Copyright ª Blackwell Munksgaard 2005 Review

doi: 10.1111/j.1600-0749.2005.00235.x

Adhesion, migration and communication in

melanocytes and melanoma

Nikolas K. Haass, Keiran S. M. Smalley, Ling Li
and Meenhard Herlyn*
The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104,
USA
*Address correspondence to Dr Meenhard Herlyn,
e-mail: herlynm@wistar.org
Summary
Under normal conditions, homeostasis determines
whether a cell remains quiescent, proliferates, differ-
entiates, or undergoes apoptosis. In this state of
homeostasis, keratinocytes control melanocyte
growth and behaviour through a complex system of
paracrine growth factors and cell–cell adhesion mole-
cules. Alteration of this delicate homeostatic balance
and can lead to altered expression of cell–cell adhe-
sion and cell communication molecules and to the
development of melanoma. Melanoma cells escape
from this control by keratinocytes through three
major mechanisms: (1) down-regulation of receptors
important for communication with keratinocytes
such as E-cadherin, P-cadherin, desmoglein and con-
nexins, which is achieved through growth factors
produced by fibroblasts or keratinocytes; (2) up-regu-
lation of receptors and signalling molecules not
found on melanocytes but important for melanoma–
melanoma and melanoma–fibroblast interactions
such as N-cadherin, Mel-CAM, and zonula occludens
protein-1 (ZO-1); (3) loss of anchorage to the base-
ment membrane because of an altered expression of
the extracellular-matrix binding integrin family. In
the current review, we describe the alterations in
cell–cell adhesion and communication associated
with melanoma development and progression, and
discuss how a greater understanding of these pro-
cesses may aid the future therapy of this disease.
Key words: melanoma/metastasis/cadherins/cell adhe-
sion molecules/integrins
Received 18 March 2005, revised and accepted for pub-
lication 5 April 2005
Introduction
The epidermal melanin unit of the human epidermis
denotes the symbiotic relationship between one mel-
anocyte and approximately 36 associated keratinocytes
(Fitzpatrick and Breathnach, 1963; Jimbow et al., 1976).
Melanocytes are located in the basal layer of the epider-
mis, where they occur in a life-long stable ratio of 1:5
with basal keratinocytes. This balance is maintained
through regulated induction of melanocyte division. In
order to proliferate, melanocytes need to decouple from
the basement membrane and from the keratinocytes,
retract their dendrites, divide, and migrate along the
basement membrane before they finally re-couple to
the matrix and to keratinocytes to form another epider-
mal melanin unit (reviewed in Haass and Herlyn, in
press). Melanocyte growth is controlled by the sur-
rounding keratinocytes by (1) extracellular communica-
tion through paracrine growth factors, by (2) intracellular
communication through second messengers and signal
transduction and by (3) intercellular communication
through cell–cell adhesion molecules, cell–matrix adhe-
sion, and gap junctional intercellular communication
(reviewed in Haass et al., 2004). Under normal condi-
tions, homeostasis determines whether a cell remains
quiescent, proliferates, differentiates, or undergoes
apoptosis (reviewed in Bissell and Radisky, 2001). Dys-
regulation of the homeostasis may disturb the balance
of the epidermal melanin unit and trigger a continuous
proliferation of the melanocytes, which may lead to the
development of melanoma. The hallmarks of solid
tumours are uncontrolled proliferation, derangement of
cellular and morphological differentiation, invasion, and
metastatic spread to distant organs. These characteris-
tics can be in part attributed to alterations in adhesion
and communication between neoplastic cells and the
normal cells in their immediate microenvironment
(reviewed in Hanahan and Weinberg, 2000; Park et al.,
2000). The exact molecular mechanisms of this dysreg-
ulation in melanoma are yet unknown. However, it is
likely that melanoma cells escape from control through
keratinocytes through (1) down-regulation of receptors
important for communication with and adhesion to kera-
tinocytes (e.g. E-cadherin); (2) up-regulation of receptors
and signalling molecules not found on melanocytes but
important for melanoma–melanoma and melanoma–fi-
broblast interactions [e.g. N-cadherin, melanoma cell
adhesion molecule (Mel-CAM), zonula occludens pro-
tein-1 (ZO-1)]; and (3) loss of anchorage to the base-
ment membrane because of an altered expression of
the extracellular-matrix binding integrin family. In this
review, we will focus on these three mechanisms.

