ARTICLE
Auteur(s) : Marina Ziche, Lucia Morbidelli
Section of Pharmacology, Department of Molecular
Biology, University of Siena, Siena, Italy
accepté le 12 Juin 2009
Features of tumor vascularisation
Angiogenesis is the main process mediating the expansion of the
blood vessel network during development, tissue regeneration and in
pathological conditions such as cancer.
The growth of new blood vessels is regulated by a sequential
cascade of cellular events which involves:
- – the directional sprouting of outgrowing endothelial
cells to form a solid cord
- – their attractive and repulsive positioning with
subsequent network formation and establishment of flow
- – the maturation of the resulting vasculature with
recruitment of periendothelial mural cells and acquisition of the
quiescent vascular phenotype. This series of events is associated
with distinct endothelial phenotypes and corresponding molecular
signatures designed as tip cells (invading lamellipodia- and
filopodia-rich cells), stalk cells (following remodelling and
lumen-forming cells) and phalanx cells (quiescent endothelial
cells).
In tumors, the expanded vasculature provides nutrients required
for tumor growth, but the newly formed and remodelled blood vessels
have multiple abnormalities that distinguish them from normal
vessels, and limit their efficiency. Tumor blood vessels are highly
irregular, tortuous, have arterio-venous shunts, blind ends, lack
smooth muscle and innervation, and have incomplete endothelial
linings and basement membranes. All components of the vessel wall,
including endothelial cells, pericytes and basement membrane are
indeed abnormal. Structural defects results in impaired endothelial
barrier function, vessel leakiness, poor blood flow, hypoperfusion
and increased interstitial pressure, thus limiting the diffusion
and efficacy of anticancer drugs.
Typical tumor angiogenic factors such as vascular endothelial
growth factor (VEGF), and fibroblast growth factors (FGFs) are able
to drive the early stages of angiogenesis and induce the abnormal
vessel phenotype. The process is nonetheless controlled by the
balance of multiple and complex angiogenic factors and inhibitors.
Among them, nitric oxide (NO) has been reported to contribute to
tumor biology and vascularization with multiple cellular and
molecular effects and sometimes with divergent properties.
Examining the role of NO in angiogenesis and tumor cell development
can help the design of novel drugs potentially aimed at producing
vessel normalization thus improving drug delivery and anticancer
treatments.
NO and cancer
After the initial discovery of NO, several actions in both
physiology and pathological conditions have been attributed to this
gaseous mediator. Most of them are divergent, depending on the
concentration, the duration of its release, the cell type and the
presence of scavengers or other reactive molecules in the
microenvironment, which may impair or otherwise amplify the effects
of NO.
In the last three decades, the role of NO in tumor cell biology
and tumor angiogenesis has been firmly established. However, many
articles have been published suggesting contradicting results (see
[1-4] as recent reviews).
A solid tumor consists of cancer cells and host-derived cells,
including tumor-infiltrating leucocytes and cells of the tumor
vasculature, especially endothelial cells. One or more of these
cellular constituents may be responsible for the production of NO
in the tumor microenvironment [5] (figure 1). Functional
roles for tumor-derived NO in cancer progression and spreading
represent a complex combination of NO-mediated effects on tumor
cell proliferation and invasiveness and the functions of
immune/stromal cells infiltrating tumors. It has been proposed that
NO also promotes tumor growth by regulating tumor blood flow and
maintaining the vasodilated tone of tumor microvasculature. In
addition to angiogenesis stimulation, NO can promote metastasis by
increasing vascular permeability, and up-regulating matrix
metalloproteases (MMPs). Recently, it has been reported that NO
released by metastatic tumor cells may impair the immune system,
which facilitates their escape from immunosurveillance and
metastasis of tumor cells [2, 6]. Moreover, an association between
NO production, resistance to chemotherapeutic drugs and
angiogenesis has been demonstrated [7].
In this intricate scenario, the present review will be
particularly focused on the proangiogenic role of NO in tumor
angiogenesis, providing experimental data in support of it.
NO and NO synthases (NOS) involved in tumor
angiogenesis
NO is a short-lived, gaseous, free radical that is produced by the
activity of specific NOS isoforms starting from the precursor
L-arginine [8]. NO is a highly diffusive, hydrophobic molecule and
it is therefore a key signalling molecule in inflammation-driven
diseases including cancer [9].
