IJC

International Journal of Cancer

Vascular cell adhesion molecule-1 (VCAM-1)—An increasing

insight into its role in tumorigenicity and metastasis
Martin Schlesinger and Gerd Bendas
Department of Pharmacy, Rheinische Friedrich-Wilhelms-University Bonn, 53121 Bonn, Germany

Vascular cell adhesion molecule-1 (VCAM-1) first attracted attention more than two decades ago as endothelial adhesion
receptor with key function for leukocyte recruitment in term of cellular immune response. The early finding of VCAM-1 binding

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to melanoma cells, and thus a suggested mechanistic contribution to metastatic spread, was the first and for a long time the
only link of VCAM-1 to cancer sciences. In the last few years, hallmarked by a growing insight into the molecular understand-
ing of tumorigenicity and metastasis, an impressive variety of VCAM-1 functionalities in cancer have been elucidated. The
present review aims to provide a current overview of VCAM-1 relevance for tumor growth, metastasis, angiogenesis, and
related processes. By illustrating the intriguing role of VCAM-1 in cancer disease, VCAM-1 is suggested as a new and up to
now underestimated target in cancer treatment and in clinical diagnosis of malignancies.

Structural and functional aspects of VCAM-1 biology
VCAM-1 (CD106) was discovered independently by two
groups in 1989. First named INCAM-110 due to the TNF-a
or IL-1 “inducibility” on HUVEC cells, it was later termed
VCAM-1 when its ability to mediate a firm melanoma cell
adhesion was revealed.1,2 Generally, VCAM-1 is expressed on
the luminal and lateral side of endothelial cells under inflam-
matory conditions, mediating rolling and adhesion of various
subsets of leukocytes as prerequisite for recruitment from
blood into tissue.3,4 Therefore it is a keyplayer in the immune
surveillance to numerous diseases and a VCAM-1 knock-
down in mice results in embryonic death.5 It is also
expressed on bone marrow stromal cells and therefore
involved in the homing of human CD34 early hematological
progenitor cells to the bone marrow stroma.6,7 In 1990 the
integrin a4b1 (very late activation antigen-4, VLA-4) was
identified as a first ligand for VCAM-1 mediating firm adhe-
sion of B cells to lymphoid germinal centers.8 Additionally,
the integrins a4b7, aMb2, a9b1, and aDb2 have also been
revealed as VCAM-1 binding partners, but VLA-4 emerged
as the best investigated one.9–16 VCAM-1 belongs to the
immunglobulin (Ig) superfamily of proteins, comprising of
several extracellular Ig-like domains, a transmembrane region
and cytoplasmatic domain of 19 amino acids.1,17 In activated
endothelial cells, VCAM-1 is localized in lipid-raft-like plat-
forms with the tetraspanins CD9, CD81, and CD151, referred
Key words: VCAM-1, VLA-4, metastasis, cancer, angiogenesis
DOI: 10.1002/ijc.28927
History: Received 4 Jan 2014; Accepted 16 Apr 2014; Online 26 Apr
2014
Correspondence to: Dr. Martin Schlesinger, Department of
Pharmacy, Rheinische Friedrich-Wilhelms-University Bonn, An der
Immenburg 4, 53121 Bonn, Germany, Tel.: 149-228-735238, Fax:
149-228-734692, E-mail: martinschlesinger1@gmx.de
as tetraspanin-enriched microdomains, suggested to support
VCAM-1 surface expression and function.18–20 Two VCAM-
1 splice variations in humans have been identified, consisting
of seven (7d) or six (6d) Ig-like domains, the latter lacks the
fourth domain.21–24 Domains one and four have been
revealed as binding sites for VLA-4 (Fig. 1).24,25 VCAM-1
(6d) binds VLA-4 with a higher affinity under soluble condi-
tions compared to VCAM-1 (7d), but 7d VCAM-1 is more
efficient in mediating cell adhesion and spreading.26 The
intracellular VCAM-1 terminus is connected to the actin
cytoskeleton via Ezrin and Moesin.27,28 VCAM-1 can also be
cleaved from the endothelial surface to a soluble (s)VCAM-1,
which is increased in various diseases.29 VCAM-1 expression
is stimulated under inflammatory conditions by a multitude
of signals like cytokines, ROS, oxLDL, high concentrations of
glucose, TLR agonists, or shear stress.30–38
Beside endothelial cells, it is also expressed on follicular
dendritic cells, macrophages in the spleen and thymus, and
Kupffer cells in the liver under noninflamed conditions.39
Because of its wide distribution in human tissues and organs,
VCAM-1 participates in a plenty of pathophysiological situa-
tions like autoimmune diseases, cardiovascular disease, or
infections.40–42 For a detailed view on VCAM-1, its expres-
sion and signaling during diseases, the reader is referred to a
brilliant review recently published by Cook-Mills et al.20
The focus of the present review is given to the upcoming
understanding of VCAM-1 functionalities in tumor progres-
sion and metastasis.
Contribution of vascular expressed VCAM-1 to metastasis
Already in the late 1980s, when a first insight was provided
into the endothelial leukocyte adhesion, the relevance of these
adhesive events also for tumor cell (TC) adhesion and metas-
tasis has been predicted.43 The first report on the importance
of VCAM-1 for melanoma adhesion to the endothelium dates

