Multistage carcinoma Flashcards
What kind of mutations can be seen in cancer?
- TSG loss
- oncogene activation
- mutations that allow cells to grow faster than their neighbours offering them a selective advantage
10 hallmarks of cancer
- evading growth suppressors
- avoiding immune destruction
- sustaining proliferative signalling
- replicative immortality
- tumour-promoting inflammation
- activating invasion and metastasis
- inducing/acessing vasculature
- genome instability + mutations
- deregulating cellular metabolism
- resisting cell death
What kinds of cells are in epithelial tumours?
- cancer cells + stromal cells
- blood vessels, ,cancer-associated fibroblasts, immune/inflammatory cells + factors
- blood cancers can also have stromal cells
What are 90% of tumours made from?
epithelial cells - these cells are more exposed to the environment and damage
What are the stages of the cell cycle?
Go, G1, S, G2, M
What regulates the cell cycle?
- cyclins and CDKs
- growth factors stimulate the cell to enter from quiescent G0 state to G1
Which cyclin/CDK is important in inhibition of the G phase of the cell cycle?
- cyclin D CDK 6/4
- growth factor induced
- upregulated by growth factors
- can be overexpressed in cancers
What is the raf-MEK-ERK pathway?
- growth factors such as GFG, EGF are produced by stromal cells and activate tyrosine kinase receptors
- these activate ras which phosphorylates raf which phosphorylates MEK1+2 which phosphorylates ERK1+2
- ERK1+2 can then enter the nucleus and activate cell cycle and survival genes
What kind of mutations can occur in the raf-MEK-ERK pathway that lead to cancer?
- tyrosine kinase receptor activation
- ras activation (most common in K least in H)
- b-raf activation - seen in 50% of melanomas
How are activating mutations of tyrosine kinase receptors treated in cancer?
- small molecule inhibitors bind intracellularly and prevent target binding to the receptor
- not selective but cheap
- Ab inhibitors block receptors specifically but are expensive
How are activating mutations of ras treated in cancers?
- difficult to target with small molecule inhibitors
- cant use Abs as ras is inside the cell
- recently some ras mutations such as B-raf in melanoma can be inhibied
PI3K pathway?
- PI3K is made of 2 subunits
- p85 interacts with receptors
- p110 phosphorylates lipids in the membrane
- growth factors bind receptors and activate PI3K which phosphorylates PIP2 into PIP3
- PIP3’s negative charge helps it to recruit many proteins such as AKT involved in cell survival
PTEN can turn PIP3 back to PIP2
What kinds of mutations can happen in the PI3K pathway to cause cancer? How can these be targeted?
- p110 activation -> more Akt and cell survival - seeen in breast and coloreactl and kinase inhibitors can be used but with bad side effects at PI3K is important in many processes
- Akt activation can be treated with kinase inhibitors
- PTEN deletion is seen in 30% of tumours highest in prostate
What is angiogenesis?
- budding of new blood vessels off of existing ones
- endothelial cells respond to angiogenic signals and start to move and divide towards them
- laminin and collagen degrades the basement membrane
- seen in wound healing and cancer
How is angiogenesis induced?
- as tumours grow or during wound healing, new cells have less access to oxygen (hypoxia) and express VEGF
- this induces new blood vessels in loops to allow blood to flow through the new tissue
- angiogenesis can also be activate by ras activating mutations that stimulate the production of VEGF even without hypoxia
Not all tumours will induce angiogenesis? WhY?
- those growing in places with lots of blood vessels may not suffer from hypoxia
- lung, liver brain etc
Other than cancer cells, which other cells might produce VEGF in response to hypoxia?
- stromal and immmune cells within a tumour
How do cancer cells invade and metastasize?
- tumour cells degrade the basement membrane
- some cells become more invasive and can invade their surroundings when provided with new or existing blood vessels
- cancer cells enter vessels by degrading their basement membrane
- some may manage to attach to endothelial cells, leave the blood vessels and invade secondary sites
Why is metastasis so rare?
epithelial cells aren’t designed to be in the blood so they can die or get broken down or struggle to attach to endothelial cells to leave the vessels at secondary sites
What are some common sites of metastasis?
- places with good blood supply such as the lung, liver, brain or bone
- not the heart or other muscles as contractile force destroys the cells
- some cancers have places they metastasise to more commonly such as prostate cancer going to the bone- there may be nutrients in the bone that support prostate cancer cells well
What are the 3 epithelial cell-cell junctions? Which are most important in cancer invasion and metastasis?
- tight junctions stop movement of fluids such as in the gut
- gap junctions pass messages between cells
- adherens junctions are the most important in metastasis and tell cells to stop moving and dividing due to neighbours or can allow cell growth following cell loss or altered signalling
What is the structure of an adherens junction?
two membranes are held together by E-cadherin. E-cadherin binds Beta catenin binds alpha catenin binds actin
- parallel actin filaments stabilise the junctions and prevent migration
What changes in adherens junctions can allow cell migration in cancer?
- E-cadherin gene silenced or deleted
- E cadherin degraded (done in wounds)
- inherited mutations - some people have one inactive copy of e-cadherin that makes them more susceptible to breast cancer
- alpha catenin also seen inactivated in cancers
What can happen with HGF in cancer?-
- cross-talk between cancer cells and fibroblasts can cause them to see cancer as a wound and produce HGF
- high levels of HGF constantly lead to no junctions and lots of migration