For a comprehensive description of NO biosynthesis and NOS
isoform regulation and expression we refer to pertinent literature
[10]. In this review, particular attention will be paid to the
endothelial constitutive (eNOS) and inducible (iNOS) isoforms. The
first is mainly present on vascular endothelium and produces
nanomolar amounts of NO in a calcium-dependent manner. The
inducible isoform is overexpressed in most of the solid tumors
analyzed so far, and produces micromolar concentrations of NO in a
calcium-independent manner. The distinction, however, is not so
clear since there is evidence that iNOS can be induced in the
endothelium by for example inflammatory cytokines, while many tumor
cells express eNOS [11]. This finding highlights the problem of
lack of efficacy by NOS inhibitors designed to be specific for the
various synthases and proposed as antitumor strategies.
NO contribution to vascular biology
NO contributes to cardiovascular regulation by multiple mechanisms,
such as vascular tone (vasodilation), vascular remodelling
(inhibition of smooth muscle cell proliferation), and cell-cell
interactions in blood vessels (inhibition of platelet adhesion and
aggregation; inhibition of monocyte adhesion) [12]. NO is involved
in the regulation of basal systemic, coronary, and pulmonary
vascular tone through the production of cyclic guanosine
3′,5′-monophosphate (cGMP) in smooth muscle cells, inhibition of
the vasoconstrictor peptide endothelin-1, and inhibition of
norepinephrine release from sympathetic nerve terminals [12].
eNOS-dependent NO production has been also shown to contribute
significantly to the endothelium-protective effect of vasodilating
peptides (as substance P and bradykinin) [13-15], drugs such as
angiotensin-converting enzyme inhibitors [16] and
growth/vasopermeabilizing factors such as VEGF [17].
Multiple roles of NO in tumor angiogenesis
Early experimental studies have shown that induction of iNOS in
tumor cells promotes angiogenesis (by upregulating VEGF
expression), which increases microvascular density and tumor
progression [18-22]. Inhibition of NOS, genetically or with
pharmacological agents, has been shown to reduce VEGF levels and
inhibit tumour angiogenesis [23-26].
The strongest data supporting a fundamental role for NO in tumor
angiogenesis come, however, from the histological examination of
tumor specimens, revealing a significant relationship between high
angiogeneic activity (i.e. microvessel density or VEGF expression)
and iNOS expression in human brain, head and neck, lung, breast,
stomach, colon tumors, etc. (see [27-36] among others). Together
these findings definitely indicate that cancer-derived NO mediates
tumor angiogenesis, invasion and growth.
The contribution of NO to tumor angiogenesis is multifaceted. NO
has been shown to mediate angiogenesis by direct and indirect
mechanisms. Beside its direct, stimulating effects on endothelial
cells, NO has been demonstrated to be a mediator of angiogenic
factor activity and to control transcriptionally angiogenic stimuli
expression in endothelial, tumor and stromal cells. Conversely, it
has been reported that antiangiogenic molecules and drugs lead to
NOS inhibition and that NO downregulates angiogenesis-inhibitor
expression. The permissive action of exogenous or
endogenously-produced NO on angiogenesis will be particularly
examined.
Firstly, NO exposure increases DNA synthesis, cell proliferation
and migration of endothelial cells through the soluble guanylate
cyclase-cGMP pathway, as well as through S-nitrosylation or
nitration of specific target proteins [13, 37-40]. Recently, a role
for NO in the mobilization of stem and progenitor cells has also
been described [41].
Secondly, NO has been shown to mediate the function of many
angiogenic factors. VEGF, sphingosine-1-phosphate, angiopoietins,
oestrogen, shear stress and metabolic stress activate eNOS through
phospholipase-C/Ca2+-calmodulin binding and
phosphoinositide 3-kinase (PI3K)-Akt-induced and
adenylate-cyclase-protein-kinase-A-induced phosphorylation [42-49].
VEGF can also activate eNOS by the recruitment of heat shock
protein 90 [41, 50, 51] and upregulation of eNOS mRNA and protein
[52, 53]. Further, VEGF increases angiogenesis in both
iNOS+/+ and iNOS–/– mice, but not in
eNOS–/– mice, supporting a predominant role for eNOS in
VEGF-induced angiogenesis and vascular permeability [41].
Additionally, NO or reactive nitroderivative species interfere
with the synthesis and activation of the pro-metastatic and
pro-angiogenic family of matrix metalloproteinases (MMP), enzymes
involved in the degradation of the basal membrane of blood vessels
[38, 54, 55]. The role of NO in the balance between MMPs and their
tissue inhibitors (TIMPs) has been studied in vitro in
microvascular endothelial cells and in vivo in the avascular rabbit
cornea model. Data reported in figure 2 indicate that
endogenously-produced NO is able to promote MMP-2 activity in
endothelium stimulated by VEGF, by promoting MMP-2 gene
up-regulation and down-regulating TIMP-1 and 2 expression
(figure 2A-C).