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 2 VCAM-1 in tumorigenicity
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Figure 1. Different mechanisms of VCAM-1 contribution to cancer progression and metastasis. TCs entering the blood are immediately sur-
rounded by platelets. This clot can stick in the vasculature due to size restriction. VLA-4 positive TCs in turn can adhere to VCAM-1 on acti-
vated endothelium (a) and later on transmigrate into the subendothelium (b). TCs attached to the endothelium can recruit myeloid cells to
the nascent metastatic niche, which bind to VCAM-1 and are helpful for a successful metastatic development (c). TCs aberrantly expressing
VCAM-1 can receive pro-survival signals due to interactions with VLA-4 positive macrophages in the lungs (d). In the bones VCAM-1 can
activate VLA-4 expressing preosteoclasts leading to bone destruction.Structure of VCAM-1 and interaction partners: In the enlarged section
of the figure, the molecular structure of VCAM-1, consisting of seven Ig-like domains, is illustrated. VCAM-1 is localized in tetraspanin con-
taining microdomaims, is cleaved from the cell surface by ADAM8, 9, 12, and 17, and interacts with VLA-4 via domains 1 and 4. [Color fig-
ure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

from 1989.2 A number of interesting in vitro studies followed, kidney carcinoma, and naturally blood borne tumors like leu-
which confirmed a crucial role of VCAM-1 for the adhesion kemia and lymphoma cell lines.44,45 A pretreatment of
of VLA-4 positive TCs, such as melanoma, osteosarcoma, human endothelial cells with IL-1, TNFa, or bacterial

