Galectins: matricellular glycan-binding proteins linking cell
adhesion, migration, and survival
M. T. Elolaa, C. Wolfenstein-Todela, M. F. Troncosoa, G. R. Vastaband G. A. Rabinovichc,*
aInstituto deQu?micay Fisicoqu?micaBiol?gicas(IQUIFIB),FacultaddeFarmaciayBioqu?mica,Universidad
de Buenos Aires, Jun?n 956 (C1123), Buenos Aires, Argentina
bCenter of Marine Biotechnology, University of Maryland Biotechnology Institute, 701 East Pratt Street,
Baltimore, Maryland 21202, USA
Aires, Argentina, Fax: +54 11 4783–2869, e-mail: email@example.com
Received 29 January 2007; received after revision 7 March 2007; accepted 28 March 2007
Abstract. Galectins are a taxonomically widespread
family of glycan-binding proteins, defined by at least
one conserved carbohydrate-recognition domain with
a canonical amino acid sequence and affinity for b-
galactosides. Because of their anti-adhesive as well as
pro-adhesive extracellular functions, galectins appear
to be a novel class of adhesion-modulating proteins
collectively known as matricellular proteins (which
include thrombospondin, SPARC, tenascin, hevin,
and disintegrins). Accordingly, galectins can display
de-adhesive effects when presented as soluble pro-
teins to cells in a strong adhesive state. In this context,
the de-adhesive properties of galectins should be
considered as physiologically relevant as the pro-
adhesive effects of these glycan-binding proteins. This
article focuses on the roles of mammalian galectins in
regulation of these functions. Although careful atten-
tion should be paid when examining individual
galectin functions due to overlapping distributions,
these intriguing glycan-binding proteins offer promis-
wide variety of pathological processes, including
cancer, inflammation, and autoimmunity.
Keywords. Galectins, adhesion, de-adhesion, spreading, migration, inflammation, immunity.
Galectins (Gal) are a ubiquitous, ancient family of
carbohydrate-binding proteins defined by at least one
conserved carbohydrate-recognition domain (CRD)
with a canonical amino acid sequence, and affinity for
b-galactosides. Galectins are present in vertebrates,
protochordates, invertebrates, mushrooms such as
Agrocybe cylindracea and Coprinus cinereus, and
viruses [1, 2].
To date, 15 distinct galectins have been identified in
mammals. However, the inclusion of Gal-11, which
was first characterized as a lens-specific protein called
GRIFIN (galectin-related interfiber protein) remains
controversial. In fact, Gal-11 lacks two of the seven
key amino acid residues conserved in most galectin
CRDs and did not display b-galactoside-binding
activity even when these two residues were mutated
to the conserved motif [1, 3]. According to their
structure, galectins have been classified as: a) mono-
* Corresponding author.
?Birkh?user Verlag, Basel, 2007
Cellular and Molecular Life Sciences
valent galectins, containing a single CRD, that may
form homodimers to become functionally bivalent; b)
bivalent tandem-repeat galectins possessing two
CRDs; and c) chimeric galectins with a single CRD
terminal sequence (prototype galectins). Gal-4, -6, -8,
-9, and -12 have two non-identical CRDs in tandem
with a short linker sequence (tandem-repeat type
galectins), and are most likely derived from an
ancestral duplication of a single-CRD galectin .
Gal-3 is the only chimeric galectin found to date, and
possesses one CRD (COOH-terminal domain), an
extended R domain consisting of glycine/proline
repeats, and a short NH2-terminal end (N domain).
Galectins recognize glycoconjugates that contain
Galb1,4GlcNAc (LacNAc) sequences that can be
present on N- or O-linked glycans [6, 7]. In the
intracellular milieu, galectins bind to their ligands
preferentially through protein-protein interactions,
and regulate intracellular processes, including pre-
messenger RNA (mRNA) splicing, cell cycle progres-
sion, apoptosis, and cell proliferation .
extracellular milieu through a non-classical endoplas-
mic reticulum (ER)/Golgi-independent pathway [9,
10]. Therefore, the efficiency of galectin export is not
affected by brefeldin A, a drug that blocks ER/Golgi
evidence indicates that the galectin secretion mecha-
nism involves the formation of exovesicles generated
by membrane blebbing . Gal-1 secretion was
initially described by Cooper and Barondes  in
skeletal muscle cells, although the molecular mecha-
nisms involved in this secretory pathway remained
elusive for many years. Recently, Nickel’s group has
demonstrated that secretion of Gal-1 from mamma-
lian cells depends on functional interactions between
the lectin and its counter-receptors . Thus, single-
site mutations in Gal-1 caused both counter-receptor
binding and export deficiencies in CHO cells. More-
over, wild-type Gal-1 failed to export from a CHO
mutant cell line defective in a Golgi apparatus-
resident UDP-galactose transporter. Therefore, func-
tional interactions with counter-receptors seem to be
essential for the overall Gal-1 export process.
Two models have been proposed by Nickel for this
non-conventional secretory pathway. First, b-galacto-
receptors may function by exerting a pulling force at
the extracellular side of the putative translocation
porerequired for directionaltransport ofGal-1across
the plasma membrane. In a second model, counter-
receptors could act as export receptors for Gal-1: i.e.
b-galactoside-containing glycolipids from the extrac-
ellular leaflet of the plasma membrane may be
by a plasma membrane resident enzyme. Subsequent-
ly, retrotranslocation of counter-receptors occupied
by Gal-1 would mediate export to the extracellular
Although both models are speculative, they are
consistent with experimental results demonstrating
Gal-1 translocation at the level of the plasma mem-
brane [9–11, 13]. Further, pharmacological evidence
showed that Gal-4 secretion is impaired in epithelial
cells following treatment with an inhibitor of glyco-
In the case of Gal-3, Ochieng?s group demonstrated
that Gal-3 may be able to interact directly with
membrane lipids in solid-phase assays, and sponta-
neously penetrate the lipid bilayer of liposomes in
either direction, in an energy-independent manner
. A unique stretch of sequence of the Gal-3 N-
terminus domain may be determinant for secretion
, although Gal-3-containing exosomes have also
been described . In summary, secretory processes
of different galectins may involve both non-vesicular
and vesicular pathways. Further studies are required
to identify membrane translocation-specific compo-
nents of the export machinery.
Although the generally held view is that galectins are
soluble proteins secreted to the extracellular milieu,
the urate channel/transporter (UAT), which was later
designated as Gal-9, is a clear exception . Com-
puter modeling and lipid bilayer studies of the urate
channel/transporter predicted a molecular model
containing four transmembrane domains, two extrac-
ellular b-galactoside-binding sites, and the intracellu-
lar amino and carboxy termini; the unique linker
portion comprises two transmembrane domains and
the intracytoplasmic loop . Therefore, for the first
time, membrane targeting was demonstrated for a
galectin family member, although cytosolic and se-
creted forms of Gal-9 have also been described .
A wide range of biological functions have been
described for galectins, including regulation of cell
adhesion, migration, cell growth, apoptosis, and pre-
mRNA splicing. Extracellularly, they bind to b-
galactoside-containing glyconjugates of extracellular
matrix (ECM) components and cell surface adhesion
has identified a novel role for galectins as versatile
regulators of cell-cell and cell-matrix interactions.
Galectins display the capacity to act as biological
cross-linkers for ECM proteins and cell surface
receptors, implicating galectins as a novel class of
matricellular proteins that modulate cellular interac-
tions [19, 20] (Fig. 1). Examples of matricellular
2M. T. Elola et al. Galectins as typical matricellular proteins
proteins that serve as adapters between cells and the
ECM are thrombospondin, tenascin, SPARC, osteo-
pontin, and hensin. Thrombospondin-1, for example,
stimulates the loss of focal adhesions and stress fibers
in spread adherent bovine aortic endothelial cells
plated on fibronectin (FN).
Several biochemical and functional properties of
galectins fit with those features of matricellular
proteins: 1) they do not contribute to structural roles
cell-matrix interactions; 2) they bind to many cell
surface receptors, ECM proteins, cytokines, and
proteases; 3) they function as both soluble and
insoluble (substrate) proteins in the ECM; 4) they
show de-adhesive as well as adhesive properties; 5)
targeted deletion of galectin genes does not affect
embryogenesis, suggesting redundancy of biological
functions (although some abnormalities are present)
This review article focuses on the agonistic/antago-
nistic roles of mammalian galectins in cell adhesion,
spreading, and migration as strongly regulated and
interconnected functions. These processes are re-
quired for survival of normal anchorage-dependent
cells. Moreover, attached non-transformed cells,
which cannot spread, undergo a particular process of
homeless-induced apoptosis called anoikis which is
caused by loss of cell anchorage and can be prevented
by laminin (LN), FN, and Gal-3 [7, 21, 22]. Thus, a
deeper understanding of the pleiotropic functions of
this evolutionarily conserved protein family should
contribute significantly to address fundamental ques-
tions in cell biology.
