Blood, Vol. 95 No. 6 (March 15), 2000:
pp. 1900-1910
REVIEW ARTICLE
Cell adhesion receptors in lymphoma dissemination
Paul Drillenburg and
Steven T. Pals
Department of Pathology, Academic Medical Center, University of
Amsterdam, Amsterdam, The Netherlands.
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Abstract |
Regulated lymphocyte trafficking is essential for the control and
integration of systemic immune responses. This homing process disperses
the immunologic repertoire, guides lymphocyte subsets to the
specialized microenvironments that control their differentiation and
survival, and targets immune effector cells to sites of antigenic insult. This review discusses data indicating that the adhesion receptors regulating the trafficking of normal lymphocytes are also
expressed and functionally active in their malignant counterparts, the
non-Hodgkin lymphomas. These "homing receptors" appear to mediate
the highly tissue-specific dissemination of specific lymphoma subtypes,
such as lymphomas of the mucosa-associated lymphoid tissues and
lymphomas of the skin. Furthermore, as a result of their capability to
enhance lymphoma dissemination and to transduce signals into the cell,
promoting cell growth and survival, adhesion receptors may contribute
to lymphoma aggressiveness. Taken together, the data offer a framework
for understanding the dissemination routes of non-Hodgkin lymphomas and
suggest that adhesion receptors, specifically those of the CD44 family,
may present useful tools to predict prognosis in patients with lymphomas.
(Blood. 2000;95:1900-1910)
© 2000 by The American Society of Hematology.
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Introduction |
Successful defense of the body against microbial
invasion is critically dependent on the presence of lymphocyte clones
with the right antigen specificity at the right position at the right time. To accomplish this task, evolution has created great
antigen-receptor diversity and has equipped lymphocytes with exquisite
motility. Most mature lymphocytes recirculate continuously, going from
blood to tissue and back to the bloodstream again.1 This
recirculation is not random, but rather is guided by
lymphocyte-endothelial recognition and subsequent diapedesis, directing
lymphocyte homing.2-5 Thus, lymphocyte-endothelial
interaction is a central regulatory point in the immune system,
controlling the access of specialized lymphocyte subsets to particular
tissues and influencing the nature of local immune and inflammatory
responses. At the molecular level, this process is regulated by
adhesion receptors on the cell membrane of lymphocytes and their
counterreceptors on endothelial cells in concert with chemokines.
Specialization of both lymphocyte subsets and endothelial cells in
their expression of adhesion receptors allows lymphocytes to move
selectively to specific functional compartments of the immune system,
such as the mucosa- and skin-associated lymphoid
tissues.2-5
Adhesion receptors play a key role in many biologic processes such as
embryogenesis, hemostasis, and inflammation.3-16 Their function is to orchestrate cell-cell and cell-extracellular matrix interactions and is complex and dynamic. As has also been emphasized in
a recent review by Shattil et al,10 engagement of adhesion receptors with their ligands does not represent a simple Velcro-type of
interaction, but instead transduces signals into the cell-regulating cytoskeletal organization,7,8,10 cell cycle
progression,9 and cell survival17,18 through a
process known as outside-in signaling. On the other hand, cytoplasmic
signals, for example, generated via antigen or chemokine receptors,
regulate the cell surface expression and functional activity of
adhesion receptors, a process termed inside-out
signaling.7,10,13,14,16,19 The adhesion molecules involved
in lymphocyte homing constitute a structurally diverse group of cell
membrane receptors belonging to distinct adhesion receptor families,
that is, the selectin,11 the integrin,7 the
immunoglobulin,6 and the CD44 families.13 Each
of these receptors exhibits specific ligand-binding properties that are
needed for specific tasks in the trafficking process.2-5 For example, when blood flows through postcapillary venules in lymphoid
tissues, lymphocytes slow down and roll on the endothelial surface. In
most instances, this rolling is mediated by interactions of adhesion
receptors of the selectin family with their carbohydrate ligands. Major
selectins involved in lymphocyte homing are L-selectin and E-selectin,
which are expressed on the lymphocyte and endothelial cell surface,
respectively. Once the rolling process has slowed down the cells, they
are arrested at the right site by activated integrins on the lymphocyte
cell surface interacting with their immunoglobulin family
counterreceptors on the endothelium, resulting in
extravasation.2-5 Integrins with an important function in lymphocyte homing are 
L
2,
41, and 47.