150 Pigment Cell Res. 18; 150–159

 Adhesion, migration and communication in melanocytes and melanoma

oma cells show an increase in expression of melanoma

Cell–cell adhesion of melanocytes and
melanoma cells
Cell–matrix interactions shift from collagen IV- and lami-
nin-mediated adhesion in normal melanocytes to attach-
ment through collagen I- and vitronectin-binding
receptors in melanoma cells. The changes in matrix
adhesion receptor composition often reflect aggressive
properties of melanoma cells as they invade the dermis
from the epidermis (reviewed in Johnson, 1999; Nesbit
and Herlyn, 1994). Cell–cell adhesion receptors show
similar changes during tumour progression (Figure 1).
Among the classical cadherins, there is a shift from
E-cadherins found on normal melanocytes for attach-
ment to keratinocytes to N-cadherin on melanoma cells,
which allows coupling to fibroblasts and endothelial cells
in the tumour stroma (Hsu et al., 2000). Even if melan-
oma cells express E-cadherin, it does not appear
functional. Whereas normal melanocytes express few
cell–cell adhesion receptors of the immunoglobulin gene
superfamily of cell adhesion molecules (CAMs), melan-
cell adhesion molecule (MCAM, Mel-CAM, MUC18,
CD146), L1 cell adhesion molecule (L1-CAM, CD171),
activated leukocyte cell adhesion molecule (ALCAM,
CD166), vascular cell adhesion molecule 1 (VCAM-1,
CD106), intercellular cell adhesion molecule 1 (ICAM-1,
CD54), and carcinoembryonic antigen-related cell adhe-
sion molecule 1 (CEACAM1, CD66a). The adhesive
functions of cellular adhesion molecules in homophilic
and heterophilic interactions are well documented, but
their contributions to the malignant phenotype are less
defined.
Mel-CAM mediates homologous and heterologous
interactions between melanoma cells and endothelial
cells respectively via a heterophilic Ca2+-independent
adhesion to a currently unidentified ligand (Johnson
et al., 1997; Shih et al., 1997a,b). In melanocytic cells
expression of Mel-CAM is first found in nevi, when the
cells have separated from the epidermal keratinocytes
and have migrated into the dermis (Kraus et al., 1997;
Shih et al., 1994). With progression to malignancy, Mel-

Figure 1. Cell–cell adhesion of

melanocytes and melanoma cells.
Melanocytes adhere to keratinocytes via
E-cadherin and desmoglein, which enables
them to communicate with each other
through gap junctions (A). In melanoma
cells E-cadherin is down-regulated. They
interact with each other through N-
cadherin, Mel-CAM/Mel-CAM ligand, avb3
integrin/L1-CAM, ALCAM and connexins,
with fibroblasts through N-cadherin and
connexins, and with endothelial cells
through N-cadherin, Mel-CAM/Mel-CAM
ligand, avb3 integrin/L1-CAM, a4b1 integrin/
VCAM-1 and connexins (B).