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Schlesinger and Bendas
endotoxin resulted in an expression-dependent increment of
VCAM-1 and in adhesion of human malignant melanoma
cells.43,46
In first in vivo studies mice were injected with inflammatory
mediators like TNFa, IL-1b, SDF-1, or exposed to surgical
stress indicating an increased expression of pulmonary VCAM-
1, which resulted in an augmented number of pulmonary met-
astatic foci after TC injection. Metastasis could be reduced by
antibodies directed against VLA-4 or VCAM-1.47–50 In these
earlier studies, VCAM-1 was conferred to mediate firm adhe-
sion of the TCs to the vessel wall as a prerequisite for a subse-
quent transmigration, while the endothelium is activated by
host or TCs’ secreted cytokines or by concurrent disease proc-
esses like infection or sepsis.2
Two aspects remained not adequately answered by these
studies, (i) whether VCAM-1 is also involved in TC transen-
dothelial migration and (ii) how endothelial cells are acti-
vated locally for increased VCAM-1 expression. Studies
provided evidence that endothelial VCAM-1 mediates, next
to firm adhesion of VLA-4 positive TCs also their transmi-
gration.51,52 Concerning the underlying mechanisms, the
endothelial cell retraction for opening occluding junctions
between the cells were explained with a transient Ca21
increase in endothelial cells, culminating in a calmodulin
mediated phosphorylation of myosin light chains.53
Nowadays the VCAM-1 “outside-in” signaling in endothe-
lial cells has been realized by several other mechanisms.
VLA-4 binding to VCAM-1 stimulates intracellular Ca21
release and affects L-type calcium channels. A parallel activa-
tion of Rac-1 GTPase leads to an activation of the NADPH
oxidase NOX2,54–56 which in turn generates low concentra-
tions of reactive oxygen. Reactive oxygen dismutates to
hydrogen peroxide, which oxidizes the prodomain of matrix
metalloproteinases 2 and 9 within minutes.57,58 Thus, MMPs
are autocatalytically activated and digest the intercellular tight
junctions and components of the extracellular matrix paving
the way for transendothelial cell migration.57,58 Recently, Lee
et al. established a chimeric (rabbit/human) antibody by
phage-display technology, which binds specifically to the
sixth Ig-like domain in human and murine VCAM-1 on vas-
cular endothelial cells.59 This antibody alleviated transmigra-
tion of U937 monocytic cells and fresh isolated human
monocytes through a HUVEC layer, but had no influence on
cell adhesion of U937 cells to HUVECs. The authors state
that the sixth Ig-like domain in VCAM-1 interacts with tetra-
spanins CD9, CD81, and CD151 and thus directly affects
downstream signaling which may regulate transendothelial
migration.
This emphasizes the dual function of VCAM-1 for
immune and TC adhesion to and transmigration through
endothelial cells.
Concerning the spatial and temporal aspects of VCAM-1
expression, numerous studies were dedicated to endothelial
activation leading to arrest of TCs at the vascular wall. Next
to inflammatory mediators, even the shear force of blood has
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3
an important impact on endothelial activation status and
VCAM-1 expression. TCs entering the blood are immediately
surrounded by platelets and several subtypes of leukocytes.
This clot can become stuck in small vessels due to its size
and have an influence on blood flow velocity, which finally
has an impact on adhesion receptor expression. This area of
altered VCAM-1 expression can potentially serve as a harbor
for circulating TCs.
Mild shear stress of 12 N cm22 had a cytoprotective effect
on TNFa primed HUVECs with a reduced expression of
VCAM-1 compared to static conditions. NFjB function seemed
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to be responsible for the attenuated proinflammatory effects.60
In line with this, further groups reported that higher shear rates
of about 18–20 N cm22 inhibit VCAM-1 expression on vascu-
lar endothelial cells activated by cytokines, coculturing with
smooth muscle, or TCs.38,61,62 Haddad et al. reported of proin-
flammatory effects of lower shear rates (0.9–9 N cm22) to
TNFa or coculture-activated HUVECs and an augmented
VCAM-1, ICAM-1 and E-selectin expression.38 Because higher
shear rates were identified as an inhibitor for endothelial
CAMs expression, Haddad et al. proposed a threshold above
which flow performs anti-inflammatory effects to vascular
endothelial cells.38 However, the molecular mechanisms behind
the shear flow mediated effects in endothelial cells (e.g., G
protein-coupled receptors) leading to a NFjB activation and a
VCAM-1 deregulation were not elucidated in these studies.
A more relevant activation of the endothelium in course
of metastasis relies on TC and host cell agglomerates. During
the period of transit in the blood, TCs are vulnerable to
death induced by shear stress or by immune surveillance.63
TCs entering the blood flow are immediately surrounded by
platelets in a P-selectin dependent fashion, which provide
