(American Journal of Pathology. 1998;153:11-16.)
© 1998 American Society for Investigative Pathology
What Is the Role of Vascular Endothelial Growth Factor-Related Molecules in Tumor Angiogenesis?
Roberto F. Nicosia
From the Department of Pathology and Laboratory Medicine, Allegheny
University of the Health Sciences, Philadelphia, Pennsylvania
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Introduction
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Growth of solid tumors depends on angiogenesis, the
process by which new blood vessels develop from the endothelium of a
pre-existing vasculature.1
Tumors promote angiogenesis by
secreting growth factors that stimulate endothelial migration,
proliferation, proteolytic activity, and capillary
morphogenesis.2
Newly formed blood vessels supply the tumor
with nutrients and oxygen, dispose of its metabolic waste products, and
generate paracrine stimuli, which further promote tumor cell
proliferation and invasiveness.1,3
Among the known angiogenic factors, vascular endothelial growth factor
(VEGF) has emerged as a central regulator of the angiogenic process in
physiological and pathological conditions.4
This molecule
was first named vascular permeability factor by Dvorak and co-workers
because of its potent stimulatory effect on the permeability of the
tumor microvasculature.5
Ferrara et al6
coined
the term VEGF to describe a mitogenic factor that selectively
stimulated endothelial cell proliferation and angiogenesis. The same
molecule was independently discovered by others.7,8
Connolly et al9
reported that vascular permeability factor
was mitogenic for endothelial cells and had the capacity to stimulate
vascular proliferation. Sequence analysis of cDNAs demonstrated that
vascular permeability factor and VEGF were the same
molecule.4
Recently, the VEGF family of growth factors has
expanded with the addition of four new molecules: placenta growth
factor (PlGF), VEGF-B, VEGF-C, and VEGF-D (Table 1)
.10-13
VEGF and VEGF-related molecules have homologous amino acid sequences
including eight cysteine residues, which are also found in
platelet-derived growth factors A and B, and bind to the same class of
tyrosine kinase receptors.4,8
In this issue of the
American Journal of Pathology, Salven et al14
report that VEGF-B and VEGF-C are expressed in a variety of human
tumors. This commentary briefly reviews our knowledge of this field and
critically evaluates the potential role of VEGF-related molecules in
tumor angiogenesis and neoplastic progression.
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VEGF
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VEGF comprises four main isoforms produced by alternative
splicing of mRNA: VEGF121,
VEGF165, VEGF189,
VEGF206.4,15
A fifth isoform,
VEGF145, has been found in placental cells and carcinoma
cells from the female reproductive tract.16
VEGF molecules
have a signal peptide sequence and are secreted as homodimers through
conventional pathways.4
The mature form of VEGF is the
VEGF165 homodimer, which has a molecular weight of~ 45
kd. VEGF189 and VEGF206 are the most basic
isoforms, bind to heparin with greater affinity than
VEGF165, and are almost completely sequestered in the
extracellular matrix. VEGF121, which is slightly acidic
because it lacks the basic amino acids responsible for heparin binding,
is the most soluble isoform. In the extracellular compartment, plasmin
cleaves a portion of the VEGF molecule, generating a 34-kd protein that
consists of the first 110 NH2-terminal amino
acids.17
This may be a mechanism whereby bioactive VEGF is
released by proteolysis from larger isoforms sequestered in the
extracellular matrix.4,17
VEGF binds with high affinity to two tyrosine kinase receptors: VEGF
receptor (VEGFR)-1 (Flt-1) and VEGFR-2
(KDR/Flk-1).4,18,19
Binding of VEGF causes
receptor dimerization followed by autophosphorylation of the receptor
and signal transduction. There are significant differences between
VEGFR-1 and VEGFR-2. For example, endothelial cells without endogenous
VEGFRs migrate and proliferate in response to VEGF when transfected
with VEGFR-2 but lack such responses if transfected with