Whereas CD44 presumably is of minor importance in the physiology of
lymphocyte homing, recent studies indicate that this class of adhesion
receptors is of great significance for lymphocyte migration to sites of inflammation.20-26 At these sites, CD44 may interact with
its major ligand, hyaluronate, which is expressed on the luminal
surface of activated endothelium.
Apart from their physiologic functions, adhesion receptors are also
involved in tumor invasion and metastasis.12 The
non-Hodgkin lymphomas (NHLs) represent the malignant counterparts of
normal lymphocytes, arrested at specific stages of maturation. This
review describes the paradigm of lymphocyte homing and discusses data indicating that the adhesion receptor programs directing the homing of
normal lymphocytes are, at least partly, preserved in lymphomas. These
adhesion receptors contribute to lymphoma aggressiveness and appear to
determine the highly tissue-specific dissemination patterns of certain
lymphoma subtypes.
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Lymphocyte adhesion receptors in the regulation of lymphocyte homing |
An overview of the most important lymphocyte adhesion receptors
involved in homing, their distribution on various lymphocyte subsets,
their ligands, sites of interaction, and predominant role(s) in homing
is given in Table 1. Before we focus on the specific roles of these molecules, we will discuss the general principles of lymphocyte-endothelial interaction.
Engagement of lymphocytes with endothelium directs lymphocyte homing
and is a multistep process 2-5,27-30 (Figure
1). The initial step consists of a loose
"tethering" engagement between the lymphocyte and the
endothelium, leading to a rolling movement of the lymphocyte over the
vascular endothelium of the postcapillary venule (Figure 1). This step
generally is mediated by molecules of the selectin family, which are
strategically localized on the tips of the cell membrane's
microvilli,31-33 thus allowing for effective interaction of
the selectin with its sialomucin ligand. However, other molecules such
as the integrins, 41 and
47, and CD44 also can mediate rolling.21,30,34-36 Lymphocyte rolling is transient and
reversible, unless followed by a signal leading to activation of
adhesion molecules of the integrin family. These molecules, that is,
L2, also known as lymphocyte
function-associated molecule (LFA)-1, 41,
and 47, mediate stable adhesion and
promote migration of lymphocytes across the vessel wall (Figure 1). The
extremely rapid integrin activation that must occur in the bloodstream
is mediated by cytokines of the chemokine family, interacting with their G protein-coupled receptors.37 Recently, several
chemokines like SDF-1, SLC (6-C-kine), BLC/BCA-1, MIP-3, MIP-3,
IP10, Mig, and TARC have been identified that are capable
of mediating rapid (milliseconds) integrin-dependent lymphocyte arrest
under flow conditions.38-40a Consistent with their
important regulatory role in homing, these chemokines display
site-specific production as well as specificity for distinct lymphocyte
subsets 39,40a-45 (Table 2).
For example, the chemokine SLC is specifically expressed by high
endothelial venules and selectively recruits naive T cells, expressing
the chemokine receptor CCR7, into the secondary lymphoid organs,43 whereas TARC recruits CCR4-positive memory T
cells to the skin.40a BLC/BCA, by contrast, is involved in
the recruitment of B cells into B-cell areas. This molecule is
specifically expressed in B-cell follicles, presumably by follicular
dendritic cells (FDC). Disruption of CXCR5, the receptor for BLC, leads
to a disturbed development of primary follicles and germinal centers in
the spleen and Peyer patches.44,46 In addition to
chemokines, heparan sulfate (HS) proteoglycans expressed on endothelium
or extracellular matrix contribute to integrin activation and promote
diapedesis by concentrating and presenting chemokines to their
receptors (Figure 1). Because specific modifications of HS chains
appear to determine cytokine-binding specificity, chemokine interaction with HS proteoglycans may add an additional level of specificity to the
lymphocyte-endothelial cell interaction cascade.47-49
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| Fig 1.