Galectin-1 in cell-substrate adhesion
stages: attachment, spreading, and formation of focal
adhesions and actin-containing stress fibers. Cell
spreading and rearrangements of the cytoskeleton
are required for survival of normal, non-transformed
cells. Gal-1 shows both pro-adhesive and anti-adhe-
sive functions, as it can potentiate or inhibit cell-ECM
and cell-cell interactions. Several adhesion studies
were performed using Gal-1 as a substrate. Initial
reports demonstrated that Gal-1 contained in ECM
the adhesion of A121 ovarian carcinoma cells to
has been demonstrated by several authors (Fig. 1b).
Ahmed et al.  performed adhesion assays with
B142 lymphoblastoid cells, coating plates with Gal-1,
either in its dimeric or polymerized state, and found
that the dimeric lectin was unable to promote
of 0.6 mg/well. Similarly, Skrincosky et al.  found a
of A121 ovarian carcinoma cells to polymerized Gal-
adsorbed dimeric Gal-1. Further, the adhesion of
splenocytes to plates coated with sheep spleen Gal-1
has been reported .
Gal-1 promotes the adhesion of normal and cancer
cells toECM glycoproteins such asLN [27–29].Zhou
and Cummings  reported that Gal-1 from porcine
heart promoted the Ca2+-independent adhesion of
CHO and F9 cells to LN, in a lactose-inhibitable
manner. Similarly, Mahanthappa et al.  demon-
strated that Gal-1 mediates adhesion of olfactory rat
neurons to LN-coated coverslips; the number of
adherent cells increased as the amount of substrate-
bound Gal-1 increased, and thiodigalactoside (TDG),
a non-metabolizable competitive inhibitor of Gal-1,
completely inhibited the lectin effects. Given these
observations, it was hypothesized that Gal-1 could
mediate in vivo olfactory axon fasciculation by cross-
linking adjacent axons and promote axonal adhesion
to the ECM.
In addition, Gal-1 has been shown to enhance A375
and A2058 human melanoma cell adhesion to LN.
Adhesion assays have shown that recombinant Gal-1
a dose-dependent manner (Fig. 1a), while anti-Gal-1
stimulation of cell attachment. Therefore, it is likely
that local increase or decrease of Gal-1 expression in
the tumor microenvironment may play a critical role
during attachment and detachment of cancer cells
throughout cancer progression .
Moreover, in human ovary carcinoma, increasing
concentrations of rGal-1 induced a dose-dependent
increase in adhesion to LN-1 in AZ224 and AZ382
cells,aswellas anincrease inOVCAR-3celladhesion
to FN. Therefore, Gal-1 can modulate interactions
between LN-1/FN and glycoconjugates at the cell
surface . In certain cases, both adhesion and
example, Gal-1-transfected colon cancer Colo201
apoptosis of the transfected tumor cells was also
In contrast to these findings, negative regulation of
cell adhesion to LN/FN substrates by Gal-1 has also
been well documented. These results are in accord-
ance with the de-adhesion model postulated for
Figure 1. Model of cell to substrate adhesion mediated by galectins. (a) Low concentrations of soluble (S) galectins promote adhesion of
LN/FN. (b) Immobilized galectins promote cell adhesion by crosslinking cell membrane galectin receptors. Addition of high
concentrations of the S galectin to cells already adhered to immobilized galectin promotes de-adhesion by interacting with receptors.
to both LN/FNand galectin cellmembranereceptors suchas integrins, which are themselvesreceptors for LN/FN. (d) Cells engineeredto
on the galectin type, different levels of galectin secretion, the cell type, and distinct cell membrane receptors for each galectin. Thus,
galectin can promote cell adhesion to LN or FN (by bridging galectin cell membrane receptors and LN/FN). On the other hand, the
secreted galectin can induce de-adhesion by interacting with both LN/FN and integrins. The model has been simplified, considering that
only one type of galectin and only two different cell membrane galectin receptors are present. Other galectin cell membrane receptors:
2BP, cancer antigen CA125, carcinoembryonic antigen (CEA), GM1 ganglioside, etc. .
4 M. T. Elola et al.Galectins as typical matricellular proteins
Table 1. Cell adhesion mediated by galectins.
ProbeCell type AdhesionRef.
A121 human ovarian carcinoma
A121 human ovarian carcinoma
rat olfactory neurons
ECM (Gal-1 containing)›
CHO, F9 teratocarcinoma
A375, A2058 human melanoma
AZ224, AZ382 human ovarian carcinoma
OVCARC-3 human ovarian carcinoma
C2C12 murine myoblast
IL-2-activated human T-cells
human vascular smooth muscle
various murine and human tumor cells
A375 human melanoma
LN, FN, ECMfl
murine RAW117-H10 large-cell lymphoma
MDA-MB-435 human breast carcinoma
MOLT-4 human T lymphoblastoid
murine endothelial cells›
human endothelial cells›
human thymic epithelial cells›
transfectedColo201 human colon cancerFN, LN, collagen›
human T-cells collagen I fl
XK4-A3 human breast adenocarcinoma
11-9-1-4 human breast carcinoma, HT-1080
human fibrosarcoma, PC-3 human prostate carcinoma
A375 human melanoma
LN, FN, collagen IVfl
murine thymic epithelial cellsfl
MDA-MB-435 human breast and DU-145
human prostate carcinomas
murine dendritic cells
murine lung vascular endothelial cells
human endothelial cells›
murine melanoma cells›
BT-549 human breast carcinoma
Evsa-T human breast carcinoma
LN, collagen IV›
LN, FN, vitronectin›
PC-3 human prostate carcinoma
MDA-MB-435 human breast carcinoma
human endothelial cellsfl
human endothelial cellsfl
Gal-4 immobilized T84 human colon cancerGal-4 coating›
HeLa, CHO, NIH-hIR
human Jurkat T-cells
HeLa, CHO-P, HaCaT
HeLa human cervix carcinoma
1299 human lung carcinoma
immobilizedhuman eosinophilsGal-9 coating›
MM-RU human melanoma
mouse Th1 lymphocytes
endogenoushuman eosinophilsactivated human endothelial cells›
MCF-7 human breast carcinomaLN, vitronectin fl
FN, collagen IVfl
FN, collagen I›
Ca9-22 human oral carcinoma139
Eol-1 human eosinophilic leukemia
activated human endothelial cellsfl
HFL-1 human lung fibroblastsfl
ECM, extracellular matrix; LN; laminin; FN; fibronectin; Anti-Gal; anti-galectin antibody.
soluble proteins to cells strongly adhered to a sub-
strate. Elegant studies by Barondes? group clearly
demonstrated that the addition of soluble Gal-1 to
differentiating C2C12 mouse myoblasts plated on LN
inhibits cell adhesion and spreading (Fig. 1c). This
effect is carbohydrate-dependent since TDG almost
completely blocks this inhibitory effect. Moreover,
when myoblasts are stably transfected with an ex-
pression vector engineered to constitutively secrete
Gal-1, cells also show defects in adhesion and spread-
ing on LN. Besides, pre-digestion of LN with glyco-
sidases blocks Gal-1-induced inhibition of cell adhe-
sion, demonstrating that Gal-1 binding to LN, and not
to the cell surface, mediates dettachment . In fact,
myoblast-derived Gal-1 binds to both LN and to a7b1
integrin,the prominent LN-binding integrin on differ-
entiating skeletal muscle cells, and can effectively
inhibit the association between LN and this integrin
Similarly, exogenous Gal-1 inhibited interleukin-2
(IL-2)-induced T-cell adhesion to ECM glycoproteins
. Adding rGal-1 substantially decreased the
adhesion of activated T-cells to whole ECM or intact
LN or FN in a dose-dependent manner (Fig. 1,c).
Moreover, an antibody against Gal-1 almost com-
pletely abrogated theanti-adhesiveeffectofthe lectin
on the different ECM components, while TDG
partially abolished T-cell attachment. In addition,
Gal-1 prevented the actin cytoskeleton-mediated
spreading of IL-2- or phorbol-myristate acetate
Furthermore, Gal-1 and plasma FN were equally
suitable as attachment substrates for smooth muscle
cells (SMCs), and the binding to Gal-1 was strikingly
reduced by lactose . Soluble Gal-1 inhibited the
attachment of SMC to LN in a dose-dependent
manner, and Gal-1 also inhibited SMC spreading on
LN through binding to both a1b1integrin on SMC and
to LN  (Fig. 1c).
In rat Leydig cells, addition of Gal-1 (14 mM) caused a
70% decrease of cell adhesion onto uncoated plates
compared with basal values. Simultaneous incubation
of these cells with Gal-1 and lactose prevented this
effect. When cells were cultured on LN-1-coated
plates, enhanced adhesion was observed, and cells
were protected from Gal-1-induced detachment .
