Lecture 13: Angiogenesis Flashcards
Tumour >2mm requires
blood supply
Lack of oxygen can lead to
cancer cell death
The growth and metastasis of tumours depends
on angiogenesis. When blood supply is deficient,
the tumours don’t grow, necrosis occurs.
* The formation of new vessels by sprouting
growth from preexisting blood vessels
* Angiogenesis is a key process in tumour growth
and metastasis
* Provides tumor with a nutrient supply and
removes metabolic products
Angiogenic event sequence
- HIF-1 induction
- HIF-1 upregulates VEGF and MMPs
- VEGF promotes endothelial cell proliferation and MMPs
- Destruction of basement membrane/support matrix by MMPs
- MMPs cause release of angiogenic growth factors held in matrix
- Migration and proliferation of endothelial cells
- Expression of integrins by developing endothelium
- Capillary sprout formation
- Vascularisation of tumour and formation of capillary loops
Vascular structures
Tumour cells are within interstitial matrix with VEGF floating. On top is a basement membrane with pericytes and on top endothelial cells
- Hypoxia induces HIF-1
- In normoxia, HIF-1 is
usually quickly
degraded - Low O2
leads to HIF1 activation - HIF-1 can also be
upregulated by
oncogenic signalling,
e.g. EGFR, HER2,
Akt, etc.
- HIF-1 upregulates VEGF in transformed cells
- HIF-1 can be activated by:
- Oncogenic signals
- Loss of TS function
- Dysregulation of HIF-1
degradation
3.VEGF
promotes
endothelial
cell
proliferation
and MMPs
VEGF induces
MMPs from
endothelium
- Destruction
of basement
membrane
by MMPs
MMP-1, MMP-2,
MMP-7, MMP-9
breakdown support
and expose
endothelium
- Expression of integrins
by developing
endothelium
- Signaling via avb4 integrins
-reduces p53 activity - reduces BAX
- reduces p21 expression
- Increases BCL-2 expression
- Formation of capillary sprouts
- Sprouting is led by the tip cell
- Tip cells can sense their environment to direct
migration - Migrating cells – dividing cells – differentiating
cells - Stalk cells are more proliferative
- Apoptosis (sculpting canal)
- Basement membrane deposition
- Vascularisation of tumour and
formation of capillary loops
- Recruitment of pericytes to support new
blood vessels - Tumour now has access to blood supply
- Capillary bed can be chaotic (corkscrew
vessels)
Angiogenic factors – VEGF
- VEGFA – commonly referred to as VEGF
- Secreted homodimeric glycoprotein with endothelial
cell mitogenic activity - VEGF stimulates endothelial cell migration and
proliferation - Expression is regulated by hypoxia
- numerous splice variants-7 isoforms
- VEGF Receptors
- VEGFR 1, 2, and 3 (Tyrosine kinase receptors)
- VEGFR2 expression is the key mediator of VEGFinduced angiogenesis
- Signalling activates NOS, Akt, STAT3, MAPKs
Angiogenic factors – Angiopoietins
- Angiopoietins (Ang1 and Ang2)
- Receptors: Tie2-RTK
- Ang1 stabilizes vessels, endothelial cell survival signals, and
maintains endothelial barrier - Ang2 destabilises vessels (NB sprouting), mainly produced by
endothelial cells. VEGFA, PDGFB, IGF1 induce Ang2
expression. Stored in granules – exocytosis promoted by
hypoxia - Ang2 normally functions as an ANg1 antagonist, promotes the
dissociation of pericytes from pre-existing vessels and
increases vascular permeability, facilitaties the infiltration of
proteases, cytokines and angiogenic myeloid cells
Anti-angiogenic factors
- Angiostatin – inhibits bFGF-induced migration and
proliferation (MMPs cleave plasminogen to form angiostatin) - Endostatin –internal fragment of collagen XVIII
- IFN-α and –β – suppresses synthesis of bFGF and IL-8
- Thrombospondin-1 – secreted by different cell types. Tsp1
inhibits endothelial cell growth and can cause autocrine FasL
signalling