Lymphocyte interaction with endothelium.
In the postcapillary venules selectin-sialomucin interactions mediate
"rolling" of lymphocytes on endothelium. Chemokines presented by
heparan sulfate proteoglycans on the endothelium can bind to chemokine
receptors, which are G protein-coupled 7-membrane-spanning molecules.
This leads to activation of members of the integrin family on the
surface of lymphocytes. Interaction of integrins with their ligands
results in stable adhesion of lymphocytes to endothelium and in
diapedesis.
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In the multistep lymphocyte-endothelial cell interaction model
described above (Figure 1), specificity is determined by unique combinations of primary and secondary adhesion receptor pairs, as well
as by chemokine-mediated activation events.4,27-30,33,43 For example, whereas lymphocyte homing to peripheral lymph nodes is
directed by the adhesion receptors (1) L-selectin and (2) LFA-1, and by
the chemokine (3) SLC, homing to the skin is mediated by the adhesion
receptors (1) CLA and (2) LFA-1 and by the chemokine (3)
TARC.33,40a,43 Important factors regulating the adhesion
receptor profile of lymphocytes are prior antigenic stimulation and
state of activation.2-5,50 Imprinting of the lymphocyte at
the site of antigenic experience leads to expression of a specific set
of adhesion receptors on the lymphocyte. These "homing" receptors
permit interaction with endothelial area codes "vascular
addressins," crucial in tissue-specific recirculation of lymphocytes
to the sites of primary antigenic stimulation. Combinations of
lymphocyte adhesion molecules and vascular addressins involved in
tissue-specific homing are 47/MAdCAM-1 for homing to mucosa-associated lymphoid tissues (MALT), cutaneous lymphocyte antigen (CLA)/E-selectin for homing to skin, and
L-selectin/peripheral lymph node addressins (PNAds) for peripheral
lymph node homing. Binding of E7 to the adhesion
molecule E-cadherin expressed on epithelial cells is involved in
positioning lymphocytes in epithelium (Figure
2).
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| Fig 2.
Lymphocyte migration.
Lymphocyte migration is strictly regulated by cell adhesion receptors
on lymphocytes (lymphocyte homing receptors) and endothelium (vascular
addressins). Naive lymphocytes migrate randomly through the body
because they express both 47 (for mucosal
homing) and L-selectin (for homing to peripheral lymph nodes).
Migration of activated lymphocytes to sites of inflammation involves
several receptor-ligand pairs, including selectin-sialomucin,
41-VCAM-1,
41-CS-1, and CD44-hyaluronate
interactions. Homing of memory lymphocytes is largely restricted to
organs of primary antigenic stimulation. By binding to their vascular
addressins, lymphocyte homing receptors
47, L-selectin, and CLA mediate
tissue-specific homing to the mucosa, peripheral lymph node, and skin,
respectively. Interaction of E7 with E-cadherin
A metastasisexpressed on epithelial cells is involved in
positioning of lymphocytes in the epithelium of skin and mucosa. The
NHLs related to lymphocyte populations with tissue-specific homing
properties are shown in the boxes. These tumors usually display
tissue-specific dissemination patterns and express homing receptors
corresponding to the tissue of origin.
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Adhesion receptors in lymphoma dissemination |
At least 3 sets of clinical observations suggest that conserved
homing programs might play an important role in the dissemination of
NHLs.51 First, NHLs related to small resting lymphocytes, such as lymphocytic and mantle-cell lymphoma, usually are disseminated to multiple sites at presentation, whereas NHLs related to activated lymphocytes, such as diffuse large B-cell lymphomas, often are initially localized.52 These differences in dissemination
propensity presumably reflect the recirculating versus sessile
character of the normal counterparts of these NHLs. Second, extranodal
NHLs arising in the MALT or the skin preferentially disseminate to mucosal sites and skin, respectively.52-59 This strongly
suggests that they make use of specific area codes, similar to those
used during normal lymphocyte homing. Third, specific lymphoma
dissemination to sites of (micro)trauma and inflammation has been
reported.51,59 This phenomenon might be explained by
interaction of tumor cells with activated endothelium at the site of
injury. In the following paragraphs, studies focusing on the role of
specific adhesion receptors in lymphoma dissemination are discussed.