Tumor cell adhesion to LN was also evaluated by
Andr? et al. , using galectin-saturated cells and/or
matrix. The authors found that Gal-1 saturation of
reactive sites on the cell surface reduced adhesion
experimental manipulations led to reduced binding of
various tumor cells. These effects might be associated
with competitive inhibition of critical cell surface
binding sites (Fig. 1c). Although these results led to
the conclusion that immobilized Gal-1 promotes cell
adhesion, experiments performed with soluble Gal-1
enhanced cell adhesion was observed, in other cases
Gal-1 had the opposite effect. These differences could
be attributed to a) different cell-membrane receptors
for Gal-1 according to the cell type (a distinct
glycoconjugate ligand); b) distinct cell-membrane
receptors in each cell type for FN or LN, i.e. not only
therepertoire ofintegrins,but othernon-galectincell-
surface ligands, which may indirectly influence galec-
tin binding; c) co-expression in the same cell type of
Gal-1 and other galectins which could exert opposite
adhesive and/or apoptotic effects; or d) variations in
galectin concentration and oligomerization state.
Galectin-1 in cell-cell adhesion
Gal-1 has been demonstrated to induce homotypic
aggregation in different cell types. For example, in
A375 human melanoma cells Gal-1 mediated homo-
typic cell aggregation, at least in part through binding
to the glycoprotein 90K/Mac-2 binding protein (90K/
MAC-2BP), an oligomer which can bind various
molecules of Gal-1 and Gal-3. This effect was
specifically blocked by lactose or by a monoclonal
antibody (mAb) against 90K/Mac-2BP. Two possible
mechanisms have been postulated to explain this
effect: (1) because of the bivalent nature of Gal-1, it
might bind to 90K/Mac-2BP displayed on the cell
surface of different cells; (2) Gal-1 might interact
simultaneously with 90K/Mac-2BP and other cell-
surface glycoconjugates from different cells .
Interestingly, homotypic cell aggregation mediated
by Gal-1 has recently been demonstrated to be
inhibited by synthetic lactulose amines .
The possible role of Gal-1 in heterotypic adhesion of
tumor cells to vascular endothelium has been pro-
posed by several authors as a crucial step related to
tumor cell invasion and metastasis. For example,
Lotan et al.  (Table 1) showed that Gal-1 is
expressed in mouse hepatic sinusoidal EC, and that
murine RAW117-H10 large-cell lymphoma cell adhe-
sion to hepatic sinusoidal EC or lung microvessel EC
was inhibited by anti-Gal-1 antibodies. Similarly, in
the adhesion of MDA-MB-435 cells to human EC,
accumulation of Gal-1 was detected at the contact
sites between breast tumor cells and the endothelium
Gal-1 also mediated the adhesion of MOLT-4 lym-
phoblastoid cells to thymic epithelial cells, an inter-
action that could be specifically blocked by anti-Gal-1
antibodies, and by b-galactoside-related sugars. Gal-1
has been shown to be expressed in thymic epithelial
6 M. T. Elola et al.Galectins as typical matricellular proteins
cells, but not in MOLT-4 cells. In addition, antibodies
to CD43 and CD45, two well-known T-cell surface
cells to immature cortical thymocytes . These
thymic epithelial cell interactions during positive or
negative selection, showing a potential role for this
Taken together, these results suggest that Gal-1 can
have a positive effect on cell-cell interactions.
Galectin-1 in cell migration
An important role of different galectins is associated
with the regulation of cell migration and invasiveness,
metastatic processes. Cell migration occurs through
adhesion to numerous components of ECM with
cell motility, which involves the reorganization of the
actin cytoskeleton, mainly through modifications of
integrin-ECM interactions; and (3) invasion, which
involves the degradation of ECM proteins by tumor-
secreted proteolytic enzymes (serine proteases, cath-
epsins, and metalloproteinases (MMP) such as MMP-
2, MMP-9 and MMP-14) .
Different reports described the involvement of Gal-1
in cell migration and chemotaxis. For instance, Gal-1
affected SMC migration in cell culture by interacting
with integrins and ECM proteins such as LN and
cellular FN. In brief, membranes from transwell
chambers were precoated with Gal-1 or LN, and
SMC migration was induced by platelet-derived
growth factor (PDGF) placed in the lower compart-
1 affected SMC migration on FN or LN, membranes
precoated with these glycoproteins were treated with
Gal-1 on the upper surface. The results were clear:
precoating with Gal-1 on the upper side resulted in
30% inhibition of SMC migration on FN, but signifi-
cantly increased the migration of these cells on LN.
The inhibitory effect of Gal-1 might be caused by
steric hindrance of interactions between ECM pro-
teins and cellular receptors in the presence of Gal-1
Kiss and colleagues investigated the cell migration
properties of Gal-1 in gliomas and colon cancer cells.
The authors demonstrated that Gal-1 significantly
enhanced the in vitro migratory capacity of human
U87 glioblastoma cells in a lactose-inhibitable man-
ner, and increased the amount of polymerized fila-
mentous actin. Furthermore, microinjection of Gal-1
antisense oligonucleotides in U87 glioblastoma cells
induced a significant decrease (~20%) in the motility
of these cells as compared to controls [45, 46]
(Table 2). Similarly, this group  performed com-
tumor astrocytes which were stably transfected with
the quantitative expression of proteins involved in
actin polymerization. Interestingly, Maeda et al. 
demonstrated that Gal-1, but not Gal-3, enhanced the
migratory activity of hepatic stellate cells (liver-
specific pericytes), which are usually mobilized when
the liver is injured and migrate to sites of necrosis to
accumulate and exert their functions. In addition, in
Schwann cells, oxidized Gal-1 stimulated migration
from both the proximal and distal stumps of trans-
peripheral nerve injury . Recently, Alge et al. 
evaluated the effects of Gal-1 on the migratory
capacity of human retinal pigment epithelial cells.
Interestingly, a significant reduction of the migratory
activity was observed when Gal-1 expression was
silenced by small interfering RNA (siRNA). Taken
together, these results agree with cell invasiveness
studies using a proteomic approach for the compar-
ison of highly and poorly invasive mammary carcino-
ma cells; in these studies Gal-1 membrane expression
was identified as a signature of cell invasiveness .
Accordingly, both the treatment with Gal-1-specific
antisense oligodeoxynucleotides or polyclonal anti-
Gal-1 antibodies resulted in inhibition of EC migra-
tion, which suggests an essential role for Gal-1 during
angiogenesis , as originally proposed by pioneer-
ing experiments performed by Clausse et al. .
Notably, dendritic cells (DCs) derived from human
monocytes showed enhanced migration across ECM
when matured in the presence of Gal-1 . When
migration of Gal-1-treated or LPS-treated DCs was
analyzed by Matrigel, Gal-1-treated DCs migrated
significantly better toward an MIP-3b gradient than
LPS-treated cells. In contrast, transendothelial migra-
tion across EC monolayers was similar for both cells.
Consistent with the high migratory phenotype, Gal-1
induced high expression of MMP-1, MMP-10, and
MMP-12 in treated DCs. Therefore, Gal-1 may serve
to regulate the migratory phenotype of DC through
inflammatory tissues and the ability of mature DC to
respond to chemotactic signals.
Nevertheless, antagonistic effects on cell migration
were also documented for Gal-1 by several authors.
For instance, we have demonstrated that Gal-1 has an
inhibitory effect on leukocyte migration in an in vivo
model of acute inflammation, when the lectin was co-
injected or injected before phospholipase A2. This
effect was almost completely abrogated by the anti-
Gal-1 antibody. Histopathological studies showed a
clear reduction of the inflammatory process evi-
denced by a diminished number of infiltrated poly-
morphonuclear neutrophils (PMNs) and a reduction
in the number of degranulated infiltrating mastocytes
inhibits IL-8-induced PMN chemotaxis in a concen-
tration-dependent manner. Transendothelial migra-
tion assays revealed that Gal-1 inhibits IL-8-stimu-
lated PMN migration through monolayers of ECs.
Intravital microscopy studies in mouse mesenteric
microvasculaturedemonstrated acritical roleforGal-
1 in selective attenuation of leukocyte rolling, adhe-
sion, and migration. Gal-1 has also been shown to
markedly reduce the migration of eosinophils in
comparison to P-selectin in ex vivo cultures of
human nasal polyps. In summary, Gal-1 induced a
decrease both in the relative distance covered by
eosinophils and in their migration speed as visualized
by quantitative videomicroscopy. Budesonide mark-
edly increased Gal-1 expression and inhibited eosino-
target for the anti-inflammatory effects of this protein
. Similarly, Hittelet et al.  demonstrated that
Gal-1 markedly decreased the motility of HCT-15,
LoVo, and CoLo201 human colon cancer cells, an
effect that was partially neutralized by anti-Gal-1
with Gal-1 inhibits leukocyte recruitment into the
peritoneum in a model of rat peritonitis . Recent-
ly, Gal-1 was shown to inhibit T-cell migration across
ECs;these cells were induced toexpress high levels of
Gal-1 upon exposure to prostate cancer cell-condi-
tioned medium. The reduction in T-cell trafficking
across the EC monolayer in the presence of increased
cell surface Gal-1 occurred in absence of T-cell death,
and was not caused by any increase in T-cell adhesion.
