cancer cells
→ CAFs provide a wide range of signalling molecules including VEGF (which contribute to angiogenesis)
→ activated status also ensures that they produce high levels of collagen and other enzymes to remodel the ECM
→ Cancer cells and CAFs release lysyl oxidase (LOX)
→ which crosslinks collagento form tracks for cancer to migrate on
TME - hypoxia
TME is acidic.
TME is hypoxic so triggers angiogenesis:
→ Hypoxia triggers cancer cells to produce VEGF
→ this acts as a ligand for VEGFR present on endothelial cells
→ VEGFR signalling is relayed to the nucleus to induce gene expression and trigger cell proliferation
Cancer cells respond to the hypoxic TME by activating hypoxia-inducibe factors (HIFs):
→ HIFs are transcription factors
→ that enable cells to turn on the necessary genes to adapt the hypoxic environment
Hypoxic conditions can further promote cancer progression:
→ Hypoxic conditions can form reactive oxygen species to cause more mutations
Hypoxia can cause cellular stress - normal cells utilise the unfolded protein repsonse (UPR) and ER associated degradation (ERAD) pathway to relieve ER stress. If ER stress cannot be relieved apoptosis is induced.
Cancer cells manipulate UPR signalling to avoid apoptosis
Cancer cells constantly exposed to ER stress. They therefore increase the expression of UPR associated proteins to make the process more efficient and to degrade misfolded proteins
They also increase the expression of pro-survival factors and bock the expression of pro-apoptotic factors
Cancer cells increase the activity of the ERAD pathway to cope with prolonged ER stress