Selectins and their carbohydrate
ligands
L-selectin; homing to peripheral lymph nodes.
L-selectin, like the other members of the selectin family, consists of
lectin, epidermal growth factor, and short consensus repeat
domains.11 L-selectin is expressed by lymphocytes,
monocytes, and neutrophils and is rapidly down-regulated on cell
activation.60 In vitro evidence for a selective role of
L-selectin in lymphocyte homing to peripheral lymph nodes came from
experiments demonstrating that monoclonal antibodies (mAbs) against
L-selectin interfere with binding of lymphocytes to high endothelial
venules of peripheral lymph nodes, but not to high endothelial venules
of Peyer patches.61 In vivo inactivation of L-selectin by
mAbs or gene knockout results in a nearly complete inhibition of
lymphocyte homing to peripheral lymph nodes, whereas homing to Peyer
patches remains largely intact.33,62-64 The PNAds, the main
ligands for L-selectin, are selectively but not exclusively expressed
on high endothelial venules in peripheral nodes.65
Anti-PNAd (mAb MECA-79) decreases lymphocyte adherence to peripheral
lymph node high endothelial venules by 60% to 90%.65 The
MECA-79 epitope is a carbohydrate moiety that decorates a number of
different protein backbones including CD34 and
GlyCAM-1.5,66,67 Lymphocyte homing to peripheral lymph
nodes also is markedly reduced in (1,3) fucosyltransferase Fuc-TVII
knockout mice, which are deficient in selectin ligands.68
Hence, both L-selectin and its ligands are needed for lymphocyte homing
to peripheral lymph nodes (Figure 2).
Studies of L-selectin expression on NHLs have shown that the vast
majority of nodal lymphomas express L-selectin (Table
3). This holds for low-grade and aggressive
B-cell lymphomas, as well as for T-cell lymphomas with a primary nodal
localization.69 By contrast, expression of L-selectin in
extranodal lymphomas is variable. Aggressive mucosal B-cell and T-cell
lymphomas are generally L-selectin negative.69,70
Similarly, cutaneous T-cell lymphomas express low levels of
L-selectin71 (Table 3). However, 2 types of
gastrointestinal tract lymphomas express L-selectin, low-grade B-cell
lymphoma of MALT-type and malignant lymphomatous polyposis
(MLP).69,72 Whereas MLP, a variant of mantle-cell lymphoma,
typically shows widespread dissemination to both mucosal sites and
peripheral lymph nodes, MALT-type lymphoma generally disseminates to
mucosal sites only. Possibly, in the dissemination of the latter
lymphoma type to peripheral lymph nodes, other steps in the
lymphocyte-endothelial interaction cascade are rate
limiting.4,27 Alternatively, because Helicobacter
pylori antigens promote the growth of gastric lymphoma
cells,73 the absence of antigenic stimulation within the
peripheral lymph node microenvironment might explain the low incidence
of MALT-type lymphoma at these sites.
Cutaneous lymphocyte antigen; homing to the skin.
CLA is a carbohydrate antigen that is closely related to the sialyl
Lewis x antigen (sLex).2,74,75 CLA is present on a minor
subset (10%-15%) of memory T lymphocytes in the peripheral blood,
tonsils, and lymph nodes.75,76 However, 40% to 90% of the
T cells in the normal and inflamed skin, respectively, are CLA
positive.75,77,78 CLA mediates skin homing via interaction with E-selectin, which is constitutively expressed on skin
endothelium2,79 (Figure 2).