VEGFR-1.20
VEGFR-1 is, however, capable of mediating
PIGF-induced endothelial cell proliferation and plasminogen activator
expression.61
Gene knockout experiments have confirmed a
critical role in angiogenesis for both VEGFR-1 and
VEGFR-2.21,22
Inactivation of the VEGFR-2 gene causes
failure of vasculogenesis, the process of de novo formation
of blood vessels from undifferentiated
mesenchyme.21
VEGFR-2 knockout embryos are unable to form
blood islands and to generate hemopoietic precursors. Targeted mutation
of the VEGFR-1 gene does not affect the differentiation of endothelial
cells but causes a disorganized assembly of the developing
vasculature.22
Because of vascular abnormalities, both
VEGFR-1 and VEGFR-2 knockout embryos die in utero between
days 8.5 and 9.5. Embryos having a single (VEGF+/-) or both VEGF (VEGF
-/-) alleles defective suffer from a failure of vasculogenesis,
leading to intrauterine death by day 10 to 12.23
The
demonstration of a vasculogenic defect also in heterozygous embryos
(VEGF+/-) suggests that there is a critical threshold of VEGF levels
below which new blood vessels are unable to form.23
VEGF stimulates the migration and proliferation of arterial, venous,
and microvascular endothelial cells as well as angiogenesis in
vivo and in vitro.4,6,7,9
VEGF promotes the
balanced degradation of the extracellular matrix around the sprouting
endothelium by inducing the expression of urokinase-type plasminogen
activator, tissue-type plasminogen activator, plasminogen activator
inhibitor-1,24
and interstitial collagenase.25
By enhancing the permeability of venules to circulating proteins
including fibrinogen, VEGF is believed to facilitate the perivascular
deposition of fibrin, which further potentiates
angiogenesis.26
Through its capacity to induce nitric
oxide, VEGF may also mediate the vasodilation and increased blood flow
that precede angiogenesis.27
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PlGF
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The PlGF gene encodes three alternatively spliced isoforms with
different secretion patterns, heparin binding affinities, and
dimerization properties: PlGF-1, PlGF-2, and
PlGF-3.10,28-30
PlGF binds with high affinity to VEGFR-1
but not to VEGFR-2.31
The expression of PlGF is restricted
to the placenta and is not observed in the majority of normal adult
tissues.30
Because it forms heterodimers with VEGF, which
are less potent than VEGF homodimers, PlGF may reduce the
bioavailability of active VEGF molecules.32
PlGF, however,
can also potentiate the activity of suboptimal concentrations of
VEGF.31
Recently, Ziche et al33
reported that
recombinant PlGF-1 purified from overexpressing eukaryotic cells was as
effective as VEGF and basic fibroblast growth factor in stimulating
angiogenesis in the rabbit cornea assay. They also noticed that the
mitogenic effect of PlGF-1 was dependent on the endothelial cell type.
On this basis, they suggested that the preferential target of PlGF-1 is
the endothelium of postcapillary venules, whereas VEGF stimulates with
equal potency both macrovascular and microvascular endothelium.
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VEGF-B
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VEGF-B is present in a variety of normal organs and is
particularly abundant in heart and skeletal muscle. There are two
alternatively spliced isoforms of VEGF-B: VEGF-B167 and
VEGF-B186.11,34,35
VEGF-B167 is a
highly basic heparin-binding protein which, similarly to
VEGF189 and VEGF206, remains associated with
the cell or the extracellular matrix and is not released into the
culture medium unless cells are treated with heparin.
VEGF-B186 homodimers, on the other hand, are readily
secreted.34
VEGF-B can form disulfide-linked heterodimers
with VEGF and influence the bioavailability of this molecule, as
described for PlGF.11,34
VEGF-B stimulates endothelial cell
proliferation, but it does not bind to VEGFR-2. Recent studies indicate
that the function of VEGF-B is mediated by VEGFR-1 (Olefsson,
Kerpelainen, Mandriota, Pepper, Aase, Kumar, Ganji, Jelisch, Shibuya,
Alitalo, and Eriksson, unpublished manuscript).
