Download Angiogenesis

Module 1-b
Angiogenesis
Angiogenesis
In order for a tumor to grow beyond 2 mm^3, it must have a
steady supply of amino acids, nucleic acids, carbohydrates, oxygen,
and growth factors for metastasis and continued growth.
Tumors must stimulate angiogenesis, the growth of new blood
vessels from preexisting ones so as to obtain these nutrients.
Cascade of Events in Angiogenesis
The endothelial cell's machinery begins to produce
Newly
formed
blood
tubes
are
stabilized
by
The
Matrix
endothelial
metalloproteinases
cells vessel
begin
(MMP)
to
divide
are
produced
new
molecules
including
enzymes.
These
enzymes
Specialized
Sprouting
endothelial
molecules
called
cells
roll
adhesion
up
to
form
a
Individual
blood
vessel
tubes
connect
to cells,
form
specialized
muscle
cells
(smooth
muscle
(proliferate)
to
dissolve
the
and
tissue
migrate
in
front
out
through
of
the
sprouting
the
dissolve
tiny
holes
in
the
sheath-like
covering
molecules
blood
vessel
called
tube.
integrins
(avb3,
avb5)
The angiogenic
growth
factors
bind
toserve
specific
located on the endothelial cells
blood
vessel
loops
that
can
circulate
blood.
pericytes)
that
provide
structural
support.
Blood receptors
Diseased
or
injured
tissues
produce
and
release
growth
dissolved
vessel
tip
holes
in
order
of
to
the
accommodate
existing
vessel
it.
towards
(basement
membrane)
surrounding
all
existing
growth
factors
bind
to their
receptors,
the endothelial
cells angiogenic
become activated.
asOnce
grappling
hooks
to help
pull
thenearby
sprouting
(EC)
of
preexisting
blood
vessels
flow
then begins.
the
diseased
tissue
(tumor).
blood
vessels.
Signals
arevessel
sent
from
the
cell's surface
the nucleus.
factors
(proteins)
thattodiffuse
into the nearby tissues
new
blood
sprout
forward.
Angiogenic Switch
Angiogenic Switch
Balance is important in every aspect of life !
Antiangiogenesis Targets for Therapy
and Imaging
• Neovasculature
• Proteases that breakdown the ECM (e.g. MMPs)
• Growth factors that stimulate endothelial cell
proliferation (e.g. VEGF, PDGF, bFGF, IL-8)
• Integrins that allow adhesion of endothelial cells (e.g.
avb3)
• Endothelial cell apoptosis (e.g. TNF…)
• Pre-existing Vasculature
• Various Vasculature Targeting Agents
Timeline of Anti-angiogenic Therapy
• 1971: The field began in early 1970s with Judah
Folkman’s hypothesis that tumor growth would be
halted if it were deprived of a blood supply
• 1989: Dr. Napolene Ferra identified and isolate VEGF
• 1996: Dr. Jeffery Isner published first clinical trials
regarding VEGF
• 2004: FDA approves first antiangiogenic drug to treat
colorectal cancer (Avastin)
Is it possible to detect neo-angiogenic vessels ?
The specificity of αvβ3-integrin –NP was
demonstrated by inhibiting αvβ3 transfected K293 cell binding to
vitronectin. Effective affinity = 50 pM (per
particle).
Integrin avb3-Targeted
300 copies/Nanoparticle
Gold NanoBeacons (GNB)
Pan et al. 2010 FASEB J, 25, 875-882
Early angiogenic vessels
Sprouting
No full circulation yet
How Early We Are Able to Detect?
Early detection of immature, nascent angiogenic vessels with Photoacoustics Imaging!
MATRIGEL MOUSE MODEL
720 nm
720 nm
14 days
avb3-GNB
Pan et al. 2010 FASEB J, 25, 875-882
720 nm
Atherosclerotic Plaque and Angiogenesis
In vivo T1 sagittal section spin-echo image
to display long axis of aorta from aortic
arch to diaphragm of cholesterol-fed rabbit
Pan D. et al. Circulation 2010, 122, A20216