Angiogenesis

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Angiogenesis
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CONTENTS
MECHANISM
PATHOLOGY EFFECT
TYPE
DEFINITION
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DEFINITION
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What is angiogenesis
Angiogenesis is the formation of new blood
vessels from pre-existing vessels.
Angiogenesis is a normal process in growth and
development, as well as in wound healing.
However, this is also a fundamental step in the
transition of tumors from a dormant state to a
malignant state.
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Angiogenesis is a process controlled by certain
chemicals produced in the body. Some of these
chemicals stimulate cells to repair damaged blood
vessels or form new ones. Other chemicals, called
angiogenesis inhibitors, signal the process to
stop.
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The balance hypothesis of the 'angiogenic switch'.
Angiogenesis is tightly controlled by the balance
of two sets of counteracting factors
angiogenic activators and inhibitors.
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The angiogenic process
The angiogenic process is a critical process for
new cell and tissue growth?
The 4 major steps of endothelial cells in angiogenesis
1. Breaking through of the basal lamina that envelopes existing blood vessels
2. Migration toward a source signal
3. Proliferation
4. Formation of tubes
The 4 major steps of endothelial cells in
angiogenesis
1. Breaking through of the basal lamina that
envelopes existing blood vessels
2. Migration toward a source signal
3. Proliferation
4. Formation of tubes
Like most processes in homeostatic cellular
systems, angiogenesis is a complex, highly
regulated system. A large number of
pro-angiogenic growth factors have been
identified, many of which are capable of inducing
all 4 of the above steps. One of the primary
factors among these is a protein known as VEGF.
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Sprouting angiogenesis
Intussusceptive angiogenesis
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Sprouting angiogenesis
Sprouting angiogenesis was the first identified
form of angiogenesis. It occurs in several
well-characterized stages.
First, biological signals known as angiogenic
growth factors activate receptors present on
endothelial cells present in pre-existing veins.
Second, the activated endothelial cells begin to
release enzymes called proteases that degrade the
basement membrane in order to allow endothelial
cells to escape from the original (parent) vessel
walls.
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The endothelial cells then proliferate into the
surrounding matrix and form solid sprouts
connecting neighboring vessels. As sprouts extend
toward the source of the angiogenic stimulus,
endothelial cells migrate in tandem, using
adhesion molecules, the equivalent of cellular
grappling hooks, called integrins. These sprouts
then form loops to become a full-fledged vessel
lumen as cells migrate to the site of
angiogenesis. Sprouting occurs at a rate of
several millimeters per day, and enables new
vessels to grow across gaps in the vasculature.
It is markedly different from splitting
angiogenesis, however, because it forms entirely
new vessels as opposed to splitting existing
vessels.
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Intussusceptive Angiogenesis
Intussusception, also known as splitting
angiogenesis, was first observed in neonatal
rats. In this type of vessel formation, the
capillary wall extends into the lumen to split a
single vessel in two. There are four phases of
intussusceptive angiogenesis.
First, the two opposing capillary walls establish
a zone of contact.
Second, the endothelial cell junctions are
reorganized and the vessel bilayer is perforated
to allow growth factors and cells to penetrate
into the lumen.
Third, a core is formed between the two new
vessels at the zone of contact that is filled
with pericytes and myofibroblasts. These cells
begin laying collagen fibers into the core to
provide an extracellular matrix for growth of the
vessel lumen.
Finally, the core is fleshed out with no
alterations to the basic structure.
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Intussusceptive Angiogenesis
Intussusception is important because it is a
reorganization of existing cells. It allows a
vast increase in the number of capillaries
without a corresponding increase in the number of
endothelial cells. This is especially important
in embryonic development as there are not enough
resources to create a rich microvasculature with
new cells every time a new vessel develops.
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The diagram of the difference between two kinds
of angiogenesis
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Different phases of embryonic
vascular development.
Intussusceptive angiogenesis
Sprouting angiogenesis
Endothelial precursors (angioblasts)
differentiate to early endothelial cells (phase
1), which become assembled into a primitive
capillary plexus (vasculogenesis) (phase 2). This
emerging network expands via intussusceptive
growth, intercalated growth and sprouting
(angiogenesis) (phase 3), after which it becomes
remodelled via pruning, fusion and regression of
pre-existing vessels into a tree of arteries,
capillaries and veins (phase 4).
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Modern terminology of angiogenesis
Besides the differentiation between Sprouting
angiogenesis and Intussusceptive angiogenesis
today there exists the more common
differentiation between the following types of
angiogenesis .
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Modern terminology of angiogenesis
Vasculogenesis Formation of vascular structures
from circulating or tissue-resident endothelial
stem cells(angioblasts), which proliferate into
de novo endothelial cells. This form particularly
relates to the embryonal development of the
vascular system.
