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Antiangiogenic Therapy for Cancer: Current and Emerging Concepts

Antiangiogenic Therapy for Cancer: Current and Emerging Concepts

ABSTRACT: Angiogenesis is an essential step in the growth and spread of solid tumors-the cause of more than 85% of cancer mortality. Inhibiting angiogenesis would therefore seem to be a reasonable approach to prevent or treat cancer. However, tumor angiogenesis differs from normal angiogenesis in that the resulting vessels are tortuous, irregularly shaped, and hyperpermeable. These abnormalities result in irregular blood flow and high interstitial fluid pressure within the tumor, which can impair the delivery of oxygen (a known radiation sensitizer) and drugs to the tumor. Emerging evidence suggests that antiangiogenic therapy can prune some tumor vessels and normalize the structure and function of the rest, thereby improving drug delivery and normalizing the tumor microenvironment. This normalization effect may underlie the therapeutic benefit of combined antiangiogenic and cytotoxic therapies. This paper reviews current and emerging concepts of the mechanism of action of antiangiogenic therapies and discusses the implications of these mechanisms for their optimal clinical use.

We have known for nearly a
century that tumors induce
growth of new blood vessels.[
1,2] In 1971, Folkman proposed
that blocking angiogenesis should be
able to arrest tumor growth.[3] A few
years later, Gullino demonstrated that
cells in precancerous tissue acquire
angiogenic capacity on their way to
becoming cancerous, and thus proposed
that inhibition of angiogenesis
be used to prevent cancer.[4] In the
past 3 decades our understanding of
angiogenesis in general, and tumor
angiogenesis in particular, has grown
exponentially, culminating in the approval
of the first antiangiogenic
agent, bevacizumab (Avastin), for the
treatment of advanced colorectal
cancer and spawning more than 60
clinical trials using a variety of antiangiogenic
agents.[5,6]

The widely accepted mechanism
of action of antiangiogenic therapy is
that these agents prevent the growth
and metastasis of tumors by inhibiting
the formation of new vessels.
While this notion holds true, data from
randomized clinical trials show that
when used as monotherapy, currently
available antiangiogenic agents produce
modest objective responses and
do not yield long-term survival benefit
in patients with solid tumors.[7-9]
However, when given in combination
with chemotherapy, bevacizumab, an
antibody directed against vascular endothelial
growth factor (VEGF), produced
unprecedented increases in
survival (5 months) in patients with
metastatic colorectal cancer.[10]
These data support the earlier predictions
of Teicher, who postulated that
combined administration of antiangiogenic
therapy and cytotoxic (chemotherapy
and radiation) therapy would
yield maximum benefit because such
combinations would destroy both
compartments in tumors: the cancer
cells and the endothelial cells.[11]

However, this theory seems paradoxical.
If antiangiogenic agents destroy
the tumor vasculature, the
delivery of chemotherapeutic agents
and oxygen to the tumor would be
compromised, resulting in less cytotoxicity
and radiation resistance. The
emerging concept of vascular normalization
provides researchers with a
potential resolution to this paradox:
this hypothesis posits that judicious
application of antiangiogenic agents
can improve the function of tumor
vasculature and thus improve the delivery
of oxygen and drugs to tumor
cells.[12,13] Here I review this emerging
counterintuitive concept and the
currently well-accepted view that antiangiogenic
therapy inhibits neovascularization,
as well as the importance
of optimizing the dose and sequencing
of these therapies.

Role of Angiogenesis in
Tumor Progression

In adults, normally occurring
neovascularization is largely limited
to female reproductive organs and
healing wounds. Otherwise, adult
neovascularization occurs as a result
of a pathologic situation, such as cancer.
Although tumors can initially coopt
normal blood vessels to support
growth, a new blood supply is required
for the tumor to grow beyond
1 to 3 mm. This concept has been
firmly established by many supported
studies and is well illustrated by a
study that found numerous small thyroid
gland tumors in individuals who
died of other causes.[14] Prior to the
development of tumor vasculature, tumors
are dormant.[15] For angiogenesis
to occur, the effect of proangiogenic
factors must outweigh the effect of the
antiangiogenic factors. When the balance
tips towards proangiogenesis, the
tumor undergoes what has been described
as the angiogenic switch, which
fosters the development of new vessels
and allows tumor progression to ensue.[
16] Further, once angiogenesis is
prompted, tumors become invasive locally
and systemically.