Similarly, when Gal-1 was added to the upper surface
of Matrigel in transwell chambers, the lectin caused a
reduction in T-cell migration through Matrigel which
was abrogated by anti-Gal-1 antiserum. The ability of
Gal-1 to inhibit T-cell migration across the endothe-
lium and sites of inflammation endows Gal-1 with
novel anti-inflammatory properties .
Altogether, these reports support the concept that
Gal-1 promotes cell migration, a function that corre-
progression, angiogenesis, liver and axonal regener-
ation, and other biological events. Nevertheless, it
seems apparent that the biological roles of Gal-1 are
tissue-specific since it also decreases cell migration of
most immune cells investigated, providing a rational
basis for its anti-inflammatory properties.
Galectin-2 in cell-substrate adhesion
Cloning and expression of Gal-2 was first performed
by Barondes? group [61, 62]. Gal-2 has been shown to
exhibit a distinct expression profile, compared to
Table 2. Cell migration and motility mediated by galectins.
Galectin typeCell typeMigration/Motility Ref.
U87 human glioblastoma
rat hepatic stellate cells
rat Schwann cells
human retinal pigment epithelial cells
human umbilical vein endothelial cells
human dendritic cells
human colon cancer
BW5147, PhaR2.1, BWC2GnT murine T-cell lines
human monocytes and macrophages
human tumor astrocytes
human breast carcinoma
DLKP lung squamous cell carcinoma
human colon cancer
U373 human glioblastoma
CHO-P hamster ovarian
T98G, U373 human glioblastoma
HCT-15, CoLo201 human colon cancer
human Jurkat T-cells
8 M. T. Elola et al. Galectins as typical matricellular proteins
other members of the galectin family, and is mainly
confined to the gastrointestinal tract [63, 64]. Rat and
human Gal-2 have been pointed out as cell adhesion
modulators. Gal-2 has been shown to bind to carbo-
hydrate residues on T-cell surface proteins such as b1
integrins, but not CD3 or CD7.
Cell adhesion studies of T-cells were performed with
collagen type I or FN as matrix compounds to test if
bivalent Gal-2 might bridge glycan chains of the
matrix and cell surface glycoproteins. After Gal-2
treatment, adhesion was significantly reduced or
enhanced when T-cells bound to collagen I or FN,
respectively. Lamina propria-derived T-cells reacted
in a similar manner. In contrast, Gal-1 reduced the
adhesion to both matrix compounds, and Gal-7 was a
rather weak effector. When T-cells were pre-incubat-
ed with integrin-specific mAbs before adding Gal-2,
cell adhesion to collagen I was significantly inhibited
by mAbs against b1, a1, and a2integrins, whereas the
adhesion to FN was blocked by b1-, a3-, a4-, and a5-
cell surface enhanced adhesion to FN, and b1-integrin
was one of the main T-cell surface ligands involved,
whereas Gal-1 reduced this binding under similar
conditions . Furthermore, it is noteworthy that
some tubulin isoforms have been shown to be ligands
for Gal-2 . This observation might be related to
regulation of microtubule polymerization or reorgan-
ization. However, the mechanisms and physiological
relevance of this interaction remain to be elucidated.
Further studies on Gal-2 are needed to address its
putative role in cell to substrate adhesion. To date, no
experimental evidence has been reported on cell-cell
interactions or cell migration mediated by this lectin.
Galectin-3 in cell-substrate adhesion
Positive regulation of cellular adhesion mediated by
Gal-3 has been demonstrated in certain models.
Exogenously added Gal-3 showed pro-adhesive prop-
Truncated Gal-3, which lacks the amino-terminal
region with the R domain but contains the CRD, did
not promote PMN adhesion . This result was
explained by the fact that Gal-3 can function biva-
lently, and to self-associate it requires its R domain,
which forms intermolecular aggregates in a concen-
tration-dependent manner (up to 1 mM) [67, 68].
In addition, Gal-3 has been demonstrated to be
essential for rapid adhesion of Gal-3-transfected
versus Gal-3-null expressing BT-549 human breast
carcinoma cells to LN and collagen IV, but not to FN
. Interestingly, Gal-3-transfected cells showed
higher levels of a6b1 integrin . Other studies
demonstrated that fast spreading and adhesion of
breast carcinoma cells to tissue culture plates was
by fetuin. Moreover, adhesion to elastin – a specific
ligandof Gal-3–was dramatically improvedbyGal-3,
suggesting that the lectin released by fetuin might be
rich tissues such as the lungs .
Likewise, overexpression of Gal-3 in Evsa-T human
breast cancer cells has been shown to specifically
influence cell adhesion to various plastic-immobilized
ECM proteins. In fact, the adhesion of Gal-3-trans-
fected cells to LN-, FN-, or vitronectin-coated wells
was 48, 60, and 39% higher than that found for non-
transfected cells, and lactose blocked the effects
on LN-coated dishes and morphological spreading-
associated features (protrusions, F-actin-positive ruf-
fles, leading edges, and F-actin reorganization) were
detected in cells overexpressing Gal-3 . Similarly,
normal fibroblasts engineered to overexpress Gal-3
have also been shown to reorganize the actin micro-
filaments in order to spread .
Inufusa et al.  have reported that anti-Gal-3
antibodies and the competitive disaccharide lactose
inhibited cell adhesion to LN of the highly metastatic
adenocarcinoma XK4-A3 in vitro, as well as liver
metastasis in vivo. The cellular response to extracel-
cell stage or cell type: i.e. primary- and late-stage
breast carcinoma cells responded differently to exo-
genously added Gal-3, since only the former showed
increased adhesiveness in Matrigel assays .
Complete absence of effects and negative modulation
of cell adhesion to ECM proteins by Gal-3 has also
adhere toLN,butthe addition oflactoseor anti-Gal-3
mAb failed to inhibit adhesion, suggesting that Gal-3
in these cells might not be functioning in cell adhesion
. Likewise, A2058 and A375 melanoma cells have
been shown to express Gal-3 on their surfaces and to
to LN, and anti-Gal-3 antiserum did not alter cell
adhesion . On the contrary, other studies have
shown that soluble Gal-3 blocked the adhesion and
spreading of baby hamster kidney epithelial cells on
LN-1-coated plates , as expected for matricellular
proteins (Fig. 1c).
Ochieng et al.  demonstrated that high levels of
Gal-3 on the cell surface downregulated cellular
adhesion to ECM proteins, in agreement with the
cell de-adhesion hypothesis. To address this issue,
different cell types were incubated without or with
rGal-3 prior to plating onto LN-, collagen IV-, or FN-
coated wells. As expected, soluble Gal-3 inhibited cell
adhesion to the ECM proteins (Fig. 1c) in a dose-
concentration of ~3 mM; this effect was abrogated in
the presence of lactose.
Remarkably, Gal-3 was later demonstrated to be
endocytosed and to be involved in the endocytosis of
b1integrins (CD29) from the cell surface to intra-
cellular vesicles via the caveolae pathway. In fact,
saccharide-dependent binding of Gal-3 to the cell
surface was sufficient to trigger its own endocytosis
and that of CD29: preincubation of breast carcinoma
cells with high concentrations of rGal-3 (~5 mM)
mediated total sequestration of integrins in intra-
cellular vesicles . Similarly, Gal-3 regulation of
a4b7integrin expression has also been reported .
Based on these data, a model was postulated in which
are sufficient for trafficking and/or redistribution of
integrins on the cell surface, thereby enhancing
cellular spreading and motility, and remodeling of
adhesion plaques. However, at high concentrations of
Gal-3, b1integrins (CD29) are endocytosed by the
cells and consequently remain not available for firm
In conclusion, in most of the cases studied, both
exogenously added recombinant Gal-3 and Gal-3
from transfected cells showed positive regulation of
cellular adhesion to ECM glycoproteins. However,
some reports suggest that this galectin can negatively
regulate cell adhesion. These differences may prob-
ably rely on a) galectin ligands involved in cell to
substrate adhesion, b) cell-membrane receptors in
each cell type for FN or LN, and c) co-expression of
various galectins in the same cell type.
Galectin-3 in cell-cell adhesion
Homotypic cell adhesion mediated by Gal-3 was
originally reported by Inohara and Raz , who
showed that transfected sf9 insect cells expressing
Gal-3 underwent homotypic cell adhesion in the
presence of asialofetuin. Metastatic cancer cells have
been demonstrated to aggregate homotypically in a
Gal-3-dependent manner to form multicellular intra-
vascular clumps at sites of primary adhesion of tumor
cells to the endothelium . This spontaneous
carcinoma cell homotypic aggregation was shown to
cell surface Thomsen-Friedenreich
(TFAg) and Gal-3 [42, 80].