shelter from the hostile environment. Activated platelets in
turn secrete an abundance of cytokines (e.g., CCL2, CCL3,
CCL5, CCL7, Gro-a)64–66 which are able to stimulate the
endothelium and furthermore attract bone marrow-derived
cells (BMDCs).67 BMDCs like neutrophils or monocytes
expressing P-selectin glycoprotein ligand-1 interact with acti-
vated platelets and contribute to the TC platelet clot.68,69 Fur-
ther platelet adhesion receptors also participate in the
binding between platelets and BMDCs. This clot can induce
an activation and VCAM-1 expression of the endothelium.
Khatib et al. explained a mechanism of sinusoidal endo-
thelium activation by highly metastatic colorectal or lung car-
cinoma cells in the liver.70 They identified a host
proinflammatory response of hepatic Kupffer cells due to
direct TC contact or proximity. Activated Kupffer cells
secrete increased concentrations of TNFa or IL-1a finally
leading to an upregulation of sinusoidal adhesion receptors
like VCAM-1, ICAM-1, E- and P-selectin, which create a
hospitable environment for a metastatic niche. Activation of
endothelial cells due to the contact to other cells has been
referred by several groups. Damle et al. showed that endothe-
lial VCAM-1 expression is mediated by T lymphocyte subpo-
pulations and requires direct intercellular contact.38,71,72
 4 VCAM-1 in tumorigenicity
The direct interaction between circulating TCs and the
endothelium has been shown to induce expression of adhe-
sion receptors.73,74 Langley et al. revealed an increase in
VCAM-1 expression in cardiac, hepatic and cerebral vascular
beds in a murine model of spontaneous melanoma metastasis
and detected negligible TNFa and IL-1a concentrations, pro-
viding further evidence for a VCAM-1 induction by direct
cell to cell contact.75
Simiantonaki revealed a pronounced raise in VCAM-1
and other CAMs expression due to treatment of HUVECs
with supernatant of different TCs prior stimulated with LPS,
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TNFa, or IL-1b.76 Sipos et al. found that tumor injection
was followed by a long-term VCAM-1 overexpression on
brain microvessels in vicinity to the metastatic foci.77
L€aubli et al. demonstrated a microvascular endothelial
activation due to TC contact, but for a proper activation the
presence of both leukocytes and platelets were required.78
The authors proved that selectin-mediated cell interactions
are indispensible for a microvascular endothelial activation.
Next to an enhanced VCAM-1 expression, a release of CCL5
from endothelium was detected ensued by a monocyte
recruitment to the metastatic microenvironment. This study
exemplarily refers to the importance and growing insight into
the involvement of chemokines in cancer metastasis. Several
mechanisms have been elucidated how chemokines contrib-
ute to metastasis. The best studied receptors and ligands in
this context are CXCR4-CXCL12 and CCR7-CCL21 due to
their wide expression on TCs, often guiding the TCs to their
organ-specific destination.79–81 CCL2, also known as Mono-
cyte Chemoattractant Protein-1 (MCP-1), has turned out to
be involved in metastasis by recruiting myeloid cells or
inflammatory monocytes, respectively, to the nascent meta-
static foci.82,83 This could be shown for colon cancer metasta-
sis to the liver, in which a myeloid subset (CD11b/Gr1mid)
was recruited to early hepatic metastases. Ablation of myeloid
cell recruitment led to failure of metastasis.84,85 For human
breast cancer cells metastasizing to the lung, an enrichment
of CCR2 expressing inflammatory monocytes and subsequent
macrophages on the metastatic nodules could be discov-
ered.86,87 Wolf et al. revealed that tumor derived CCL2
enhanced the vascular permeability thereby facilitating the
TC extravasation.88 Muschel et al. demonstrated that the
recruitment and retention of myeloid cells in the tumor
vicinity fundamentally depended on endothelial VCAM-1
expression, which is induced by TCs expressed tissue fac-
tor.89,90 Beside VCAM-1, also vascular adhesion protein-1
(VAP-1) was essential for myeloid cell retention. Blocking
VCAM-1 or VAP-1 elicited a mitigated number of myeloid
cells and a diminished TC survival and metastasis. VCAM-1
expression is not constitutive but induced by TC clot secreted
tissue factor and has no influence on TC attachment to the
pulmonary vasculature. Hence the VCAM-1/VLA-4 interac-
tion seems to account for myeloid cell but not for TC reten-
tion. Data finally suggest that VCAM-1 has more functions
in the metastatic cascade than mediating an initial and firm
endothelial adhesion of VLA-4 positive TCs. Recruitment
and retention of prometastatic myeloid cells to the metastatic
niche seems to be a further contribution of VCAM-1.
Role of VCAM-1 in angiogenesis
Angiogenesis is a characteristic of solid tumor development
since tumor growth bigger than 1–2 mm3 needs the develop-
ment of new blood vessels to have a sustainable supply with
oxygen and nutrition.91 Metastatic foci not shaping new
venous sprouts stay in a latent mode with an equilibrium
between proliferation and apoptosis.92 The developing vessels