Interestingly, mycosis fungoides and other subtypes of cutaneous
lymphoma express CLA75,80,81 but not the mucosal homing receptor 47 (Drillenburg and Pals,
unpublished observation). On the other hand, gastrointestinal T-cell
lymphomas express the mucosal homing receptor
47,82 but not CLA (Table 3).
Hence, the malignant counterparts of 2 normal lymphoid tissues express mutually exclusive adhesion molecules concordant with their tissue of
origin. The highly selective expression of CLA on cutaneous T-cell
lymphomas suggests that CLA mediates the skin-specific dissemination of
these lymphomas in vivo (Figures 2 and 3).
Integrins
Integrins form a large family of heterodimeric transmembrane
glycoproteins consisting of noncovalently associated - and
-subunits.7 Only limited numbers of integrins are
expressed on lymphocytes. They serve as receptors and mediate
interactions of lymphocytes with a variety of cells as well as with
components of the extracellular matrix. Integrins expressed on
lymphocytes are not constitutively active but their function is
activation dependent.2-5,7,19
L2 (LFA-1).
The leukocyte integrin L2, which is
generally designated by its original name LFA-1, is one of the most
important integrins of the immune system. It mediates lymphocyte
interactions with other cells, including adhesion to
endothelium,3-5,88-93 dendritic cells,85,86
follicular dendritic cells (FDC),87 and
epithelium.88 The ligands for LFA-1 on endothelium are the
intercellular adhesion molecules (ICAM)-1, -2, and
-3.29,89-91 LFA-1 interaction with ICAM-1 plays a major
role in lymphocyte adhesion and transmigration through high endothelial
venules at various anatomic sites.3-5,29,92,93 Lymphocytes
share LFA-1 with other leukocytes. Defective expression of the
2-subunit leads to impaired emigration of leukocytes
from the blood to sites of inflammation, resulting in severe
immunodeficiency.94
This integrin supports in vitro invasiveness of T-cell hybridomas and
lymphoma cell lines in hepatocyte and fibroblast monolayers and
promotes experimental lymphoma metastasis in nude
mice.95-98 In human lymphomas, expression of LFA-1 is
closely related to lineage derivation and stage of
differentiation.99 Although an initial study by Clayburger
et al100 suggested an association between the absence of
LFA-1 expression on lymphoma cells and unfavorable prognosis,
subsequent studies by these authors101 as well as by our
own laboratory99,102 did not confirm this finding. Whether
or not expression of ICAM-1, a major ligand of LFA-1, plays a role in
lymphoma dissemination and disease outcome is controversial. Our own
studies in large-cell NHLs did not reveal a relation of ICAM-1
expression with either dissemination or prognosis102; however, Terol et al103 recently reported that ICAM-1
correlates inversely with dissemination and overall survival in
aggressive NHLs.
Integrin 41.
The leukocyte integrin 41 is unique among
1-integrins because it is not only involved in
cell-matrix but also in cell-cell interaction. It can bind the CS-1
domain of the extracellular matrix component fibronectin as well as the
vascular cell adhesion molecule (VCAM)-1, a transmembrane glycoprotein.
The latter molecule is constitutively expressed by FDC and is induced
on endothelium at sites of inflammation.
Integrin 41 plays an important role in
lymphocyte migration to sites of inflammation, including inflamed
joints in rheumatoid arthritis and inflammatory brain lesions in
experimental allergic encephalitis, an animal model for multiple
sclerosis 104-107 (Figure 2). During antigen-specific
B-cell differentiation, 41 in concert with LFA-1 mediates the binding of germinal center B lymphocytes to
FDC.83,108 This interaction is crucial for B-cell selection and for affinity maturation.109,110 It has been
demonstrated that 41-VCAM-1 as well as
LFA-1-ICAM interaction inhibits apoptosis of germinal center B cells
in vitro.17 This suggests that
41 (and LFA-1) may have a dual role in
the germinal center. Apart from mediating physical contact between B
cells and FDC, these integrins may contribute to the B-cell selection
process via outside-in signaling.17,111
In human NHLs, 41 is widely expressed in
a pattern that matches the expression on related stages of normal
lymphocyte differentiation.70,112 Like binding of normal
germinal center B cells, the binding of the tumor cells of
follicle-center cell lymphomas to FDC cells is mediated by
41.113 This interaction may
play a role in the ongoing somatic hypermutation process in these
lymphomas, which is believed to be antigen driven.114
Transformation of follicular lymphoma to a diffuse phenotype is
associated with loss of FDC from the tumor, rather than with
down-regulation of 41 on the tumor
cells.113 As with LFA-1, no consistent association between 41 expression and disease parameters has
been found in NHLs.70,112 Conceivably, functional overlap
between LFA-1 and 41 causes redundancy in
interactions relevant for lymphoma dissemination, including those with
endothelium and FDC (see below). Furthermore, because the function of
integrins is activation dependent, their expression per se does not
reflect their function.