In another model, Gal-3-mediated homotypic aggre-
gation was demonstrated to be associated with the
1/-3 on adjacent cells. Both 90K/Mac-2BP and galec-
tins were found to be deposited in the ECM, where
they may interact with different matrix components,
thereby mediating cell adhesion .
been shown to mediate MDA-MB-435 breast carci-
MB-435 cells, and a synthetic TFAg-specific peptide,
developed by phage display, inhibited this interaction
as well as breast cancer cell homotypic aggregation
. Recently, the finding by phage display technol-
ogy of two specific peptides that bind to Gal-3 CRD
opened a revolutionary way to develop galectin
inhibitors. These Gal-3 inhibitory peptides interfered
with rolling and stable adhesion of human breast
carcinoma cells to bone marrow EC, and dramatically
reduced homotypic cell aggregation . In fact, the
3 – has been demonstrated to sequester Gal-3 and to
inhibit homotypic tumor cell aggregation, tumor
growth, and metastasis [83, 84].
3 expressed on EC could interact with carbohydrate
cell adhesion and metastasis. For instance, PC-3
human prostate carcinoma cells, which do not express
Gal-3, bindtoEC inamanner thatcanbeinhibitedby
anti-Gal-3 mAbs . Similarly, an anti-Gal-3 mAb
inhibited MDA-MB-435 human breast carcinoma cell
rolling and adhesion to human umbilical vein endo-
thelial cells (HUVECs) under flow conditions .
plays a key role in the adhesion of B16-F10 murine
melanoma cells to the lungs. In addition, the lectin
constitutively expressed on lung vascular EC surfaces
served as an anchor for circulating B16-F10 cells.
Alternatively, Gil et al.  studied the immunohis-
PMN adhesion and transmigration through EC mon-
olayers and found a markedly enhanced Gal-3 ex-
pression in the plasma membrane of EC after PMN
adhesion, suggesting that EC-derived Gal-3 could
regulate PMN-EC interactions.
In addition, Gal-3 has been postulated as a substrate
for matrix metalloproteinases such as MMP-2 and
MMP-9, which are capable of efficiently cleaving the
Ala62-Tyr63bond in the R domain of full-length Gal-3
CRD .MMP-2-cleaved Gal-3 displayed ~20 times
greater affinity for HUVECs compared to the full-
length protein , which might play an important
role in tumor invasion and angiogenesis: i.e. cleaved
Gal-3 cannotdimerize,but retains itsability tobind to
10M. T. Elola et al. Galectins as typical matricellular proteins
glycoconjugates, thus competing with intact Gal-3
In DCs, Gal-3 is constitutively expressed on the cell
surface and is involved in the adhesion of L-selectin-
activated lymphocytes. In fact, adhesion of L-selectin-
triggered lymphocytes to DCs was significantly re-
duced by anti-Gal-3 mAbs and by specific carbohy-
drate ligands. High concentrations of rGal-3 inhibited
the interactions between DCs and lymphocytes, an
effect that was reverted by specific carbohydrate
ligand was induced on L-selectin-triggered lympho-
cytes to interact with Gal-3 on the cell surface of DCs
In conclusion, the role of Gal-3 in modulating
intercellular adhesion has been extensively docu-
mented. It appears that cell-cell adhesion is promoted
in cells expressing Gal-3, and this process can be
inhibited by anti-Gal-3 antibodies, or by soluble rGal-
3 – as would be expected for matricellular proteins.
Galectin-3 in cell migration
Potential roles of Gal-3 in cell migration and invasive-
ness have been well documented in different models.
Liu and colleagues described a novel role for this
glycan-binding protein as a potent chemoattractant
for monocytes and macrophages . The authors
showed that Gal-3 induced human monocyte migra-
tion both in vitro and in vivo in a dose-dependent
>1 mM (relatively high concentrations, probably
required for Gal-3 dimerization/oligomerization);
this effect was specifically inhibited by an anti-Gal-3
mAb or specific carbohydrate ligands. Both the N-
terminal and C-terminal domains were involved in
this activity, which was mediated, at least in part,
through a pertussis toxin-sensitive (G-protein-cou-
because, unlike monocytes, there are very few chemo-
kines reported to be chemoattractants for differenti-
ated macrophages (including MCP-1 – the major
monocyte chemoattractant) . Therefore, it is
possible to speculate that Gal-3 is one of the major
factors involved in the influx of macrophages to
inflammatory sites. Gal-3-deficient mice consistently,
developed significantly reduced numbers of perito-
neal macrophages compared to wild-type (WT) mice
when treated with thioglycolate .
In addition, Gal-3 was able to markedly stimulate
human tumor astrocyte migration in vitro in Hs683,
T98G, and U373 cells cultured on Gal-3-coated plates
and monitored by video cell tracking, while Gal-1 and
Gal-8 were weaker stimulators. Furthermore, the
three galectins appeared to be involved in tumor
astrocyte invasion of the surrounding brain parenchy-
ma, since their expression levels were higher in the
most invasive parts of the xenografted glioblastomas
bound to the substrate- markedly enhanced the
migration of primary breast carcinoma cells .
Gal-3 overexpression was associated with increased
cell surface expression of the a4b7integrin, causing
enhanced adhesion to ECM glycoproteins as well as
an increase in invasiveness and spreading-associated
features . Similarly, Gal-3-transfected human
breast carcinoma cells were shown to invade through
Matrigel-coated filters at ~3 times the rate of parental
cells . Gal-3-transfected DLKP lung squamous
cell carcinoma cells were also rendered more motile
and invasive through ECM in vitro . With respect
to the migration of ECs, Gal-3 was shown to be an
endothelial ligand for NG2 chondroitin sulfate pro-
teoglycan in MAEC cells, and anti-Gal-3 mAbs
inhibited NG2-induced motility by 70% . In the
the stroma, and Gal-3 has been reported as a
modulator of thymocyte migration by interfering
with cell adhesion and promoting subsequent de-
adhesion. Gal-3 purified from thymic epithelial cells,
alone or in combination with LN, displayed chemo-
tactic effects, especially on CD4+CD8+thymocytes,
although this lectin significantly inhibited adhesion of
thymocytes to epithelial cells .
In very elegant studies, overexpression of the enzyme
b1,6 N-acetylglucosaminyltransferase V (Mgat5),
which catalyzes the addition of b1,6GlcNAc to N-
glycans leading to subsequent elongation with poly-
LacNAc, has been shown to increase cell motility and
tumor formation, while a Mgat5-deficient phenotype
suppressed mammary tumor growth and metastasis in
polyoma middle T transgenic mice . Addition of
low concentrations of rGal-3 (up to 2 mg/ml) to the
dependent cell spreading and motility in Mgat5+/+
tumor cells plated on an FN substrate, in a carbohy-
drate-dependent manner. Gal-3 stimulated integrin-
mediated activation of focal adhesion kinase (FAK)
and phosphatidylinositol 3-kinase (PI3K) as well as
a5b1translocation to fibrillar adhesions . On the
contrary, Gal-3 did not alter the motility of rat hepatic
stellate cells, although Gal-1 significantly augmented
colleagues  demonstrated that addition of Gal-3
on Matrigel-coated substrate strongly decreased the
CoLo201 human colon cancer cells; this effect could
not be neutralized by anti-Gal-3 antibodies. In human
glioblastoma U373 cells, downregulation of Gal-3
using antisense strategies generated knockdown cells
with significantly higher motility when cultured on
LN-coated substrates as compared to non-transfected
control cells. Likewise, knocking down Gal-3 expres-
sion in glioma cells resulted in increased glioma cell
motility on LN substrates .
The above-mentioned evidence strongly supports the
concept that Gal-3 regulates cell migration. It pro-
of the major factors mediating the influx of macro-
phages to sites of inflammation. In addition, Gal-3
whereas it reduces the migration of colon and
glioblastoma cancer cell lines. These opposing results
might be related to differences among target cells that
may include different cell surface receptors for Gal-3
and for FN/LN, as well as distinct expression profiles
of multiple galectins present in each cell type.
A better understanding of the role of Gal-3 in cell-
matrix interactions, cell-cell adhesion, and cell migra-
tion will be critical to examine the role of this
endogenous lectin as a candidate target for therapeu-
tic intervention. It is important to keep in mind that
cell surface glycoconjugates are tissue-specific, and
can differ significantly among cell types. Moreover,
Gal-3 can modulate the expression, cell surface
distribution, and endocytosis of some receptors (e.g.
Galectin-4 in cell adhesion
Gal-4 was initially cloned from rat intestine , and
its localization was found to be restricted to the
epithelium of the alimentary tract, including oral
mucosa, esophagus, and intestinal mucosa [105–108].
in cell adhesion processes. In fact, plate-coated Gal-4
supported adhesion of the T84 human carcinoma cell,
and this effect was significantly inhibited by lactose in
a dose-dependent manner, implying that the immobi-
lized lectin interacted with one or more receptors at
the cell surface in a carbohydrate-dependent manner.