are in a stage of energy and indicate attenuated levels of
endothelial adhesion molecules on their surfaces. The down-
regulation of VCAM-1, first described for melanoma and car-
cinoma,93,94 serves most probably as a tumor protecting
mechanism by attenuating the immune response for leuko-
cyte infiltration.95 The reduced adhesion molecule expression
on tumor microvessels is related to the TC secretion of basic
fibroblast growth factor (bFGF) and vascular endothelial
growth factor (VEGF).96,97 Also the in vitro treatment of
endothelial cells with proinflammatory TNFa or IL-1a could
not compensate a bFGF or VEGF pretreatment to recover
VCAM-1 expression completely.95,96 Recently, Egfl7 (also
known as VE-statin) expressed by many carcinomas was
shown to promote a tumor escape by hampering VCAM-1
expression on tumor endothelial cells.98
On the contrary to the above mentioned observations,
other studies report on an upregulation of VCAM-1 after
VEGF stimulation of endothelial cells.99–101 However, in
these studies the VEGF treatment was conducted for 24 hr or
less. So it is tempting to speculate that an initial VEGF incu-
bation fosters cellular adhesion molecule expression, whereas
a prolonged treatment impairs expression levels.
Next to the nascent tumor microvasculature, also a sys-
temic inhibitory effect of a primary tumor on the interaction
of leukocytes with the vessel wall could be detected.96 The
authors speculated that angiogenic factors released from the
large primary tumor are responsible for this effect. Wang
et al. could overcome the downregulation of adhesion mole-
cules in angiogenic microvessels by applying recombinantly
expressed calreticulin, a chaperone protein normally involved
in antigen loading of MHC I molecules. Thus they obtained
a reconstitution of VCAM-1 expression on HUVEC cells in
vitro.102 With the help of a calreticulin gene transfer using
recombinant Sindbis viruses intramuscularly injected into
mice, bearing orthotopic liver tumors, an increased number
of CD41 and CD81 cells could be attained within the
tumors, which reduced the tumor volume and the levels of
immunosuppressive molecules like IL-10.
Aberrantly expressed VCAM-1 on tumor cells
Next to the vascular expressed VCAM-1 and its role in
metastasis, some tumor entities show an aberrant expression
of VCAM-1 on their cells, such as breast, renal or gastric car-
cinomas.103–106 For instance, VCAM-1 is a component of a
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Schlesinger and Bendas
site-specific metastasis gene signature in breast cancer.107,108
The question arises, why do certain tumors express an endo-
thelial adhesion molecule and what is the potential benefit in
course of metastasis?
Recently, the contribution of aberrantly expressed VCAM-1
to metastasis was investigated for breast cancer cells metasta-
sizing to the lung and bones.103,109 The VCAM-1 mediated
mechanisms in these studies were excellently reviewed else-
where, so that this review shall give a short survey of the work
done so far.110,111 The TC expressed VCAM-1 does not give
any advantage concerning the endothelial adhesion, invasion
or transendothelial migration of TCs. Instead it allows a strong
adhesion and interaction with the integrin VLA-4 on mono-
cytes and tumor-associated macrophages to recruit them to
the lung tissue.112,113 Tumor-associated macrophages and
monocytes have been shown to possess numerous beneficial
effects for TCs e.g., providing protection from immune surveil-
lance. Here, the macrophages bind via their VLA-4 to cognate
VCAM-1 which provokes a VCAM-1 clustering on the TC
surface. The clustered VCAM-1 binds to the intracellular
adaptor molecule Ezrin, which then induces phosphoinositide-
3-kinase finally leading to an activation of Akt. Akt in turn
mediates prosurvival signals to the TCs and thus fosters lung
metastasis.
Comparable to the situation in the lung, VCAM-1 does
also not provide adhesion of breast cancer cells in the bone,
but rather enabling quiescent, indolent TCs in the bone to
emerge from dormancy due to novel expressed VCAM-1
driven by a NFjB signaling pathway. VCAM-1 supports
metastasis in two different ways. First, soluble VCAM-1
recruits monocytic preosteoclasts to tumor site and secondly,
the VLA-4 positive preosteoclasts bind to VCAM-1 on TCs.
This interaction leads to a differentiation of osteoclast precur-
sors to multinucleated, mature osteoclasts which subsequently
destroy bone matrix, thereby discharging growth factors.
These factors in turn activate cancer cells to promote preos-
teoclast maturation. So, VCAM-1 is able to initiate the estab-
lishment of osteolytic metastatic foci by recruiting and
activating osteoclast precursors.103,109–111
Also renal cell carcinoma is a tumor type overexpressing
VCAM-1. Wu and coworkers originally intended to investi-
gate the mechanism of cancer immunotherapy and the mech-
anisms mediating TC escape. For this, they generated a
human papillomavirus-16 E7-expressing cancer cell line and
a mouse vaccine containing E7.114 Mice were treated with the
vaccine, which led to a substantial increased number of E7-