Integrin 47;
homing to the mucosa.
The integrin 47 mediates lymphocyte
homing to the intestinal mucosa by binding to MAdCAM-1, a vascular
addressin selectively expressed on mucosal endothelium (Figure
2).63,115,116 MAdCAM-1 is an immunoglobulin family member
with domains that display homology to the adhesion receptors ICAM-1 and
VCAM-1, as well as to another mucosa-associated immunoglobulin family
member, IgA1.115 In 7-knockout mice, the
formation of MALT is severely impaired. This abnormality is caused by a
defect in lymphocyte-endothelial interaction at the stage of tight
adhesion and extravasation; 7-deficient lymphocytes show
normal rolling on the endothelial lining of the high endothelial venules of Peyer patches, but they fail to stably arrest and to transmigrate.117 Using 4-null chimeric mice,
Arroyo et al118 showed that lymphocytes lacking
4 also are unable to enter Peyer patches, whereas their
homing to lymph nodes and spleen is not disturbed. Together, these
findings demonstrate the key role of 47
in mucosal homing in the mouse. In man,
47 appears to have a similar function. It
is expressed on mucosal lymphocytes,82,119,120 and
moreover, it is present on a subset of peripheral blood memory T cells
with gut homing properties.76 Recently, the human MAdCAM-1 has been cloned.121 Like its murine homologue, it is
preferentially expressed in the MALT.122
We have studied the expression of the 47
mucosal homing receptor in NHLs.72,82 In MLP, an unusual
presentation of NHL of mantle cell type characterized by multifocal
involvement of the gastrointestinal tract, expression of
47 was present in 7 of 8 cases.72 By contrast, all cases of nodal mantle cell lymphoma in our study were 47 negative.
The association between 47 expression and
gastrointestinal tract dissemination of mantle cell lymphoma was
recently confirmed by Geismann et al.123 These authors
reported that 47, when present on nodal
mantle cell lymphoma, predicts multifocal digestive tract involvement.
In most cases of low-grade B-cell lymphoma of MALT-type (Figure
3) as well as in intestinal T-cell
lymphoma, we also observed 47 expression.
By contrast, expression of 47 on
lymphomas with a nonmucosal primary localization was
uncommon.82 Taken together, these findings suggest that
47 plays an important role in determining
gastrointestinal tract involvement by lymphoma as well as in the
characteristic mucosal dissemination often found in lymphomas of the
MALT (Figure 2; Table 3). Interestingly, Dogan et al124
recently reported that low-grade B-cell lymphomas of MALT type
up-regulate 47 after H. pylori-induced T-cell-dependent proliferation of neoplastic cells.
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| Fig 3.
Cell adhesion receptors and vascular addressins.
(A) 47 and (B) MAdCAM-1 expression in a
low-grade B-cell lymphoma of MALT type (stomach; arrow, epithelial
structures); (C) CLA and (D) E-selectin expression in a cutaneous
T-cell lymphoma.
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E7; interaction with
epithelium.
In the gut, the integrin E7 is found on nearly all
intestinal intraepithelial lymphocytes and on approximately 50% of the T cells in the lamina propria. E7 can bind E-cadherin
on epithelial cells and in this way mediates the positioning of
lymphocytes in the epithelium125 (Figure 2).