Angiogenesis Formation of thin-walled
endothelium-lined structures with /without
muscular smooth muscle wall and pericytes
(fibrocytes). This form plays an important role
during the adult life span, also as "repair
mechanism" of damaged tissues.
Arteriogenesis Formation of medium-sized blood
vessels possessing tunica media plus adventitia.
Because it turned out that even this
differentiation is not a sharp one, today quite
often the term Angiogenesis is used summarizing
all different types and modifications of arterial
vessel growth.
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pathology effects
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The relationship between tumor and angiogenesis
While there are more than 100 distinct types of
cancer (and considerable heterogeneity within
each tumor type), there exists a remarkable
similarity in the pathologic traits that
collectively drive tumor growth. Across mostif
not allmalignancies, sustained angiogenesis is
considered to be one of these central hallmarks
of cancer.
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Angiogenesis is 1 of the 6 cellular
transformations that lead to malignant growth
The establishment of sustained angiogenesis as
one of the fundamental hallmarks of cancer is
based on more than a century of research.
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Angiogenesis
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Tumor
VEGF
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Angiogenesis is a vital process in the
progression of cancer from small, localized
neoplasms to larger, growing, and potentially
metastatic tumors. To grow beyond 1 to 2 mm in
diameter, a tumor needs an independent blood
supply, which is acquired by expressing growth
factors that recruit new vasculature from
existing blood vessels. This process continues
even as the tumor matures. Thus, upregulation of
angiogenesis is a key step in sustained tumor
growth and may also be critical for tumor
metastasis
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Angiogenesis has been correlated with disease
progression and/or poor prognosis in many tumor
typesincluding lung, colon, breast, renal, and
other cancersand can be activated at different
stages of tumor development, depending on the
tumor type and microenvironmental conditions.
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Angiogenesis is essential to tumor development
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Mechanism
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VEGF the predominant mediator of angiogenesis
Among the many factors implicated in
angiogenesis, VEGF has been identified as the
most potent and predominant. The scope of
scientific research involving VEGF continues to
grow exponentially. From 1995 to 2005, the number
of VEGF-related abstracts presented at the annual
meeting of the American Society of Clinical
Oncology (ASCO) increased 50-fold, highlighting
the increased focus in research upon VEGF's role
in oncology.
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VEGF
VEGF (also known as VEGF-A, but commonly referred
to simply as VEGF) stands for vascular
endothelial growth factor. This protein plays an
important role in angiogenesis. As its name
suggests, VEGF stimulates vascular endothelial
cell growth, survival, and proliferation. As seen
in preclinical models, VEGF has been shown to
facilitate survival of existing vessels,
contribute to vascular abnormalities (eg,
tortuousness and hyperpermeability) that may
impede effective delivery of antitumor compounds,
and stimulate new vessel growth
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The VEGF family of proteins
VEGF is a member of a family of 6 structurally
related proteins (see table below) that regulate
the growth and differentiation of multiple
components of the vascular system, especially
blood and lymph vessels. The angiogenic effects
of the VEGF family are thought to be primarily
mediated through the interaction of VEGF with
VEGFR-2.
There are 4 major isoforms of VEGFA (VEGF), each
coded for by a different portion of the VEGF
gene. These isoforms are VEGF121, VEGF165,
VEGF189, and VEGF206. Although these isoforms
behave identically in solution, they differ in
their ability to bind heparin and the
extracellular matrix
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RECEPTORS OF VEGF GROWTH FACTORS
Three receptors have been identified that bind
different VEGF growth factors VEGFR1 (FLT1),
VEGFR2 (Flk1/KDR), and VEGFR3 (FLT4) (initial
receptor names are given in parentheses)
These receptors belong to the superfamily of
receptor tyrosine kinases (RTK) and, based on
their structural peculiarities, they comprise a
special class within it. Like all RTK, the VEGF
receptors are transmembrane proteins with a
single transmembrane domain .
The extracellular region of VEGFR is formed by
seven immunoglobulin-like domains (IG I-VII),
whereas the intracellular part exhibits tyrosine
kinase activity, and the tyrosine kinase domain
in these receptors is separated to two fragments
(TK-1 and TK-2) by an inter-kinase insert All
VEGFR receptors are highly homologous .
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Left A tumor (tan) produces growth factors
(yellow) that partner with receptors (orange) on
blood vessels. This partnership stimulates the
growth of new, though abnormal, blood vessels to
nourish the tumor. Research suggests that little
chemotherapy (green) can make its way through
these defective blood vessels to poison the
tumor. Right The drug Avastin (blue) blocks
growth factors from turning on their receptors.
Research suggests that some of the faulty blood
vessels begin to die off. Others form in a more
orderly structure, which as a result improves
both the delivery and the effectiveness of
chemotherapy.
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