specific CD4 and CD8 cells and also to a resistance against
the E7 expressing TCs. Finally, cells were obtained completely
resistant against vaccine induced immune response. Gene
expression profiles of these cells, compared to the originally
susceptible ones indicated VCAM-1 as the most highly
upregulated gene, so that VCAM-1 expression is anyhow
related with increased immune resistance. Looking for the
VCAM-1 mediated mechanism revealed significantly attenu-
ated numbers of antigen-specific CD81 T cells in the tumors.
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The authors suggested the following mechanism to contribute
to the observed effects. Because of the fact that CD81 and
CD41 T cells express high levels of VLA-4, it is conceivable
that the T cells migrate away from the TCs and are unable to
recognize the TC MHC receptors due to minimized con-
tact.104,115 It is well documented that VCAM-1 is able to fos-
ter the migration of CD81 T cells.116,117 In detail, it has been
revealed that VCAM-1 interaction with the VLA-4 subunit
a4 leads to an association of the a4 cytoplasmatic tail with
the adaptor protein paxillin, which then phosphorylates and
activates the focal adhesion kinase (FAK). FAK in turn binds
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to Src kinase which is involved in focal adhesion disruption
and integrin-dependent cell migration.118–120 The binding of
VCAM-1 to T cell expressed VLA-4 can also stimulate T cell
migration via the integrin aLb2.121 Nonetheless the authors
do not exclude other mechanisms to be responsible for the
observed effects.
Role of VCAM-1 in the lymphatic tissue
Immediately after cancer diagnosis, a TNM (tumor-nodules-
metastases-) staging has to be conducted to predict the
patients’ survival outcome. This emphasizes the pathological
importance of primary tumors that spread to the lymphatic
circulation. Although information provided by nodules biop-
sies are well accepted, molecular mechanisms of TC spread
in the lymphatics and especially contributions of adhesion
receptors for tumor contacts with the lymphatic vasculature
has been neglected. While studies focused on the involvement
of integrins in lymphangiogenesis, as reviewed in Refs. 122
and 123, hardly any information on VCAM-1 function were
given. In 1999 the selective markers for lymphatic endothelial
cells (LEC), Lyve-1,124 Prox-1125 and podoplanin126 have
been identified, which opened the field for a more detailed
view on lymphatic metastasis and angiogenesis. VLA-4 was
identified as a marker for proliferating lymphatic vessels
which serves as a harbor and site of accumulation for
VCAM-1 expressing TCs.103,109,127,128
Rebhun et al. on the contrary focused on the direct inter-
action between VCAM-1 and VLA-4 and withdrew from the
angiogenic involvement of VLA-4. They identified a constitu-
tive VCAM-1 expression on LEC in mice with melanomas
and generated B16F1 melanoma cells with either high a4
subunit or cells with minor a4 subunit expression. Expect-
edly, melanoma cells with high a4 levels shared a stronger
affinity to LEC than cells with less a4. By inhibition of
VCAM-1 or VLA-4 the interaction was reduced, hence other
adhesion receptors perhaps involved in cell binding can be
excluded. In vivo, the situation was similar, 80 % of mice
injected with high a4 level cells suffered from lymph node
metastases in comparison to 30% of the mice administered
with cells with normal a4 expression. B16F1 with low levels
of a4 were insufficient to produce tumors in C57BL/6J mice
and even in athymic mice.129 These findings have to be
regarded under the perspective that VLA-4 is also involved
in cell proliferation and apoptosis. For e.g., neural crest cells
 6 VCAM-1 in tumorigenicity
or retinal ganglion cells VLA-4 is reported to play an essen-
tial role in cell survival.130,131 Hence, a low VLA-4 expression
level in B16F1 cells could initiate apoptosis in these cells
which is completely independent from binding and harboring
to VCAM-1 in lymphatic vessels and could also be a reason
for the vanished number of metastatic foci.
Because of the fact that a lot of melanoma cells are VLA-
4 positive, it is reasonable that this kind of cancer has a great
tendency to establish metastatic foci in the VCAM-1 express-
ing lymph nodes and that the assessment of the lymph nodes
is an important predictor for patients’ outcome.132,133 In
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comparison to the situation in the blood, where TCs are
immediately surrounded by platelets and the interaction with
vascular endothelial cells is hampered, the LEC expressed
VCAM-1 seems to contribute to a greater extend to a direct
anchorage of VLA-4 expressing TCs to the lymphatic tissue.
VCAM-1 as biomarker and as potential therapeutic target
VCAM-1 is a key receptor in the immune surveillance
involved in many inflammatory processes like diabetes melli-
tus, impaired renal function, hemodialysis, hypertension,
rheumatoid arthritis, systemic lupus erythematosus, septic
shock or coronary artery disease.134–137 Therefore it seemed