Expression of E7 is present on celiac
disease-associated intestinal T-cell lymphomas.126
Furthermore, intraepidermal malignant T lymphocytes in mycosis
fungoides express E7127 (Figure 2; Table
3). In advanced stages of this disease with loss of epitheliotropism, expression of E7 decreases, suggesting a direct
involvement of E7 in epitheliotropism. Consistent
with this notion, we recently demonstrated a strong expression of
E7 in pagetoid reticulosis, a rare form of cutaneous
T-cell lymphoma characterized by an extreme epitheliotropism and a
pagetoid pattern of lymphocyte infiltration between
keratinocytes.128
The CD44 family
CD44 represents a family of glycoproteins encoded by a single gene
on the human chromosome 11 (Figure
4).13,129-134 The members of
this family show a broad tissue distribution and have been implicated
in a number of important biologic processes, including lymphocyte
homing and activation, hematopoiesis, and tumor progression and
metastasis.12,13,15,130,135-142 The CD44 gene consists of 19 exons.143 Structural and functional diversity of CD44 is
generated by alternative splicing messenger RNA (mRNA) involving 10 exons encoding domains of the extracellular portion of the CD44
molecule. In addition to variable exon usage, variations in
glycosylation contribute to the diversity of CD44.13
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| Fig 4.
Schematic representation of the CD44 gene and its encoded
proteins.
The extracellular domain and cytoplasmic tail of CD44 isoforms vary in
size as the result of alternative splicing. The alternatively spliced
exons are indicated by open boxes. The human v1 exon contains a
stop codon. In the model of the protein, all putative
glycosylation sites are indicated: O-glycosylation
(open circles); N-glycosylation (closed circles);
chondroitin sulfate (open squares); heparan sulfate (HS) (rod). As
indicated, the HS-binding site in exon v3 has the ability to bind
growth factors, including hepatocyte growth factor/scatter factor
(HGF/SF) and fibroblast growth factor (FGF). In addition, the
hyaluronate-binding sites (double line), the disulfide bonds
(S-S), the ankyrin binding site (. . . . .), the Ezrin-binding site
(- - -), the phosphorylation sites (P), and the putative
interaction site for the src-family kinase p56lck
are indicated. aa, aminoacid; TM, transmembrane.
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Most CD44-expressing cells express the "standard" CD44 (CD44s)
isoform translated from an mRNA species containing none of the
"variant" (v) exons.13,132,141 On hematopoietic cells
and lymphocytes this 85- to 95-kd molecule is the principle CD44
isoform.132,141,144-146 Larger CD44 isoforms containing
various combinations of variant exons are preferentially expressed on
epithelial cells,144-146 but they can also be expressed on
activated lymphocytes141,147 and aggressive malignant
lymphomas.141 During lymphocyte ontogeny and activation,
CD44 is strictly regulated, suggesting an important function in these
processess.13,135,148 Indeed, CD44 has been reported to be
involved in lymphopoiesis137 and lymphocyte
activation,149-153 as well as in lymphocyte migration and
homing.130 In the homing process, CD44 mediates lymphocyte
binding to high endothelial venules,13,130,133,154
lymphocyte rolling,21,36 and migration to inflammatory
sites.20-26 Cross-linking of CD44 on lymphocytes costimulates antigen cell receptor-mediated proliferation, cytokine release, and integrin activation through outside-in
signaling14,149-153 and leads to protein tyrosine kinase
activation. This lymphocyte activation presumably involves src-family
tyrosine kinases, because CD44 was shown to be physically and
functionally associated with the p56lck in T
cells.155 The CD44 cytoplasmic tail associates with the actin cytoskeleton via ankyrin and molecules of the ERM
family.156-158 These cytoskeletal interactions may regulate
hyaluronate binding and CD44-dependent motility as well as inside-out
signaling events.