Pigment Cell Res. 18; 150–159 151

Haass et al.
CAM expression gradually increases and is highest in
metastatic melanoma cells (Johnson et al., 1996; Leh-
mann et al., 1989; Shih et al., 1994; Xie et al., 1997).
Furthermore, Mel-CAM expression correlates with the
tumour thickness (Lehmann et al., 1989; Shih et al.,
1994).
Inhibition of Mel-CAM expression in metastatic mel-
anoma cells using genetic suppressor elements of
Mel-CAM cDNA leads to inhibition of adhesion
between melanoma cells and to down-regulation of the
tumorigenic phenotype (Satyamoorthy et al., 2001). In
melanoma–melanoma interactions, Mel-CAM and its
ligand appear to play a role as co-receptor for N-cadh-
erin, because its down-modulation disrupts gap junc-
tional intercellular communication (Satyamoorthy et al.,
2001). Furthermore, neutralizing antibodies to Mel-CAM
block melanoma metastasis in vivo and block the
homologous interaction between melanoma cells and
endothelial cells as well as the promoter and collage-
nase activity of matrix metalloproteinase-2 (MMP-2)
(McGary et al., 2002). Forced Mel-CAM expression of
human melanoma cells has an influence on later sta-
ges of the metastatic process only, namely, extravasa-
tion and establishment of new foci of growth, but is
not sufficient for this process per se (Schlagbauer-Wadl
et al., 1999). In contrast, transfection of Mel-CAM into
non-tumorigenic cells increases collagenase gene
expression, leading to increased tumorigenicity (Xie
et al., 1997). In three-dimensional skin reconstructs,
the overexpression of Mel-CAM in melanoma cells
allowed them to separate from the epidermis and
invade into the dermis through the basement mem-
brane, whereas melanoma cells with little or no Mel-
CAM were poorly invasive (Satyamoorthy et al., 2001).
Mel-CAM expression in melanocytes, nevus cells, and
radial growth phase melanoma cells is environmentally
regulated through direct cell–cell contact with keratino-
cytes (Li and Herlyn, 2000), but the mechanisms of
this regulation are not known. Even advanced primary
and metastatic melanoma cells down-regulate Mel-
CAM when intimate attachment to keratinocytes is
re-established by over-expression of E-cadherin (Hsu
et al., 2000). Loss of several tumour-associated adhe-
sion receptors in E-cadherin expressing melanoma cells
is associated with lack of invasion and increased apop-
tosis of single cells in the dermal environment (Li and
Herlyn, 2000).
Although originally described as a neuronal cell adhe-
sion molecule restricted to nervous tissues, L1-CAM
has also been detected in various other cell types as
well as a number of tumours, including osteogenic sar-
coma, squamous cell carcinoma of the lung, rhabdomy-
osarcoma and retinoblastoma (Nolte et al., 1999; Thies
et al., 2002b). There is an increase in L1-CAM immuno-
reactivity in melanomas and metastases of melanoma
compared with acquired melanocytic naevi (Fogel
et al., 2003). The expression of L1-CAM in human pri-
152
mary cutaneous malignant melanoma is significantly
associated with metastatic spread (Thies et al., 2002b).
L1-CAM mediates adhesion both via homophilic (L1-
CAM-L1-CAM) and heterophilic (L1-CAM-avb3 integrin)
mechanisms (Hortsch, 1996). In melanoma cell/melan-
oma cell and in melanoma cell/endothelial cell interac-
tions L1-CAM binds to avb3 integrin (Montgomery
et al., 1996). The interaction of L1-CAM and avb3 inte-
grin has been shown to play an important role in tran-
sendothelial migration of melanoma cells (Voura et al.,
2001).
ALCAM is involved in homophilic (ALCAM–ALCAM)
(Degen et al., 1998) and heterophilic (ALCAM–CD6)
(Patel et al., 1995) cell–cell–adhesion interactions. AL-
CAM is expressed in metastatic human melanoma cells,
whereas it is absent in non-metastatic cells (Degen
et al., 1998). Immunohistochemistry on a series of
human melanocytic lesions from common nevus to mel-
anoma metastasis revealed that ALCAM expression cor-
relates with melanoma progression (van Kempen et al.,
2000). ALCAM is, therefore, proposed to be molecular
melanoma progression marker besides the b3 integrin
subunit and ICAM-1 (see below). Using the N-terminally
truncated mutant DN-ALCAM to attenuate the function
of wild type ALCAM in metastatic cells and to assess
the overall effect of reducing homotypic tumour cell
adhesion on tumorigenicity it has been shown that the
intact cell adhesion function of ALCAM favours primary
tumour growth and represented a rate-limiting step for
tissue invasion, which supported the view that dynamic
control of ALCAM plays an important role in progression
(van Kempen et al., 2004). A broader scope on the func-
tions of ALCAM can be found in another review (Swart
et al., in press).
VCAM-1 is a cytokine inducible cell adhesion molecule
primarily found on vascular endothelial cells. As a recep-
tor for a4b1 integrin, expressed by malignant melanoma,
it facilitates melanoma cell attachment to the vascular
endothelium prior to extravasation (reviewed in Holz-
mann et al., 1998).
ICAM-1 in melanoma also correlates with melanoma
progression and increased risk of metastasis (Johnson
et al., 1989). Its expression in melanoma is stronger
than in common nevi and increases with the Breslow
index in primary melanomas (Natali et al., 1990, 1997;
Schadendorf et al., 1993, 1995). The observation that
stage I patients with ICAM-1 positive melanomas had a
significantly shorter disease-free interval and overall sur-
vival than those with ICAM-1 negative tumours (Natali
et al., 1997) and that the suppression of ICAM-1 in an
animal model reduced the metastatic capacity (Miele
et al., 1994), supported the role of ICAM-1 in melanoma
progression and metastasis. ICAM-1 can be induced in
a cell-specific manner by several cytokines, e.g. tumour