Therefore, Gal-4 might play a role in the initial
attachment and/or spreading of cells during cell
adhesion or cell migration. This effect might have
potential implications in complex physiological proc-
esses such as restitution of intestinal epithelium,
maintenance of epithelial integrity, and epithelial
wound healing . Moreover, Gal-4 was localized
by immunohistochemistry at the leading edge in
lamellipodia of subconfluent human colon adenocar-
cinoma T84 cells, and in attachment sites of newly
seeded cells, confirming its role in cell-substrate
Gal-4 in adherens junctions of porcine tongue squ-
vinculin, and uvomorulin, this lectin was suggested to
However,other roles for Gal-4 such as stabilization of
cellular junctions and membranes have been pro-
posed: Gal-4 localization in the apical surface of the
enterocytes was associated to its potential function as
a central organizer/stabilizer of lipid rafts in the
microvillar membrane , rather than to a partic-
ipation in local cell-cell or cell-matrix interactions. In
fact, pig small intestinal Gal-4 was localized at the
brush border membrane in enterocytes, and it was
considered as an intestinal brush border protein
associated with its potential natural ligands, such as
aminopeptidase N and sucrase-isomaltase (major
digestive enzymes confined to the apical enterocyte
surface) . Finally, Wasano and Hirakawa 
also proposed a role for Gal-4 in stabilizing the apical
(lumenal) membranes in rat esophageal epithelium.
Further studies are required to dissect the precise
roles of Gal-4 in the regulation of cell adhesion and
migration under physiological and pathological cir-
Galectin-7 in cell adhesion and migration
Gal-7 was almost simultaneously cloned from human
keratinocytes by Madsen et al.  and Magnaldo et
al. . Gal-7 is the first marker of epithelial
stratification whose expression does not depend on
local differentiation; this lectin is present in all
subtypes of keratinocytes, in all cell layers in epider-
mis, and also in the cornea and esophagus. Gal-7 is
secreted by proliferating, quiescent, as well as differ-
entiated keratinocytes into the culture medium .
This protein, which has been designated as a product
of the p53-induced gene 1 (PIG1), was and is among
the most highly induced genes in p53-transfected
DLD-1 colon carcinoma cells , suggesting its
potential role in the regulation of apoptosis and cell
cycle progression .
Gal-7 is localized at sites of cell-to-cell contact,
particularly in the upper layers of the human epider-
mis , but in vitro adhesion assays have not been
performed. Therefore, its putative role in adhesion is
speculative. When transfected into lymphoma cells,
Gal-7 was able to promote MMP-9 gene expression
, suggesting its pivotal role in the regulation of
12 M. T. Elola et al.Galectins as typical matricellular proteins
migration and dissemination of tumoral cells, at least
in those cancers arising from pluristratified epithelia
(i.e. some types of head and neck squamous cell
Potential effects of Gal-7 on cell migration and
spreading have been suggested by other authors. In
HeLa cells engineered to overexpress Gal-7, four- to
seven-fold increases were detected by microarray
analysis in mRNA levels for a1integrin and for ECM
proteins such as vitronectin and type XV collagen,
respectively . Thus the possibility still remains
that Gal-7 might be interacting with integrins to
mediate cell migration.
of epithelial cell migration in re-epithelization of
corneal wounds [118, 119]; healing corneas contained
significantly increased levels of Gal-7 compared with
normal corneas, and wound closure was significantly
stimulated by Gal-7, but not by Gal-1. Moreover,
immunohistochemical studies in healing corneas
showed strong Gal-7 staining in the leading edge of
the migrating epithelium, in the peripheral epithe-
lium, and at sites of cell-matrix interactions .
Further in vitro and in vivo studies are needed to
evaluate the direct involvement of Gal-7 in cell
adhesion and migration.
Galectin-8 in cell-substrate adhesion
liver cDNA library by Zick?s group . Gal-8 is
highly expressed in invasive human prostate carcino-
ma where it was first identified as prostate carcinoma
tumor antigen-1 (PCTA-1) . Alternative splicing
of gal-8 mRNA generates different transcripts encod-
ing, at least, six different protein isoforms of human
Gal-8 that are tissue-specific . Gal-8 seems to be
unique in the galectin family, with isoforms belonging
to both the prototype and tandem-repeat groups. At
least two splice variants of human Gal-8 are of the
tandem-repeat type, and differ in the length of the
linker peptide or hinge region. One of the tandem-
repeat wild-type isoforms, designated Gal-8M (Gal-8
medium), possesses a medium-sized linker peptide
without a thrombin cleavage site, while the other bi-
CRD isoform, called Gal-8L (Gal-8 long), contains
the longest linker peptide that includes a thrombin
recognition domain [123, 124]. It has been proposed
that the linker peptide provides not only cross-linking
ability without the formation of a dimer/multimer
structure, but also confers protease susceptibility.
Very elegant cell adhesion studies revealed that Gal-8
can positively or negatively regulate cell adhesion,
depending on the extracellular microenvironment.
When immobilized onto matrix, Gal-8 can be classi-
fied as a novel ECM protein with a similar potency to
FN in promoting cell adhesion and spreading due to
ligation of sugar moieties present in cell surface
integrin receptors. Actually, cells adhered and spread
that found when cells attached to FN .
In fact, the mechanism of interaction of Gal-8 with
integrins involves lectin binding to sugar moieties
(protein-glycan interactions), whereas the ligand-
molecules interacts with FN (protein-protein inter-
actions). Moreover, Gal-8 probably induced aggrega-
tion of b1 integrin subunits, which are the main
upstream activators of FAK (focal adhesion kinase)
proteins that induce integrin aggregation to trigger
cell adhesion and to initiate integrin-mediated signal-
ing cascades . Immobilized truncated Gal-8
containing only one CRD corresponding to the N-
half of the protein, termed N-Gal-8, was ~5-fold less
potent than wild-type Gal-8 in promoting cell adhe-
required to modulate cellular adhesion .
Soluble Gal-8 has been shown to selectively inhibit
cell adhesion to plates coated with LN and FN
(Fig. 1c), while it fails to inhibit cell adhesion to the
non-specific substrate polylysine. In this regard, Gal-8
also resembles other soluble ECM proteins like LN
 and FN  in that a cell adhesion protein
it is bound in excess to a cell receptor. Hence,
saturation of these cell receptors might prevent
receptor interactions with substrate- or cell attached-
adhesive molecules. In fact, the addition of excess
soluble Gal-8presumably masksintegrinbinding sites
and thus impairs cell adhesion to integrin ligands such
In line with this idea are the experiments demonstrat-
ing inhibition of colony formation in 1299 human lung
carcinoma cells transfected with the gal-8 gene: the
inhibitory effect of overexpressed Gal-8 (Fig. 1d,
lower panel) could account for an autocrine effect of
the secreted lectin that interacted with the available
cellsurface integrins,similartothe inhibitory effectof
Gal-8 when exogenously added to cells . In
addition, as mentioned above for Gal-3, soluble Gal-8
could alternatively induce the internalization of cell
mediated either upon direct binding of excess soluble
Gal-8 to cell surface integrins, or upon binding of
ECM proteins such as FN that, when soluble, could
exert an anti-adhesive effect of their own – i.e. soluble
calf serum FN can bind Gal-8. Because of their anti-
adhesive functions, Gal-8 (Fig. 1c), as well as Gal-1
and Gal-3 may be considered asnovel members of the
adhesion-modulating proteins collectively known as
matricellular proteins, which include SPARC, throm-
bospondin, tenascin, hevin, and disintegrins .
These proteins do not serve as integral components
of matrix elements, but rather function through bind-
ing to matrix proteins as well as to cell surface
The assumption that integrins are indeed the key
mediators of the inhibitory effects of Gal-8 on cell
adhesion is based on evidence of the direct binding of
Gal-8 to a3, a6, and b1and, to a very limited extent, to
a4and b3integrins in HeLa and 1299 cells . It has
been hypothesized that Gal-8 acts as an integrin
binding-protein that exerts down-modulatory effects
on integrin functions (i.e. by a mechanism involving
phosphorylation of the b1integrin cytoplasmic do-
main), instead of generating steric hindrance by
interacting primarily with cell recognition sites for
integrins or other adhesion receptors on ECM pro-
teins . Different galectins might selectively
regulate interactions of integrins with matrix proteins
in a somewhat different fashion: for example, Gal-1
might interact with integrins mainly interfering with
LN-integrin interactions (i.e. a7b1).
During cell adhesion onto immobilized Gal-8, phos-
phorylation of downstream effectors of PI3K, such as
protein kinase B (PKB), p70S6kinase (p70S6K), and
extracellular-regulated kinase (ERK)-1 and -2, was
significantly higher compared to adhesion to immo-
bilized FN . Zick and colleagues proposed that
Gal-8 can act in three different modes, depending on
the cellular context and the extracellular environ-
ment. When present at low concentrations as an
immobilized ligand (even in the presence of serum or
selected growth factors), this lectin interacts only with
high-affinity receptors of the integrin family that
promote cell adhesion, spreading, and cell migration
(Fig. 1b). In contrast, when Gal-8 is present at high
overexpressed and secreted, it can interact with low-
affinity receptors (other members of the integrin
family or different cell surface receptors) that trigger
signaling pathways involving the activation of stress-
activated kinases like JNK and the expression of the
cyclin-dependent kinase inhibitor p21. The accumu-
lation of p21 induced by soluble Gal-8 protects the
cells from potential pro-apoptotic signals and produ-
ces cytostatic effects. The third mode of action (the
pro-apoptotic effect), is exhibited either under condi-
tionsthatprevent the accumulationofp21orfollowing
a sustained deprivation of growth factors .
