Lecture 15 Angiogenesis and metastitis

Question 1

VEGF release in angiogenesis

Answer 1

oxygen- HIF(hypoxia inducible factor) binds to pVHL which makes it a target for ubiquitination
hypoxic conditions- VHL is nitosylates- HIF-a and HIG-BETA bind stabilising iit and activated transcriptiojn of vegf
VEGFR causes

Question 2

relevance

Answer 2

allows cells to survive and accumalate mtations in cells, higher in hypoxic conditions
increase density of blood vessels- deregulation of structure- haemorraging and other fac can cause metastis and invasion, normalise blood flow with antiVEGF factors(antibodies)
VEGF specific antibodies dont work- reduncancy
conbination dont work- off target effects

Question 3

Metastisis and invasion

Answer 3

spread of tumour to nearby sites

spread of tumour to distance site

Question 4

How is invasion controlled at the molecular level

Answer 4

VEGF binds VEGR(TyrK), phospho PI3K

activates PKB/AKT

Question 5

Steps of invasion

Answer 5

Focal adhesion degradation
degradation of basal membrane
inhibition on anoikis
upregulation of VEGF

Question 6

How is focal adhesion(E cadhirin) degraded

Answer 6

PKB phoso Twish protein which is able to modify the E-cadherin junction breaking them moving cells apart for migration

Question 7

how is invasion into the basement membrane coordinated

Answer 7

PKB/AKT activates NFxB which activates snail
Snail drive expressionn of matrix metalloproteases
MT1-MMP- cell curface expressed to degrade BM
migrates into the ECM and secretes MMPs(MMP-2) degrades ECM
REmoveal of anti expansion facteros f

Question 8

Inhibition of aniokis

Answer 8

for cells that have detached from ECM or neighbouring cells

PKB deactivated bad (pro apoptopic factor) therefore expression of the Bcl-2 family of anti-apoptotic proteins, no cyt c release

Question 9

Upregulation of VEGF

Answer 9

pkb/AKT activated m-tpr which uprefulates HIF

Question 10

Intravasion and extravasion

Answer 10

Homing
E selection and cd44
Adhesion
intergrin and selectin interact, a layer of specificity to metastisis

Degradation and migration
VEGF-VEGFR-PI3K-PYK2 which phosphorylates E-cadherin on both side of the cell

intergrin interaction activates MLC
MLC causes contraction of actcin fibres to pull the cell apart.
1 cell