necrosis factor-alpha (TNF-a), interleukin-1 (IL-1), and
interferon-gamma (IFN-c). The ligands of ICAM-1 are
aLb2 (lymphocyte function-associated antigen 1, LFA-1)
Pigment Cell Res. 18; 150–159
 Adhesion, migration and communication in melanocytes and melanoma
and Mac1 on lymphocytes (van de Stolpe and van der
Saag, 1996). However, the specific role of ICAM-1 in
melanoma progression remains to be determined.
Expression of ICAM-1 may promote aggregate forma-
tion with leucocytes, which can enhance survival in the
vascular system and encourage extravasation (Aeed
et al., 1988). On the other hand ICAM-1 is shed from
melanoma cells (Giavazzi et al., 1992) – possibly in a
form that inhibits lymphocyte-tumour cell interaction
and thus contribute to tumour survival (Becker et al.,
1993).
CEACAM1 is involved in intercellular adhesion and
subsequent signal transduction events in a number of
epithelia. In epithelial cells, CEACAM1 is believed to act
as a growth suppressor, since its expression was
shown to be lost or significantly down- or dysregulated
in carcinomas of liver (Hixson and McEntire, 1989),
prostate (Kleinerman et al., 1995), endometrium (Bam-
berger et al., 1998), breast (Riethdorf et al., 1997) and
colon (Nollau et al., 1997). On the other hand, CEA-
CAM1 is up-regulated in non-small cell lung cancer (Sie-
nel et al., 2003). CEACAM1 interacts with the b3
integrin subunit via the CEACAM1 cytoplasmic domain.
CEACAM1 and the b3 integrin subunit co-localize at the
tumour–stroma interface of invading melanoma masses,
suggesting that CEACAM1-integrin b3 interaction plays
a role in melanoma cell migration and invasion (Brum-
mer et al., 2001). Expression of CEACAM1 in primary
melanomas is associated with the subsequent develop-
ment of metastatic disease (Thies et al., 2002a). Fur-
thermore, the overexpression of CEACAM1 in
CEACAM1-negative melanocytic cells and melanoma
cell lines increases the migratory and invasive growth
potentials in vitro (Ebrahimnejad et al., 2004) supporting
the role of CEACAM1 in melanoma progression and
metastasis.
Growth of cells is tissue context
dependent
The function of cell adhesion molecules is profoundly
influenced by the extracellular milieu. Therefore, melan-
oma invasion should be examined under physiological
conditions, e.g. by incorporating melanoma cells into
three-dimensional skin reconstructs. Skin reconstructs
consist of artificial skin rebuilt from isolated cell popula-
tions and composed of a stratified, terminally differenti-
ated epidermal compartment of keratinocytes and
melanocytes, a dermal compartment consisting of fibro-
blasts embedded in collagen, and a well established base-
ment membrane deposited by skin cells (Meier et al.,
2000). In human skin reconstructs, melanoma cells from
different stages of progression have the same properties
as cells in situ, i.e. non-tumorigenic melanomas are
unable to invade the dermis from the epidermis, whereas
tumorigenic (advanced primary and metastatic) melan-
oma cells readily invade the dermis (Meier et al., 2000).
Pigment Cell Res. 18; 150–159
Under two-dimensional culture conditions in vitro,
melanoma cells overexpressing either the b3 integrin
subunit or Mel-CAM did not show a significant differ-
ence in growth in comparison with the control cells
transfected with the corresponding vector alone
(Figure 2A, D). In contrast, both melanoma cells overex-
pressing the b3 integrin subunit or Mel-CAM showed
striking phenotypes under three-dimensional conditions
(Hsu et al., 1998; Satyamoorthy et al., 2001). Melanoma
cells infected with the adenovirus b3/Ad5 or Mel-CAM/
Ad5 invaded deep into the dermis and formed cell nests
resembling a VGP melanoma (Figure 2B, E), whereas
the lacZ/Ad5-infected control cells spread only horizon-
tally in an RGP melanoma-like manner (Figure 2C, F).
Moreover, lacZ/Ad5-infected cells showed the clear
morphological signs of apoptosis, including nuclear con-
densation, membrane blebbing, and apoptotic bodies
(Figure 2C, F). However, the mechanism leading to this
phenomenon is yet unknown.
Keratinocytes are the masters over
melanocytes and E-cadherin
overexpressing melanoma cells
Keratinocytes down-regulate the cell surface expression
of the b3 integrin subunit and of Mel-CAM in melanoma
cells overexpressing E-cadherin (Hsu et al., 2000). In
contrast to lacZ/Ad5-infected control cells (Figure 3A, B),
melanoma cells transduced with E-cad/Ad5 grown in co-
culture with normal human keratinocytes showed a
complete down-regulation of the b3 integrin subunit and
of Mel-CAM (Figure 3D, E).
Moreover, keratinocytes inhibit invasion of E-cadherin-
overexpressing melanoma cells into the dermis in
human skin reconstructs (Figure 3C, F). Metastatic mel-
anoma cells were transduced with either lacZ/Ad5 or
E-cad/Ad5 and incorporated into the epidermal compart-
ments of skin reconstructs. E-cadherin-overexpressing
melanoma cells grew exclusively in the epidermis, at
the epidermal/dermal junction, and in the upper dermis,
displaying typical signs of apoptosis (Figure 3F). In con-
trast, lacZ-transduced cells formed strands of cell nests
that invaded deep into the dermis and were not apop-
totic (Figure 3C).
Melanocyte matrix adhesion and
melanocyte migration
The ability of a cell to adhere to its stromal microenvi-
ronment is an integral feature of tissue organization.
The integrins constitute a major family of cell–cell and
cell–extracellular matrix (ECM) adhesion proteins. In
addition to adhesive function, integrins are also involved
in signalling, and transmembrane cytoskeletal attach-
ments (reviewed in Hynes, 2002). Each integrin consists
of a non-covalently linked a and b subunit, which both
are composed of an extracellular domain, a single mem-
153
Haass et al.