Proper functioning of Gal-8 depends not only upon
the presence of its two CRDs but also upon their
orientation, determined by the length of the hinge
(linker) region. Deletion of the hinge region or single
mutations in some of the residues involved in sugar
binding (W85and W248) severely impaired the adhe-
sive/anti-adhesive and signaling capacities of Gal-8.
Truncated Gal-8 containing only the CDR corre-
sponding to the N-half of the protein, although
capable of sugar binding, was less potent than Gal-8
in promoting cell adhesion and spreading onto itself,
and completely ineffective when added solubly in
inhibiting cell adhesion to FN-coated plates. A Gal-8
truncated form containing only the C-CDR was
devoid of any adhesive/anti-adhesive activity. In
summary, Gal-8 probably requires cooperative inter-
actions between the two CRDs and a properly
oriented hinge region for effective function .
blood PMN, which was blocked by lactose .
8 (Fig. 1b) (0.3–10 mM) solution supported PMN
adhesion; however, the levels of adhesion were lower
than 40% of those induced by soluble Gal-8 (1 mM)
when PMN adhered to untreated culture plates. The
integrin aMand the promatrix metalloproteinase-9
(proMMP-9) were identified as Gal-8 ligands, and
anti-aMmAbs – but not aL– strongly inhibited PMN
adhesion induced by Gal-8. Abolition of the sugar-
binding activity of C-terminal CRD, but not N-
terminal CRD, abolished the adhesion-inducing ac-
tivity of Gal-8. Thus, Gal-8 appears to be a new player
necessary for matrix degradation . Furthermore,
(Gal-8-null) allowed the authors to demonstrate that
removal of the linker peptide greatly increased the
protease resistance of Gal-8 to elastase and trypsin.
Gal-8-null induced PMN adhesion in a manner
comparable to that of Gal-8M (an isoform of Gal-8
with a medium-sized linker peptide), suggesting that
removal of the entire hinge greatly improved stability
against proteolysis without negative effects on PMN
adhesion . Moreover, thrombin treatment of the
isoform Gal-8L (an isoform of Gal-8 with a long-sized
linker peptide) significantly suppressed its adhesion-
inducing activity by 80% [124, 133].
In order to study the adhesive properties of Gal-8 on
T-cells, human Jurkat T-cells were plated onto immo-
bilized recombinant Gal-8, glutathione-S-transferase
(GST)-Gal-8, or FN. In fact, similar adhesion rates
were obtained for each matrix, and as expected, TDG
significantly inhibited attachment to Gal-8 and GST-
Gal-8 (Fig. 1b). Moreover, extensive spreading was
also observed when Jurkat T-cells were plated onto
14M. T. Elola et al.Galectins as typical matricellular proteins
Gal-8. This effect was accompanied by a polarized
phenotype, and PI3K-dependent ERK-1, -2 activa-
ligands in Jurkat cells, since anti-a5and -b1blocking
mAbs inhibited ~60% adhesion onto immobilized
Gal-8. Interestingly, anti-Gal-8 autoantibodies from
patients with systemic lupus erythematosus blocked
the adhesion of Jurkat cells onto Gal-8-coated plates
by more than 80% . Remarkably, no experimen-
tal data have been reported to date on cell-cell
interactions mediated by Gal-8.
Collectively, these data indicate that Gal-8 can either
on whether it is presented as an immobilized or
lectin concentrations, the cellular context, and the
Galectin-8 in cell migration
Immobilized Gal-8 has been demonstrated to be
equipotent to FN in supporting cellular migration
when added to culture medium in the presence of
serum. In fact, CHO-P cells seeded in agarose doplets
readily sprouted and migrated on plates coated both
with FN and Gal-8 following 6–8 days of growth
lated glioblastoma cell migration in vitro. This obser-
vation was derived from experiments in which human
astrocytic tumor cells were grown on regular plastic
Gal-8, and followed up by video cell tracking. Under
these experimental conditions, Gal-8 significantly
increased the levels of migration of T98G and U373
cells. Remarkably, histopathological evaluation of
Gal-8 expression in human astrocytictumorsrevealed
higher immunopositive staining in blood vessel walls
compared to the rest of tumor parenchyma and
stroma, while the reverse feature was observed for
Gal-1 , suggesting that Gal-8 derived from intra-
tumoral EC might be involved in tumor cell migration
and metastasis. In contrast, when human colon cancer
cells were plated onto Matrigel, Gal-8 markedly
decreased migration rates in HCT-15 and CoLo201
cells, an effect partially blocked by anti-Gal-8 anti-
bodies. However, neither Gal-8 nor anti-Gal-8 anti-
immobilized, Gal-8 can stimulate cell migration. In
contrast, soluble Gal-8 can also reduce in vitro cell
migration, an effect expected for a matricellular
protein. Thus, Gal-8 represents a novel matricellular
protein, but the detailed mechanism(s) of action
remains to be elucidated.
Galectin-9 in cell-substrate adhesion
Gal-9 was first cloned from mouse embryonic kidney
, and further identified in human T lymphocytes
as a specific eosinophil chemoattractant [so-called
with three splicing isoforms which are named accord-
ing to the length of the linker peptide: a) long-sized
(Gal-9L, with 58 amino acids in the linker peptide), b)
medium-sized(Gal-9M, 26 aminoacids), and c)short-
sized (Gal-9S, 14 amino acids) .
Regarding cell adhesion to substrate, Asakura et al.
 demonstrated adhesion of human peripheral
blood eosinophils to Gal-9-coated dishes (30 nM). In
these experiments, significant adhesion was achieved,
which was partially inhibited by lactose. In contrast,
eosinophils failed to adhere to Gal-1-coated plates,
indicating that Gal-9 selectively mediates eosinophil
adhesion. Furthermore, this effect was cell-specific
since PMN did not adhere to Gal-9-coated dishes
under the same experimental conditions. Irie et al.
 evaluated the adhesion of the MCF-7 human
breast cancer cell line transfected with expression
collagen type IV, FN, LN, and vitronectin. Results
showed that cells expressing the Gal-9 S and L
exhibited reduced adhesion to LN, vitronectin, FN,
and collagen type-IV (Fig. 1d, lower panel). In this
regard, adhesion to FN or collagen type I of the Ca9–
22 human oral squamous cell carcinoma cell line
transfected with the gal-9 gene was evaluated by
Kasamatsu et al. . These results showed that gal-
9-transfected Ca9–22 cells showed significantly in-
creased adhesion to FN- and collagen type I-coated
plates compared to non-transfected control cells.
Thus, although as a substrate Gal-9 promotes eosino-
phil adhesion, when Gal-9 is overexpressed in differ-
ent human carcinoma cells, it can either enhance or
reduce adhesion to ECM proteins, probably depend-
ing on the target cell studied.
Galectin-9 in cell-cell adhesion
vascular endothelium. This lectin was found to be
upregulated by interferon (IFN)-g, and was implicat-
ed in the adherence of eosinophils to activated
HUVECs in vitro . EoL-1 human eosinophilic
increased binding to HUVECs treated with synthetic
double-stranded RNA poly-IC in a lactose- and anti-
Gal-9-inhibitable manner . Given these findings,
it has been hypothesized that Gal-9 might be critically
involved in the interactions between EC and leuko-
cytes during leukocyte trafficking and locomotion.
Upregulation of Gal-9 in ECs may probably favor the
adhesion and recruitment of eosinophils as an impor-
tant step in the initiation and perpetuation of inflam-
matory and allergic reactions. In this regard, endog-
enous Gal-9 mediated adhesion of eosinophils (but
not PMN) to IFN-g-activated HFL-1 fibroblasts, an
effect which was specifically abrogated by lactose and
Cell aggregation by Gal-9 was studied by several
authors. Eosinophil aggregation mediated by ecalec-
tin was demonstrated by Matsumoto et al. ,
which was dose-dependent and lactose-inhibitable. In
melanoma cells, exogenously added Gal-9 induced
cell aggregation in a lactose-inhibitable fashion,
suggesting that the interaction of Gal-9 on the surface
of melanoma cells with its ligand was required for cell
aggregation . Similarly, aggregation of MCF-7
human breast cancer cells was observed following
stable transfection with constructs for each of the
three different Gal-9 isoforms (S, M, and L) .
Finally, recent work was also performed by Zhu et al.
clusters of Th1-, but not Th2 lymphocytes in vitro
induced by Gal-9, identifying this lectin as a Tim-3-
specific ligand and suggesting that Tim-3/Gal-9 inter-
actions might have evolved to ensure Th1 cell
apoptosis and to prevent prolonged inflammation.
Taken together, these results demonstrate that Gal-9
is involved in eosinophil adhesion to endothelial cells,
suggesting possible roles in eosinophil recruitment
and infiltration during the process of fibrosis, and in
aggregation of eosinophils and malignant cells.
Galectin-9 in cell migration
Gal-9 acts as a selective chemoattractant for eosino-
phils. Gal-9 induced ~4-fold more eosinophils to
migrate than the optimal dose of recombinant IL-5.
