L18 angiogenesis

Question 1

how does hif-1 regulate vegf expression?

Answer 1

high oxygen levels= hif-1alpha hydroxylated on proline residues by proline hydroxylase= recognised and bound by ub ligase on pvhl region= adds poly-ub= proteosome= degradation

low oxygen levels= not enough o2 to drive hydroxylation= hif-1alpha associates with hif-1beta= translocate= transcribe vegf

Question 2

is von-hippel lindau disease dominant or recessive? what cancer are these people predisposed to?

Answer 2

autosomal dominant. clear cell carcinoma of the kidney

Question 3

how does vegf bind and elicit effects on endothelial cells? what are those effects?

Answer 3

vegf binds to vegfr-2 rtk= dimerisation = proliferation, survival, migration, vascular permeability

Question 4

describe the different modes of vessel formation and which ones do tumours use?

Answer 4

angiogenesis- cancer uses
vasculogenesis= endothelial precursor cells differentiate in bone marrow, circulate blood, contribute to vessel formation
intersusception- not a big role. vessel splitting
co-option-= use existing blood vessels. tumours use
vascular mimicry- tumour cells differentiate into endothelial cells = become vessels.

Question 5

stages of sprouting

Answer 5

vegf loosens endothelial junctions by regulating ve-cadherin
endothelial cells secrete proteases= ecm remodelling
selection of tip cell- flipodia (actin polymerisation) sense vegf and move
pericyte detachment via ang2
increase permeability allows plasma proteins to deposit provisional matrix layer
formation of lumen
stalk cells signal pericytes to stabilise new vessel
DLL4 maintains stalk and tip cell differentiation
tip cell moves forward using integrins to adhere to ecm
stalk cells proliferate extending the sprout
vegfr-2 downregulated in stalk cells
vessels grow towards each other, fuse
signalling between pericytes and endothelial cells to maintain quiescence, formation of gap junctions and basement membrane

Question 6

how do we specificy stalk and tip cell fate?

Answer 6

one cell express more dll4
signal to neighboring cells via notch receptors to reinforce differentiation of tip cell and surrounding cells down regulate their receptors= stalk cells

Question 6

how do we specificy stalk and tip cell fate?

Answer 6

one cell express more dll4
signal to neighboring cells via notch receptors to reinforce differentiation of tip cell and surrounding cells down regulate their receptors= stalk cells

Question 7

how do we treat renal cell carcinoma?

Answer 7

loss of vegf= common risk of kidney cancer
tumour suppressor VHL lost in RCC
increased VEGF prod
sorafenib, sunitinib monotherapies
target vegfr/ pdgfr and raf

Question 8

mechanisms of resistance to vegf mediated therapies

Answer 8

mutant tumour cells begin secreting other types of angiogenic factors- fgf, pigf

co-option, intersusception

high levels of pericytes linked to resistance

macrophages, fibroblasts, myeloid cells produce other angiogenic factors- pdgf

Question 9

how to use nanoparticles as a novel therapy?

Answer 9

nanoparticles accumulate in tumour- enhanced permeation and poor lymph drainage

deliver pharmaceutical agents

Question 10

how to use liposomes to deliver chemotherapies

Answer 10

lipid bilayer= prevent phag uptake

home the tumour

accumulate and release chemotherapy