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