A
B C

D
E F

Figure 2. Growth of cells is tissue context dependent. In vitro growth of melanoma cells SBcl2 after b3 integrin overexpression (A). Two
days after viral infection, 2 · 105 cells were seeded into six-well tissue culture plates. Cell growth was monitored daily. Average cell number
from triplicate wells was plotted for SBcl2 cells. Despite the striking phenotype in three-dimensional models (see B, C) there is no significant
difference in the growth in a monolayer (A). Effect of b3 integrin subunit overexpression on melanoma invasion and survival in three-
dimensional skin reconstructs (B, C). Virus-infected SBcl2 melanoma cells were incorporated into the epidermis of skin reconstructs as
previously described (Hsu et al., 1998). b3/Ad5-infected SBcl2 cells grew in an invasive pattern reminiscent of VGP primary melanoma (B);
whereas lacZ/Ad5-infected cells spread horizontally, resembling RGP primary melanoma (C). Control virus-infected cells at the dermal/
epidermal junction displayed apoptotic features, including nucleus condensation, membrane blebbing, and presence of apoptotic bodies (C).
Mel-CAM-dependent invasion, survival, and growth of melanoma cells in organotypic skin reconstructs (Satyamoorthy et al., 2001). SBcl-2
cells after transduction with Mel-CAM using an adenoviral vector invaded into the dermis (E), whereas control adenovector LacZ/Ad5
transduced, non-tumorigenic, Mel-CAM-negative SBcl2 melanoma cells grew in the epidermis but did not invade into the dermis (F). In vitro
growth of melanoma cells after Mel-CAM overexpression (D). Again, there is no significant difference in the growth in a monolayer as
opposed to the three-dimensional model (E, F).

brane-spanning domain, and a short cytoplasmic tail. In
total there are 18 a and 8 b subunits, giving rise to 25
distinct integrin permutations; all with different sub-
strate selectivities (reviewed in Hynes, 2002). They can
be grouped according to their evolutionary relationships
and ligand specificity. Knockout experiments have
revealed the different roles and ligand specificities of
the integrins (reviewed in Hynes, 1996, 2002). During
migration, cells project lamellipodia that attach to the
ECM. At the same time cell–ECM contacts are being
broken at the trailing edge of the cell, and thus the cells
are able to move forwards through the ECM (Raucher
and Sheetz, 2000). Interestingly, although cells require
some adhesion to the ECM to generate the traction
needed for invasion, maximal rates of cell movement
are found only at intermediate levels of adhesion. Thus,
at low levels of cell adhesion, insufficient traction is
generated to facilitate movement, whereas strong adhe-
sion to the ECM effectively blocks any motility (Palecek
et al., 1998, 1999). The optimal situation for cell invasion
is, therefore, somewhere in-between the two states,
allowing some adhesion at the leading edge of the cell