Gal-9 did not induced chemotaxis of peripheral blood
PMNs, lymphocytes, or monocytes. However, Gal-9
has potenteosinophilchemotactic activity invitro and
in vivo . Chemotactic activity of this tandem-
repeat lectin was found to be dependent on both
CRDs [146, 147]. In fact, Gal-9 exhibited significantly
high and dose-dependent chemotactic activity,where-
as the N-terminal CRD and the C-terminal CRD
at high concentrations. In contrast, Gal-1 and Gal-3
failed to exhibit detectable chemotactic activity, and
did not inhibit Gal-9 function, suggesting that differ-
ent receptors were recognized by each lectin. How-
ever, eosinophil ligands for Gal-9 have not yet been
identified ineosinophils.Chemotactic activitywas not
reconstituted by the combination of the N-terminal
CRD and the C-terminal CRD, and was inhibited
the N-terminal or C-terminal CRD (in Arg65and
Arg239, respectively, two amino acids directly involved
in carbohydrate recognition) failed to exhibit detect-
able chemotactic activity. In conclusion, the two
CRDs need to be covalently linked for full chemo-
isoforms exhibited comparable chemotactic activity
. Thrombin treatment of Gal-9, which cleaves
within the linker peptide, caused loss of chemotactic
function only in Gal-9L, as clearly demonstrated by
Nishi et al. . Jurkat T-cells constitutively ex-
pressed the isoforms of Gal-9 corresponding to the
medium- and long-sized linker peptide (26 or 58
amino acids). Moreover, Gal-9 expression was upre-
gulated by phorbol esters, which also stimulated
chemotactic activity of Jurkat T-cells .
In summary, Gal-9 acts as a potent chemoattractant
for eosinophils. The regulation and function of Gal-9
under various physiological and pathological condi-
tions, however, remain to be elucidated.
To the best of our knowledge, in vitro assays to assess
cell-substrate or cell-cell interactions have not been
reported in the literature for Gal-5, -6, -10, -11, -12, -
13, -14, or -15. However, emerging experimental
evidence such as expression and localization patterns
of certain galectins might allow some speculation
regarding their extracellular role(s). For example,
embryonic development correlates with stages of
major changes in cell-cell interactions in the intestinal
epithelium . In addition, specific localization of
Gal-11 at the interface between lens fiber cells is also
adhesion [1, 3]. Furthermore, Gal-15 is highly ex-
pressed in the endometrial luminal epithelium, and it
has been proposed as a heterophilic cell adhesion
molecule between the conceptus trophectoderm and
endometrialluminalepithelium. Therefore,this lectin
is a likely candidate as a mediator of interactions
between the endometrius and the conceptus during
the process of implantation . In fact, Gal-15
contains predicted cell attachment sequences (i.e.
RGD) that could mediate binding to integrins .
Further studies on novel members of the galectin
family should be carried out to elucidate potential
roles of these glycan-binding proteins in cell adhesion
16M. T. Elola et al.Galectins as typical matricellular proteins
Because of their anti-adhesive as well as adhesive
extracellular functions, galectins can be considered as
a novel class of adhesion-modulating proteins collec-
tively known as matricellular proteins (which include
SPARC, thrombospondin, tenascin, hevin, disinte-
grins, etc.) as originally proposed by Zick and
colleagues for Gal-8 . Accordingly, galectins
sometimes have de-adhesive effects when presented
this context the de-adhesive properties of galectins
pro-adhesive effects of these glycan-binding proteins
through different mechanisms. These glycan-binding
proteins can specifically recognize biomatrix struc-
tural glycoproteins such as LN, FN, and vitronectin as
well as cell surface integrins in a carbohydrate-
dependent manner. Contradictory observations relat-
ed to adhesive/anti-adhesive effects are likely to be
due to several problems. First, the interpretation of
results obtained for one galectin will only be unequiv-
ocal if no additional galectins or galectin ligands with
in the same tissue or cell. Second, a careful examina-
tion of experimental discrepancies in terms of con-
centrations employed is needed (i.e. high concentra-
tions of soluble Gal-3 would promote b1integrins and
Gal-3 endocytosis). Third, the valency/oligomeriza-
tion state of each galectin is a crucial parameter for
biological activities. Forth, extra- or intracellular
cleavage is one possible mechanism for down-modu-
lating the adhesive activity of Gal-3,Gal-8, and Gal-9.
Fifth, the existence of tissue-specific cell surface
receptors for galectins, with distinct glycosylation
patterns, can clearly influence the effects of galectins.
Finally, cell-surface receptors for each of ECM
glycoprotein (LN, FN, etc.) are different for each cell
type or tissue.
Regarding the co-expression of multiple galectins in a
given cell type or tissue, controversial results on their
role(s) in adhesion are probably due to overlapping/
opposite functions. By RT-PCR analysis of galectin
expression in the Colo201 human colon cancer cell
line which express not only Gal-1 and -3 mRNA, but
also Gal-4, -7, -8, and -9 mRNA.This complex pattern
clearly demonstrates that studies should consider
potential functional redundancy, and interactions
between individual galectin types. In fact, this review
summarizes many experiments in which this point has
not been taken into account. It will be essential to
evaluate the combined effect of multiple galectins
expressed in each cell type or tissue to appreciate the
full functional spectrum of the role of galectins in the
modulation of cell adhesion and migration.
Concerning LN/FN cellular ligands, different cell
types can interact differentially with FN or LN
through their repertoire of integrins and via other
receptors.For example.LN can interact with integrins
and cell-surface sulfated glycolipids(sulfatides) .
Moreover, a given integrin such as a4b1binds FN not
only by the arginine-glycine-aspartic acid (RGD)
sequence of the FN cell-binding site, but also in the
heparin-binding domain . Consequently, the
interactions between LN/FN and non-galectin cell
surface receptors may also contribute to the complex
Therapeutic applications of galectins based on their
effects on cell adhesion have also been suggested. The
concept of anti-adhesive galectin therapy  was
and colleagues [158, 159]. In this regard, two exper-
imental approaches seem to be promissory as galectin
inhibitors: short synthetic peptides and carbohydrate-
based compounds. In this sense, short synthetic
with tumor cell interactions may have special signifi-
cance for the development of new anti-adhesive
therapies. Phage display technology has allowed the
CRD . These peptides exhibited binding to Gal-3
expressed on tumor cells and inhibited homotypic
adhesion of human breast cancer cells as well as their
based galectin inhibitors, Pienta et al.  reported
that modified citrus pectin – a Gal-3 ligand – was an
effective inhibitor of B16-F1 murine melanoma lung
cell colonization as well as rat prostate cancer meta-
stasis. Moreover, synthetic analogues of naturally
occurring conjugates of carbohydrates and amino
acids (glycoamines) have also been shown to generate
efficient inhibition of cancer metastasis [40, 160].
Notably, tumor-immune escape allows malignant
progression, and Gal-1 has a crucial role in conferring
immune privilege due to its pro-apoptotic activity on
activated T-cells and its ability to skew the balance
toward a Th2 and Tregulatory-mediated anti-inflam-
matory response. In a murine model of melanoma, we
found that blockade of Gal-1 within the tumor tissue
resulted in enhanced Th1-mediated antitumor re-
sponses and increased tumor rejection . The
ability of galectins to regulate the migration and
invasiveness of tumor and inflammatory cells might
also be targeted for therapeutic purposes. For exam-
ple, knocking down Gal-1 expression, at least in
gliomas, has been shown to impair cell migration,
invasiveness, and metastasis [46, 162]. Lactosylated
steroids also blocked in vitro migration of human
3 prostate cancer cells . Finally, anti-galectin
compounds such as lectin-specific synthetic peptides
and siRNA are being developed by different groups,
opening a new era of non-toxic therapeutic strategies
for the treatment of inflammatory and neoplastic
Acknowledgements. We apologize to the authors of many relevant
references not cited because of space limitations. We would like to
give special thanks to members of the authors’ laboratories, in
particular to Marta Toscano, Juan Ilarregui, Germ?n Bianco,
Mariana Salatino, and Diego Croci for their invaluable help. We
would like to give special thanks to Fundaci?n Sales (Argentina)
for continuous support.M.T.E, C.W.T., and G.A.Raremembersof
Argentina). Work in G.A.R.?s laboratory is supported by the
Cancer Research Institute (Elaine R. Shepard Memorial Inves-
tigator, USA), Mizutani Foundation for Glycoscience (Japan),
Agencia de Promoci?n Cient?fica y Tecnol?gica (PICT 2003–05–
13787), and the University of Buenos Aires (M091, Argentina).
G.A.R. is a fellow of the John Simon Guggenheim Memorial
Foundation. Work in G.R.V.?s laboratory is supported by grants
R01 GM070589–01 from the National Institutes of Health, and
MCB-00–77928 and IOB 0618409 from the National Science
Foundation. Work in C.W.T.?s laboratory is supported by the
University of Buenos Aires and CONICET grants.
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