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VEGF-C
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VEGF-C is produced as a propeptide that is proteolytically cleaved
to a 21-kd molecule.12,35,36
Unlike some of the VEGF,
VEGF-B, and PlGF isoforms, VEGF-C does not bind to heparin. VEGF-C
increases vascular permeability and stimulates the migration and
proliferation of endothelial cells, but at a significantly higher
concentration than VEGF.12
VEGF-C binds to and induces
autophosphorylation of the tyrosine kinase receptor Flt-4,
which has been renamed VEGFR-3.12
VEGF-C also activates
VEGFR-2 but not VEGFR-1.12
Proteolytic processing of VEGF-C
generates several VEGF-C forms with increased activity toward VEGFR-3,
but only the fully processed VEGF-C can bind to VEGFR-2.36
VEGF-C has greater affinity for VEGFR-3 than VEGFR-2. The other members
of the VEGF family, with the exception of VEGF-D (see below), are
unable to activate VEGFR-3. VEGF-C is expressed during embryonal
development in regions where lymphatics sprout from venous
vessels.12
VEGF-C is present also in adult tissues, where
it is postulated to play a role in the maintenance of lymphatic
endothelial differentiation.12
VEGFR-3 is highly expressed
in angioblasts, veins, and lymphatics during embryonal vasculogenesis
but becomes largely restricted to the lymphatic endothelium in adult
tissues.12,37
VEGFR-3 is also expressed in the high venular
endothelium of lymph nodes.37
Because of their patterns of
expression, VEGF-C and VEGFR-3 have been implicated in
lymphangiogenesis, the process of formation of new lymphatics.
Exogenous VEGF-C selectively stimulates lymphatic proliferation in the
chorioallantoic membrane, whereas VEGF promotes angiogenesis from blood
vessels.38
Consistent with these observations, targeted
overexpression of VEGF-C in the skin of transgenic mice causes
lymphatic hyperplasia.39
The targeted effect of VEGF-C is
probably linked to the formation of VEGFR-2/VEGFR-3 heterodimers in
lymphatic endothelial cells.39
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VEGF-D
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VEGF-D, the newest member of the VEGF family, is 48% identical to
VEGF-C.13
Both VEGF-C and VEGF-D have long NH2-
and C-terminal extensions, which set these growth factors apart as a
subfamily of VEGF-related proteins. VEGF-D is induced by
c-fos40
and is strongly expressed in the fetal
lung during development. In the adult it is primarily found in skeletal
muscle, heart, lung, and intestine.13
VEGF-D is a ligand
for both VEGFR-2 and VEGFR-3, but does not bind to the
VEGFR-1.41
In addition, VEGF-D stimulates the proliferation
of endothelial cells.41
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Regulation of VEGF and VEGF-Related Molecules
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Members of the VEGF family are regulated by different mechanisms.
For example, serum, growth factors, and inflammatory cytokines increase
VEGF and VEGF-C mRNAs but have no effect on
VEGF-B.42,62
Amplification of the ras oncogene
causes up-regulation of VEGF4
but leaves unaltered the
expression of VEGF-B and VEGF-C.42
Hypoxia strongly induces
VEGF mRNA expression but has no significant effect on VEGF-B, VEGF-C,
or PlGF.4,42
A mutant form of p53 potentiates the
expression of VEGF mRNA but has no effect on VEGF-B or VEGF-C
mRNA.42,43
Renal cell carcinoma cells lacking the von
Hippel-Lindau (VHL) tumor suppressor gene or expressing an inactive
form of this gene exhibit abnormal regulation of VEGF production, which
is reversed by introduction of the wild-type VHL gene.44
Human chorionic gonadotropin induces expression of VEGF by
granulosa-luteal cells, decreases production of VEGF-C, and has no
effect on VEGF-B.45
Among the VEGF-related molecules mRNAs,
the VEGF-B mRNA is the most stable and is not regulated by any of the
factors examined so far.