Evidence for the critical and pathologic
role that angiogenesis plays in
cancer progression comes from studies
demonstrating that microvessel
density within the tumor-the number
of blood vessels in a defined
area-is not only prognostic in some
tumor types, but also correlates with
the development of metastases.[17]

Mechanisms of Angiogenesis

At least four cellular mechanisms
can result in the vascularization of
tumors: co-option, intussusception,
sprouting (angiogenesis), and vascu-
logenesis (Figure 1). Tumor cells can
co-opt and grow around existing vessels
to form perivascular cuffs. However,
these cuffs cannot grow beyond
the diffusion limit of critical nutrients,
and may actually cause the collapse
of the vessels due to the
compressive forces generated by tumor
cell growth (referred to as solid
stress). Alternatively, an existing vessel
may enlarge in response to the
growth factors released by tumors, and
an interstitial tissue column may grow
in the enlarged lumen and partition
the lumen to form an expanded vascular
network. This mode of intussusceptive
microvascular growth has been
observed during tumor growth, wound
healing, and gene therapy.[18-21]

Angiogenesis is perhaps the most
widely studied mechanism of vessel
formation. During angiogenesis, the
existing vessels become leaky in response
to growth factors released by
normal cells or cancer cells; the basement
membrane and the interstitial
matrix dissolve; pericytes dissociate
from the vessel; endothelial cells migrate
and proliferate to form an array
or sprout; a lumen is formed in the
sprout-a process referred to as canalization;
branches and loops are formed
by confluence and anastomoses of
sprouts to permit blood flow; and finally,
these immature vessels are invested
in basement membrane and
pericytes. During normal physiologic
angiogenesis, these vessels differentiate
into mature arterioles, capillaries,
and venules, whereas in tumors
they may remain immature.[12,22-24]

Finally, vasculogenesis occurs during
embryonic development when a
primitive vascular plexus is formed
from endothelial precursor cells (also
known as angioblasts). Circulating
endothelial precursor cells mobilized
from the bone marrow or peripheral
blood also can contribute to postnatal
vasculogenesis in tumors and other
tissues.[25,26] However, recent data
have questioned the importance and
role of these cells in tumor angiogen-
esis.[27] One of the current challenges
in tumor treatment is to discern the
relative contribution of each of the
four mechanisms of neoangiogenesis
to the formation of tumors to optimize
antiangiogenic treatment of
cancer.[28]

Structure and Function
of Tumor Vessels

Despite the critical role of blood
vessels in tumor growth and metastasis,
the structure and function of tumor
vasculature is abnormal (Table 1, Figure
2). The organized structure of the
vascular network is lost. The system
lacks defined arterioles, venules, and
capillaries, and connections among
vessels are sometimes incomplete. The
vessels themselves are irregularly
shaped with areas of dilation and constriction.
Endothelial cell arrangement
is abnormal with the cells separated
by wide gaps at one location or stacked
on one another nearby. Endothelial
cells can lose their reactivity to common
endothelial markers.[29] Similarly,
the patterns and functions of
mural cells are also abnormal. Tumor-
associated pericytes demonstrate
abnormal protein expression and morphology.
Significantly, abnormal pericytes
have a loose association with
endothelial cells, contributing to the
high vascular permeability. The differences
between normal and abnormal
vasculature are summarized in Table 1.

These structural abnormalities result
in uneven tumor perfusion and
high tumoral interstitial fluid pressure
(IFP).[13,30,31] High tumoral IFP is
caused in part by tumor vessel hyperpermeability.
In normal tissues, the
vessel is able to maintain a gradient
of fluid pressure from inside the vessel
to the outside. In tumors, this gradient
disappears and the pressure
outside the blood vessels (IFP) tends
to become equal to that inside, ie,
microvascular pressure (MVP). Similarly,
in normal tissues, the colloid
osmotic pressure (osmotic pressure
exerted by large proteins) inside blood
vessels (P) is much higher compared
to that outside (I). In tumors, these
two become approximately equal due
to vessel leakiness. The loss of these
pressure gradients between the vessels
and the tumor impedes the delivery
of large molecular weight
therapeutics to the tumor. Uneven tumor
perfusion impedes the delivery
of all blood-borne molecules, including
oxygen and nutrients as well as
chemotherapeutics.

Tumor vessel hyperpermeability
also contributes to sluggish blood flow
in tumors, which results in regions of
hypoxia and acidosis. Hypoxia contributes
to resistance to some drugs
and radiotherapy by decreasing the
availability of reactive oxygen species.
In addition, it can induce genetic
instability and upregulate angiogenesis
and metastasis genes.[32,33] Furthermore,
both hypoxia and acidosis
can impede the cytotoxic effects of
immune cells infiltrating the tumor.
Thus pathologic tumor vasculature
results in conditions that protect the
tumor from cytotoxic therapy and
from host immune cells.

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