cancer and angiogenesis Flashcards
what are the 5 main forms of cancer contributing to world wide mortality
lung stomach liver colorectal breast
in normal tissues you have a balance of rate of growth and rate of death. in cancer this is …..
disrupted
what is a neoplasm
abnormal mass of tissue, growth of which exceeds and is uncoordinated with normal tissues
what is a tumour
non-specific term meaning lump or swelling
what is cancer
any malignant neoplasm or tumour
what does metastasis mean
discontinuous spread of malignant neoplasm to distant sites
what happens in neoplasia at the cellular level (3)
excessive cellular proliferation
uncoordinated growth
tissue infiltration
what happens in neoplasia at the molecular level (2)
disorder of growth regulatory genes
develops in a multistep fashion
there is an estimate of how many driver mutations in key genes that are required for cancer
5-15
what does p53 do
stops cell cycle to enable repair to occur. if repair doesnt happen it trigger apoptosis
what is Rb and what does it do
retinoblastoma protein - stops the cell cycle
frequently it is absent or mutated in cancer
what are proto-oncogenes
normal genes whose protein product promotes growth
a proto-oncogene is turned into an oncogene as a consequence of what (3)
mutation
chromosomal rearrangement
gene amplification
what is a transcription factor that is amplified around 1000 fold in many cancers
Myc
point mutation at glycine 12 to any other amino acid locks what in the hyperactive permanently on state
Ras
what are tumour supressor genes
genes that encode proteins that discourage cell growth
there are 2 main pathways of apoptosis. these are:
intrinsic and extrinsic
what are the key steps to the intrinsic apoptosis pathway
recognition of damage by p53
upregulation of BAX (pro-apoptotic protein - usually inhibited by Bcl-2)
cytochrome C released from mitochondria and binds to APAP1 with caspase 9 in centre
what do cancer cells upregulate in regard to the intrinsic apoptotic pathways
Bcl-2
how does the extrinsic pathway of apoptosis occur
signals from outside bind to the death receptor
what do cancer cells mutate in regard to the extrinsic apoptotic pathway
the death receptor
what is the original two hit hypothesis of cancer
1st event - initiation
2nd event - promotion
the alternative theory is that multiple hits occur and that there is a lag time between exposure (1st hit) and deelopment of clinically apparent cancer
T
what are the hallmarks of cancer (6)
sustaining proliferative signalling evading growth supressors activation invasion and metastasis enabling replicative immortality inducing angiogenesis resisting cell death
what are the emerging hallmarks of cancer
deregulating cellular energetics - use glycolysis instead of oxidative phosphorylation
avoiding immune destruction
what are the enabling characteristics that allow all the hallmarks of cancer to occur
genome instability and mutation
tumour promoting inflammation
what is angiogenesis
the development of new blood vessels from the existing vasculature
angiogenesis is found in over 50 diseases including (3)
chronic inflammatory disease
vascular malformations
cancer
which blood vessels are more likely to respond to angiogenesis signals
capillaries
what are endothelial cells naturally held in check by balance of
pro-angiogeneic promoters (VEGF, PDGF, FGF) and anti-angiogenic inhibitors (thrombospondin 1)
why cant tumours grow beyond 1-2mm cubed without a blood supply
due to diffusion limits of oxygen and nutrients
as tumours grow they alter their microenvironment this includes (4)
pH
concentration of nutrients
increase in interstitial pressure
decrease in oxygen tension (hypoxia)
cells respond to the changes in tumour microenvironment by generating what
angiogenic molecules eg VEGF to extend blood vasculature to relieve pressure
why is tumour angiogenesis such a problem
- it supports growth of a tumour by providing nutrients and gas exchange
- it allows tumours to invade their surroundings
- it promotes metastasis
what are the steps in tumour induced spouting angiogenesis
- release of angiogenic factors
- activation of endothelial cells
- matrix degradation
- release of cell-matrix contacts
- endothelial cell migration and invasion
- endothelial cell proliferation
- lumen formation
- capillary formation
- vascular stabilisation
the first step of tumour induced sprouting angiogenesis is the release of angiogenic factors this is in response to certain conditions such as
stress
hypoxia
hormones