Oncology - Hallmarks of cancer Flashcards
What are the 10 hallmarks of cancer
- sustaining proliferation signalling
- evading growth suppressors
- avoiding immune destruction
- genome instability and mutation
- Inducing angiogenesis
- resisting cell death
- activating invasion and metastasis
- deregulating cellular energetics
- tumour- promoting inflammation
- enabling replicative immortality
What proteins regulate the cell cycle
- cyclin dependent kinase - become active once bound to cyclins.
- cyclins
What are mitogens
They stimulate cell proliferation by overcoming cell cycle ‘break’
How does tumonignesis occur
Retinoblastoma (Rb) protein inhibits activity of E2F transcription factor which is responsible for progression into S phase
- in cancer there is a loss of function in the Rb gene so E2F transcription factor is no longer inhibited
Why and how does targeting cyclin D-CDK 4/6-p16-Rb pathway work
- the pathway is regulated by mitogens like epidermal growth factor (EGF) e.g. Her2
- inhibiting the pathway means no phosphorylation on Rb protein so a break in the G1 transition occurs and the tumour requires Rb proteins
What is the process of evading growth suppressors
- Growth suppressors are negative regulators of proliferation
- In cancer cells, tumour suppressor genes e.g p53 is turned off
- This leads to uncontrolled cell proliferation
- In normal cell, p53 would arrest the cell at G0 until the DNA is repaired
What drugs class targets ‘evading growth suppressors ‘
Cyclin-dependent kinase inhibitors
What is the process of activating invasion and metastasis
-Breakdown with cell-cell adhesions occurs (E-Cadherin)
-this causes degradation of extracellular matrix (MMP):
so the tumour cells can break free from the primary tumour and enter into the circulatory system by intravasation and it exits via extravasation
-increased motility (chemotaxis)
some organs like the lungs have chemicals that attract tumours to it
What organs are most likely to be metastasised to
- Lungs
- Liver
- Bone
- Lymph nodes
What happens without MMP
No
- tumour invasion
- angiogenesis
- metastasis can occur
What 2 cytokines are released in the formation of new blood vessels
pro-angiogenic factors
- Vascular Endothelial Signalling Factor (VEGF)
- Fibroblast Growth Factor (FGF)
What is the process of Angiogenesis
- Hypoxia leads to tumour cells releasing pro-angiogenic factors e.g VEGF
- VEGF binds to receptors on endothelial cells of pre-existing blood vessels
- this causes the endothelial cells to be activated
- interaction leads to section and activation of proteolytic enzymes
- degradation of the extracellular matrix (ECM) allows activated proliferating endothelial cells to migrate toward the tumour
- endothelial cells deposit a new basement membrane and secrete growth factors like platelet-derived growth factors (PDGF) which attracts supporting cells to stabilise the new vessels
What drug class targets angiogenesis
inhibiting VEGF signalling
what drug class targets the activation of invasion and metastasis
1st gen hydroxamates e.g Batimastat
What is the process of genome instability and mutation
- mutation in BRAC 1 + BRAC 2 or p53 or Rb1 gene which are all tumour suppressor genes
- cancer cells use PARP enzymes to repair any break in their DNA and cancer cells produce a lot of PARP enzymes