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Expression of VEGF and VEGF-Related Molecules in Tumors
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VEGF has been found in lung, thyroid, breast, gastric, colonic,
kidney, bladder, ovary, and cervical carcinomas, as well as in
angiosarcomas, germ cell tumors, and neoplasms of the central nervous
system (reviewed by Ferrara and Davis-Smyth4). PlGF was
down-regulated in thyroid carcinomas and overexpressed in renal cell
carcinomas.46,47
Studies with cultured cells showed that
VEGF-B was expressed by a variety of tumor cells, whereas VEGF-C was
detected in a limited number of prostatic, lung, and renal carcinoma
cell lines.42
The work by Salven et al14
demonstrates different patterns of expression of VEGF, VEGF-B, and
VEGF-C in breast carcinomas, squamous cell carcinomas, lymphomas,
melanomas, sarcomas, adenomas, and papillomas.14
VEGF-B was
found by Northern blot analysis in approximately 90% of the tumors,
whereas VEGF-C was detected in half of the cases. Interestingly, 10
tumors expressed VEGF-C and/or VEGF-B but not VEGF, and four carcinomas
failed to produce any type of VEGF or VEGF-related molecule. In a
similar study, using in situ hybridization and reverse
transcriptase polymerase chain reaction, Sowter et al48
found that mRNAs encoding for VEGF and VEGF-B were up-regulated in
ovarian carcinomas relative to the normal ovarian surface epithelium.
Conversely, neither VEGF-C nor PlGF was expressed at a substantial
level.
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Potential Role of VEGF-Related Molecules in Tumor Angiogenesis
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Although more studies are needed to better define the significance
of these observations, a picture is emerging showing heterogeneity of
VEGF and VEGF-related molecules expression in human neoplasms. This
heterogeneity is not surprising, because of the distinct regulatory
mechanisms that control the expression of these growth factors. Based
on the VEGF/VEGF-related molecule profiles reported by Salven et
al,14
tumors can be divided into different groups depending
on which factors predominate. Tumors that do not produce significant
amounts of VEGF may use VEGF-related molecules to stimulate
angiogenesis. Although they are less potent than VEGF, VEGF-related
molecules have the capacity to directly activate VEGFRs and potentiate
the activity of VEGF when this factor is produced at low
levels.31
In tumors that do not express VEGF, VEGF-B, or
VEGF-C, angiogenesis may be promoted by PlGF, VEGF-D, or other
VEGF-related molecules that have yet to be described. It is also
reasonable to invoke VEGF-independent mechanisms involving other
angiogenic factors.
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Potential Role of VEGF-Related Molecules in Lymphangiogenesis and
Cancer Spread
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The discovery of VEGF-C and VEGF-D, which are both capable of
activating the lymphatic endothelial receptor VEGFR-3, has reopened the
question of lymphatic proliferation in tumors. Achen et
al41
have proposed that expression of VEGF-C and VEGF-D at
a particular site in developing embryos can attract the growth of both
hematic and lymphatic endothelial cells, whereas expression of VEGF, a
molecule that activates VEGFR-2 but not VEGFR-3, would only attract the
hematic endothelium. A similar hypothesis can be postulated for tumors,
but previous studies have failed to demonstrate lymphangiogenesis in
neoplasms.49
The reported absence or paucity of lymphatics
in tumors is intriguing, because lymphatics can proliferate in
experimental conditions.50-52
In addition, lymphatic
endothelial cells have been isolated and shown to form capillary tubes
when stimulated with endothelial growth factors.53
Evaluation of lymphatics in tumors is made difficult by the attenuated
morphology of lymphatic capillaries and the lack of markers for
lymphatic endothelial cells. The discovery of VEGFR-3 and the
development of VEGFR-3-specific probes should facilitate the
identification of lymphatics in tissue sections. Using this approach,
it would be of interest to evaluate whether tumors that produce VEGF-C
and/or VEGF-D have a greater number of lymphatics and a more aggressive
behavior than tumors negative for these factors. Should these studies
confirm the lack of lymphangiogenesis in human tumors, it will be
important to investigate the mechanisms responsible for this
phenomenon. A possible explanation could be that growth of lymphatics