These VEGF-promoted effects are eNOS- and cGMP-dependent, since
they can be blocked by preincubation with selective inhibitors of
NOS (L-NMMA) or soluble guanylate cyclase (ODQ), and reproduced by
a stable analogue of the intracellular mediator of NO (8-Br-cGMP)
or exogenous NO (the NO donor S-nitroso-N-acetyl-l,l-penicillamine,
SNAP). The relevance of the NO pathway and the MMP/TIMP balance in
VEGF-induced neovascularization (figure 3) was
substantiated in the rabbit cornea, where the neovascular growth
induced by VEGF was impaired by pre-treating the animals with a NOS
inhibitor (L-NAME) in the drinking water, or enriching the corneal
microenvironment with TIMP-2 microinjection (figure 2D).
According to the altered balance between MMPs and TIMPs by
exogenous and endogenous NO in the microvascular endothelium, the
regulation of both endothelial MMP-13 and TIMP-4 by
direct amino acid nitration has been recently reported [56,
57].
These findings, taken together, reinforce the concept of
abnormal vessel morphology and function in tumors, accompanied by
increased basement membrane degradation.
In cell culture models, eNOS is a central mediator of several
other endothelium growth stimulators, such as prostaglandin
E2 (PGE2; 58). Also, PGE2
activates the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and
promotes endothelial cell sprouting (the first step in
neoangiogenesis) through the NO/cGMP pathway [58].
Thirdly, NO is an important modulator of the expression of
endogenous angiogenic factors. An NO donor induces VEGF expression
[19] and microvascular endothelial cell proliferation through the
upregulation of FGF-2 [13] (figure 3).
NO activates the transcription factor hypoxia-inducible factor
1 α (HIF1 α), which, in turn, upregulates VEGF, thereby
promoting angiogenesis [59, 60]. NO induces HIF1 α synthesis
through MAPK and PI3K under normoxic conditions [61]. It also
impairs normoxic degradation of HIF1α by inhibiting the action of
prolyl hydroxylases [62]. A recent study found expression of
iNOS and/or eNOS in all cases of HIF1α-positive oral squamous-cell
carcinomas, which suggests that there is an NO-induced HIF1α
accumulation and subsequent tumour-promoting effects in cancer
[63].
At low levels, endogenous or exogenous NO can also serve as an
intracellular second messenger for the induction of expression of
the IL-8 gene in tumor cells, which represents an indirect
angiogenesis factor [64, 65]. Moreover, in tumor and stromal cells
NO can regulate the expression of inflammatory molecules as nuclear
factor-KB (NF-kB) and cycloxygenase-2 [66].
The commonly held concept regarding cooperation among
inflammatory mediators is indeed generally accepted both in
inflammatory-based diseases and in cancer. Overexpression, elevated
secretion, or abnormal activation of proinflammatory mediators,
such as cytokines, chemokines, prostaglandins, and nitric oxide,
and an intricate network of intracellular signalling molecules
including upstream kinases and transcription factors facilitate
tumor promotion and progression [67]. In the case of colorectal
cancer for example, the interaction of NO with cyclooxygenase
(COX)-2 seems to mediate a cooperative effect, culminating in
the increased production of VEGF [68].
Conclusion and perspectives
Many points on the role of NO in vessel biology and in particular
in tumor angiogenesis remain to be elucidated. First of all, the
controversial proposal that vasodilator nitric oxide donors be used
as therapeutic adjuvant to increase tumor blood flow and
oxygenation in order to increase the response to radiotherapy or
p53-dependent anticancer drugs [69]. However, NO combination
therapy for solid tumors does not have approval at this time.
Among the open questions we want to stress i) the unsuccessful
effort to develop selective and safe strategies to inhibit NOS
isoforms present at tumor level, ii) the paucity of clinical trials
involving NO, and iii) the genetic variations present in genes
encoding for NOS isoforms or NO pathway-related proteins in
relation to tumor risk.
A phase I clinical trial designed to use the NOS inhibitor
N-nitro-L-arginine (L-NNA) in different solid tumors documented a
correlation between the L-NNA plasma area under the curve and the
reduction in tumor blood volume [70].
Genetic comparison studies on healthy people and cancer patients
have shown that gene polymorphisms in NOS are associated with the
development of multiple cancers [71-73]. Although the functional
effect of NOS SNPs has yet to be determined in large studies, these
data support the hypothesis that abnormal NOS genes might drive
tumorigenesis in humans.
Acknowledgments
This work was partially funded by the European Community FP6
funding (LSHM-CT-2004-0050333) and the Italian Ministry of
Health-Regione Toscana.
The technical assistance of Dr Sandra Donnini is gratefully
acknowledged.
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