likely to use VCAM-1 as a predictive parameter to estimate
diseases’ severity. Initially regarded as a membrane based
receptor, Gearing et al. were the first who developed an
ELISA to quantify soluble VCAM-1 (sVCAM-1) and detected
sVCAM-1 in supernatant of cytokine stimulated cells and
surprisingly also in serum of healthy and increased levels in
the serum of sick individuals.138 VCAM-1 cellular shedding
is mediated by the membrane-anchored glycoproteins
ADAM8, 9 12, and 17, each of them characterized by a met-
alloprotease and a disintegrin domain.139–144 Since that time,
elevated serum concentrations of sVCAM-1 have been found
in patients suffering from various diseases.134 Banks was the
first who could exhibit augmented sVCAM-1 levels in serum
of 110 cancer patients.145 This was the starting point for a
plenty of investigations aiming to correlate sVCAM-1 with
cancer progression and metastasis. Other groups analyzed
VCAM-1 expression on TCs or tumor surrounding tissue by
gene arrays or immunohistochemically and correlated these
findings with tumorigenesis.
Most of the studies conclude augmented levels of VCAM-
1 with advanced oncogenesis, as for instance in stage 4 breast
cancer patients.146 Furthermore, the development of lymphe-
dema after breast cancer surgery also correlated with VCAM-
1 expression and sVCAM-1 was markedly increased after a
dose-dense regimen of chemotherapy.147,148 Similar findings
could be obtained in colorectal cancer patients, where
sVCAM-1 revealed as a biomarker for overall survival and
post-operative recurrence.29,149–151 Also in gastric and renal
carcinoma, ovarian cancer, and in indolent non-Hodgkin
lymphomas, an assessment of disease risk, cancer-free sur-
vival, or response to chemotherapy was feasible by VCAM-1
quantification.106,152–156 Taking alleviated VCAM-1 levels in
cancer as a basis, Montes-Sanchez could identify three new
glycosylated VCAM-1 isoforms resulting from HUVEC treat-
ment with tumoral soluble factors.157 These isoforms could
perhaps be helpful in future to distinguish cancer from other
diseases associated with augmented VCAM-1 levels. Nonethe-
less, it should be mentioned that by quantifying sVCAM-1
serum levels, it is not feasible to distinguish between
sVCAM-1 originating from endothelial or TCs or VCAM-1
released by angiogenic lymphatic vessels. So, a detailed infor-
mation about the current pathophysiological progress is not
derivable. This review should only provide a short overview
of the work in this field done so far but there are plenty of
brilliant studies, using VCAM-1 as a predictive marker for
cancer progression, not mentioned here.
Beside the utilization of VCAM-1 as a marker for cancer
progression, blockade of endothelial VCAM-1 adhesive func-
tions appears promising to interfere with cancer diseases. TC
or myeloid cell adhesion to the endothelium and for this rea-
son the establishment of metastatic niche could potentially be
reduced. However, direct blocking approaches of VCAM-1
by small molecules or antibodies have not been described yet.
Hence, several drugs with miscellaneous indications exhibit
anti-adhesive effects on TCs due to a downregulation of
VCAM-1 and other CAMs on endothelial cells. Morphine
demonstrated to decrease VCAM-1 expression on HUVECs
treated with the supernatant of LPS stimulated colon cancer
cells.158 Resveratrol prevented hepatic melanoma metastasis
by attenuation of IL-18 dependent expression of VCAM-1 on
sinusoidal endothelial cells,159 and Simvastatin induced a
VCAM-1 downregulation on peritoneal mesothelial cells.160
Others identified further potential target molecules responsi-
ble for an upregulation of VCAM-1 contributing to cancer
metastasis e.g. heparanase, caveolin, and IL-8.105,161,162 A
downregulation approach for VCAM-1 expressed by TCs or
LEC is currently not available.
Next to a downregulation, endothelial VCAM-1 has also
attracted attention as a potential target for drug carriers, such
as liposomes or nanoparticles.163 In first studies, immunoli-
posomes were conjugated with anti-VCAM-1 mAb or Fab’
and directed either against tumor vasculature or inflamma-
tory lesions for a site specific drug release at metastatic foci
or inflammation.164–166 Furthermore, nanoparticles of differ-
ent materials have been targeted with peptides sequences
against VCAM-1.167–169 These nanoparticle approaches
mainly intended a specific detection of areas with upregulated
VCAM-1.170–174 For instance, Serres et al. generated targeted
microparticles of iron oxide and were able to detect meta-
static lesions in mice brains up to two or three orders of
magnitude smaller than those volumes recognized clini-
cally.175 These findings provide a promising approach for
detection of brain metastases at an earlier and perhaps treat-
able stage. A sensitive detection of cerebrovascular inflamma-
tion associated with VCAM-1 upregulation is also important
for an appropriated treatment of multiple sclerosis.176
Although an advanced yielding to a direct VCAM-1 blockade
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Schlesinger and Bendas 7