Several experimental and clinical studies suggest an important role of
CD44 in the biologic behavior of NHLs and indicate that CD44 represents
a clinically useful marker predicting disease outcome. In a nude mouse
model, CD44s (but not CD44v8-10) enhances the growth and metastatic
capacity of Burkitt lymphoma cell lines.140 Engagement of
CD44 on the tumor cells with hyaluronate on the luminal surface of
endothelial cells presumably plays an important role in these
tumor-promoting effects. Furthermore, CD44 interaction with hyaluronate
in the extracellular matrix may enhance tumor cell growth by providing
a molecular bridge facilitating tumor cell attachment. The matrix might
serve as a scaffold for tumor cell growth and as a reservoir for growth
and motility factors with biologic effects on the tumor
cells.159 In this context, it is of interest that CD44
variants containing exon v3 can be decorated with HS side chains, and
by this virtue, can serve as receptors for heparin-binding growth
factors, including MIP-1, fibroblast growth factor (FGF)-2, and
hepatocyte growth factor (HGF).47,160-161 Presentation of
HGF to its receptor tyrosine kinase c-Met by HS forms of CD44 was
recently shown to promote Met activation as well as activation of the
RAS/MAP kinase and PI3 kinase pathways downstream of Met, and may
enhance tumor growth and motility.161
Clinical studies support the importance of CD44 in the biology of
human NHLs (Table 4). In diffuse large-cell
lymphomas (DLCL), we observed a strong correlation between CD44
expression and lymphoma dissemination.102,136 Furthermore,
CD44 expression is an unfavorable prognosticator in these
tumors.102 Similar findings were reported by the group of
Jalkanen139,162 for high-grade B-cell lymphomas. In a
recent study, we explored the prognostic value of CD44 in a group of
276 patients diagnosed as having DLCL of the B lineage according to
the criteria of the REAL classification.52 In this multicenter population-based study group, expression of CD44 was a
powerful prognosticator for both overall and disease-free survival in
patients with localized disease.163 In a multivariate
comparison with the clinical parameters of the International Prognostic
Index, currently used to predict prognosis in malignant lymphoma, CD44 expression was the major prognosticator for the subgroup of patients with localized nodal disease.
In all the above-mentioned clinical studies, mAbs against epitopes on
the constant part of CD44 (CD44s) were used to assess CD44 expression
(Table 4). However, in addition to CD44s, NHLs may express CD44
isoforms containing variant exons.141,164-168 These larger
splice variants appear to be predominantly expressed on a subgroup of
aggressive lymphomas.141,165,167,169 They often contain
exon v6/7 encoded sequences, which have been reported to confer
metastatic behavior in rat carcinoma cell lines.138 The
function of CD44 splice variants on lymphocytes is as yet incompletely
understood, but they presumably have a role in lymphocyte activation.
Antibodies against v6 are immunosuppressive, whereas mice carrying a
CD44v4-v7 transgene in their T cells show an accelerated immune
response against T-cell-dependent antigens.170,171 Stauder and colleagues167 studied CD44 variant expression in a
mixed group of high-grade NHLs, including precursor B-cell lymphomas, Burkitt lymphomas, and DLCL. In this group, CD44v6 was an independent prognosticator predicting tumor-related death. However, in our own
study focusing on a single diagnostic group (ie, DLCL), CD44v6 had no
prognostic value, whereas CD44s expression was an important prognosticator.163 Thus, although there is general
agreement that CD44 is a potentially useful biologic prognosticator
(co)determining lymphoma dissemination, the question whether epitopes
on the constant or variant part of the molecule are the most suitable
for assessing prognosis needs further exploration. To answer this
question, studies comparing different anti-CD44 mAbs by standardized
techniques in patients belonging to defined clinicopathologic subgroups
and receiving uniform treatment are needed.
| |
Footnotes |
Submitted June 14, 1999; accepted January 3, 2000.
Supported by grants from the Dutch Cancer Society and the Association
for International Cancer Research.
Reprints: Steven T. Pals, Department of Pathology, Academic
Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ
Amsterdam, The Netherlands; e-mail: s.t.pals{at}amc.uva.nl.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
| |
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Abstract
Introduction