154 Pigment Cell Res. 18; 150–159

 Adhesion, migration and communication in melanocytes and melanoma

A B C

D E F

Figure 3. Keratinocytes down-regulate cell surface expression of Mel-CAM by E-cadherin-expressing melanoma cells. Melanoma cells were
transduced with either E-cad/Ad5 or lacZ/Ad5. After 24 h, cells were mixed with normal human keratinocytes at a 1:5 ratio and the co-cultures
were stained 7 d later. (A) Identification of lacZ-transduced WM115 melanoma cells in co-cultures using mAb Mel-5, a melanosomal marker,
followed by Cy3-conjugated secondary antibody. (B) lacZ-transduced melanoma cells double-stained with mAb A32 defining Mel-CAM.
(D) E-cadherin-transduced melanoma cells identified in the co-cultures using mAb Mel-5. (E) E-cadherin-transduced melanoma cells
double-stained with anti-Mel-CAM mAb A32. Similar down-regulation was observed using SAP mAb against b3 subunit of the vitronectin
receptor (not shown). Scale bars: 40 lm. Keratinocytes inhibit invasion of E-cadherin-expressing melanoma cells into the dermis in human
skin reconstructs (C, F). 1205Lu metastatic melanoma cells were transduced with either lacZ/Ad5 (C) or E-cad/Ad5 (F) and incorporated into
the epidermal compartments of skin reconstructs. At maturation, reconstructs were harvested, fixed, and embedded in paraffin for
haematoxylin and eosin staining. E-cadherin-expressing melanoma cells grew exclusively in the epidermis, at the epidermal/dermal junction,
and in the upper dermis, displaying typical signs of apoptosis (F). In contrast, lacZ-transduced cells formed strands of cell nests that invaded
deep into the dermis and were not apoptotic (C). Magnification: ·20.

to generate traction and the release of contacts at the
back of the cell to allow forward motion. In this situ-
ation, integrins are critical at controlling the adhesion to
and release from the ECM. This process is termed
inside-out signalling, and provides a way for the inte-
grins to respond to cues generated intracellularly to alter
their environmental interaction. These changes of adhe-
siveness are regulated by protein–protein interactions at
the cytoplasmic tail of the integrin, altering its affinity
for its ligands. In melanoma, both aVb3 and b1 integrins
are highly expressed at the leading edge of invasive
explants (Brooks et al., 1996; Hegerfeldt et al., 2002).
The movement of primary melanoma through 3D collagen
matrix is particularly dependent upon the expression of
b1-integrin, which is expressed at the leading edge of
the explant (Hegerfeldt et al., 2002). It further seems
that this integrin is playing an organizing role in the
migratory process, as inhibition of b1 integrin activity,
using blocking antibodies, disrupts the polarity of the
explant and leads to the development of several leading
edges (Hegerfeldt et al., 2002).
The most relevant integrin combinations to melanoma
include - aVb3: which binds to fibronectin, fibrinogen,
von Willebrand factor, vitronectin, certain types of colla-
gen and laminin, and integrin a5b1: which selectively
binds fibronectin (reviewed in van der Flier and Sonnen-
berg, 2001). An important factor in metastatic spread of
melanoma is its interaction with the various compo-
nents of the ECM. Only transformed melanocytes can
survive in the altered environment of the dermis, and
this survival seems to be dependent upon expression of
the cell–ECM adhesion molecules such as the integrins.
Increased and altered expression profiles of the inte-
grins are known to be indicative of melanoma progres-
sion and melanocytes and early stage primary
melanoma do not express b3 integrin (Van Belle et al.,
1999). Thus a number of studies have reported that
expression of aVb3 and aVb1 integrins are prognostic for
melanoma progression (Albelda et al., 1990; Felding-
Habermann et al., 1992; Hsu et al., 1998; Li et al., 1998;
Melchiori et al., 1995; Natali et al., 1993; Schumacher
and Schaumburg-Lever, 1999). Of the two, aVb3 integrin
is important for adhesion of melanoma cells to dermal
collagen and the suppression of apoptosis (Montgomery
et al., 1994; Petitclerc et al., 1999). A direct role for the
integrins in melanoma progression is illustrated by
experiments showing that the forced expression of b3
integrin in an early phase melanoma (radial growth
phase or RGP) leads to functional expression of the
aVb3 integrin and an altered malignant phenotype, which