Table 1. Summary of different VCAM-1 mediated mechanisms in tumorigenesis

VCAM-1 localization Situation in cancer metastasis Functional consequences
Endothelial cells VCAM-1 expression upregulated  Adhesion and transmigration of
TCs;
 Recruitment of myeloid cells to
the metastatic niche
Angiogenic vessels VCAM-1 expression decreased Attenuated leukocyte infiltration in
angiogenic vessels
Tumor cell surface Aberrant VCAM-1 expression Recruitment of macrophages and
preosteoclasts
Effects on cancer progression
Establishment of a proper meta-
static niche (pro-tumor)
Protection against immune sur-
veillance (pro-tumor)
Prosurvival signals in TCs and
osteoclast maturation with
destruction of bone matrix (pro-
tumor)

Mini Review
Lymphatic endothelial cells Constitutive VCAM-1 expression Adhesion of VLA-4 expressing TCs Establishment of a proper meta-
static niche in lymph nodes (pro-
tumor)

The effects of VCAM-1 expression on endothelial cells, TCs, angiogenic vessels and lymphatic endothelial cells for tumor progression and metastasis
are embraced.

is currently not available, the blockade of VCAM-1 counter
receptors VLA-4 and a4b7 is well established in treatment of
multiple sclerosis and inflammatory bowel disease by the
mAbs natalizumab and vedolizumab.177,178 VLA-4 inhibition
by small molecules or heparin derivatives are also promising
approaches currently investigated.179,180 In animal trials nata-
lizumab attenuated multiple myeloma cell growth in the
bone marrow microenvironment and prevented osteoly-
sis.181,182 In an experimental model of melanoma metastasis,
natalizumab reduced the metastatic burden to the lungs.179
However, inhibition of the VLA-4/VCAM-1 interaction
affects the cellular immune response, as indicated by the
development of multifocal leukoencephalopathy due to reacti-
vation of the JC virus in some multiple sclerosis
patients.183,184 Hence, the combination of chemotherapeutic
agents with potential VCAM-1 inhibitors could have benefi-
cial effects on metastasis, angiogenesis or lymph node spread-
ing for cancer patients, but it can also have lethal adverse
effects.
Conclusions
With an upcoming understanding of the molecular context
in tumor growth and metastasis, a body of evidence
accumulated in the last few years and emerged VCAM-1 as
a keyplayer with multiple functionalities for directing the
metastatic spread of tumors, for the formation of metastatic
niche and supporting the angiogenetic process, as summar-
ized shortly in Table 1. It will be a matter of the near future
to confer these findings to derive a therapeutic benefit for
clinical cancer treatment. In term of that, morphological
VCAM-1 detection and serological quantification as a bio-
or tumor marker seems to be a promising strategy to make
clinical use of VCAM-1 functionality in tumor
development.

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