is blocked by the high interstitial pressure of tumors. In addition,
lymphatic endothelial cells may be sensitive to inhibition by tumor
cell-derived angiostatic factors such as endostatin.54
VEGF-C and VEGF-D may promote tumor progression by mechanisms other
than lymphangiogenesis. For example, lymphatic endothelial cells may
respond to VEGF-C and VEGF-D by secreting chemotactic factors for
cancer cells, thereby promoting lymphatic invasion and lymph node
metastases. VEGF-C and VEGF-D may regulate the contractility of
lymphatics by stimulating nitric oxide production, as reported for VEGF
in arteries.27
This in turn may affect the extent of
lymphatic permeation and the rate of metastasis, because lymph is
propelled to lymph nodes by periodic contractions of lymphatic
vessels.55
In addition, cancer cells that produce VEGF-C or
VEGF-D and metastasize to lymph nodes may have a growth advantage
because of their capacity to stimulate both hematic and lymphatic
endothelia.37
A similar consideration applies to lymphoma
cells the angiogenic activity of which may be mediated, at least in
part, by VEGF-C and/or VEGF-D.14,56
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VEGF-Related Molecules in Tumors: Therapeutic Implications
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The heterogeneity of VEGF and VEGF-related molecules expression in
tumors has important implications for the design of anti-angiogenic
therapy in cancer patients. Experimental animal models have
demonstrated that tumor growth can be inhibited with anti-VEGF
antibodies (reviewed by Ferrara and Davis-Smyth4). This
effect is due to the anti-angiogenic activity of the antibodies, which
starve tumor cells by cutting off their blood supply. It is also
possible that a restricted number of tumors capable of expressing
VEGFRs may be directly inhibited by anti-VEGF therapy.57,58
A clinical trial is currently evaluating the safety and efficacy in
cancer patients of a humanized anti-VEGF antibody.59
Although it is too early to make predictions, the report by Salven et
al14
suggests that there may be a subset of tumors that do
not use VEGF to stimulate angiogenesis and are therefore resistant to
anti-VEGF treatment. On this basis, tumor angiogenesis may be more
effectively blocked using a cocktail of antibodies directed against
VEGF and VEGF-related molecules. An additional approach would be to
target VEGFRs with either blocking antibodies or tyrosine kinase
inhibitors. It is, however, still unclear how interactions among VEGF
and VEGF-related molecules affect tumor angiogenesis. Future studies
with experimental models of angiogenesis should elucidate the potential
antagonism, synergy, or additive effects of different combinations of
VEGF and VEGF-related molecules. It will also be of interest to
evaluate whether there is a relation between the expression of
VEGF-related molecules, the density of microvessels in histological
section, and the aggressiveness of the tumor, as reported for
VEGF.60
Finally, studies should be carried out to evaluate
the potential role in the lymphatic spread of cancer of lymphangiogenic
factors such as VEGF-C and VEGF-D.
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Summary and Conclusion
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The work by Salven et al14
demonstrates that there is
redundancy and heterogeneity of VEGF and VEGF-related molecules
expression in human tumors. Although the biological significance of
these observations remains to be elucidated, this report suggests that
tumors from different patients use distinct repertoires of VEGF and
VEGF-related molecules to stimulate angiogenesis. In addition, some
tumors produce lymphangiogenic molecules such as VEGF-C, which may
contribute to lymph node metastasis. These findings confirm the
complexity of tumor angiogenic regulation and raise challenging new
questions for both basic researchers interested in the molecular
mechanisms of tumor progression and clinical investigators involved in
the design of growth factor-based anti-angiogenic therapy for cancer
patients.
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Footnotes
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Address reprint requests to Roberto F. Nicosia, M.D., Ph.D., Department of Pathology, MS 435, Allegheny University of the Health Sciences, Broad and Vine Streets, Philadelphia, PA 19102. E-mail:
nicosiarf{at}auhs.edu
Supported by National Institutes of Health Grant HL52585.
Accepted for publication April 14, 1998.
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Top
Introduction
VEGF