Pigment Cell Res. 18; 150–159 155

Haass et al.

corresponds to that of the later invasive form of melan-

oma (vertical growth phase or VGP). Other studies have
also shown that expression of aV or b3 integrin
increased metastatic potential of melanoma cells (Fel-
ding-Habermann et al., 1992; Filardo et al., 1996; Li
et al., 1998, 2001). Plating of aVb3 overexpressing mel-
anoma cells onto vitronectin led to increased activation
of FAK and Src, demonstrating a role for these kinases
in integrin-mediated invasion. The aVb3 integrin combina-
tion enhances melanoma cell survival on collagen by
altering the Bcl2:Bax ratio (Petitclerc et al., 1999).
Whereas overexpression of aVb3 integrin enhances mel-
anoma progression and survival, it has also been shown
A that antagonists of this integrin complex can block mel-
anoma growth by inducing apoptosis (Petitclerc et al.,
1999).
In melanocytes in situ a3b1, a6b1 (Figure 4) and avb1
are expressed, while the a1, a2, a4, a7, b2, b4, b5 and b6
subunits as well as a5b1 and avb3 are not expressed
(reviewed in Kuphal et al., in press). However, there is a
strong difference in the integrin expression pattern of in
situ melanocytes compared with cultured melanocytes.
From all above-mentioned integrins, a selective subset
of melanoma associated heterodimers namely a3b1,a6b1
and avb3 are expressed in normal cultured melanocytes,
whereas a1b1 and a4b1 are not expressed.
In situ integrin aV, a2, a3, and a4 levels are increased
in primary and metastatic melanomas (Hartstein et al.,
B
1997; Moretti et al., 1993; Nikkola et al., 2004) whereas
a6 levels are decreased (Danen et al., 1994; Natali et al.,
1993; Yoshinaga et al., 1993). However, whereas in cul-
tured cells with low metastatic potential a1, a2 and a6
levels are undetectable, highly metastatic cells – in con-
trast to tissue sections from melanoma patients – show
up-regulated a6 levels, moderate a1, and no a7 expres-
sion (Ziober et al., 1999). Integrin a3 has also been
shown to be up-regulated in cultured cells and to
enhance motility of melanoma cells (Yoshinaga et al.,
1993; Zhu et al., 2002). A broader scope on the integrin
signalling in malignant melanoma can be found in
another review (Kuphal et al., in press).

C
Conclusions
The study of cell–cell and cell–matrix adhesion in nor-
mal skin has helped us to understand which genes are

Figure 4. Keratinocytes and fibroblasts in human skin reconstructs

produce a basement membrane. Skin reconstructs were stained
with monoclonal antibodies against Collagen IV (A) and against pan-
Laminin (B). In both stainings there is a clear demarcation of the
basement membrane as indicated by the positivity of Collagen IV
and Laminin, respectively. Human foetal foreskin was stained with
the mAb GoH3 against the a6 integrin subunit, showing the basal
layer of the epidermis (C). A counter-staining of the a6 integrin
subunit (green in D) and HMB45 (red in D) shows that the a6
D integrin subunit is not only expressed in the basal keratinocytes,
but also in the melanocytes (co-localization, yellow in D).

156 Pigment Cell Res. 18; 150–159

 Adhesion, migration and communication in melanocytes and melanoma
down-regulated or functionally dysregulated in melan-
oma. We have learned that E-cadherin is a critical
adhesion receptor between melanocytes and keratino-
cytes and we have defined how growth of melano-
cytes can be stimulated by growth factors. We are
beginning to understand how melanocytes migrate
over the basement membrane to separate from each
other. Least is known about the mechanisms of
growth control that stop the melanocytes from prolifer-
ating and migrating and that make them extend their
dendrites far into the epidermis. We need to under-
stand the contributing factors that control growth, mor-
phology and positioning of melanocytes. We expect
each of the contributing regulatory mechanisms to be
deregulated in melanoma cells. In turn, melanoma cells
may be forced to revert to growth control by keratino-
cytes, even with pharmacological approaches. Poten-
tially a static balance can be obtained if melanoma
cells respond to the same signals as melanocytes in
the epidermis, albeit in a distant organ where they
have metastasized.
Acknowledgements
We thank all members of Meenhard Herlyn’s lab for intellectual
support. We apologize to all those colleagues whose important
work we could not cite due to space limitations.
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