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Int. J. Cancer: 65,717-722 (1996)
0 1996 Wiley-Liss, Inc.
q b
Publicaion of the InternationalUnion Aqainst Cancer
PuDlcal on de I UP on InletnationdieContre le Cancer
BIOLOGY OF TUMOR CELL INVASION: INTERPLAY OF CELL ADHESION
AND MATRIX DEGRADATION
Jyrki HEINO~
Medic& Research Laboratoiy and Department of Medical Biochemistry, UniversiQ of Turku, FIN-20520 Turku, Finland.
Invasion of malignant cells requires altered cellular interaction with extracellular matrix. Integrin-typecell adhesion receptors play an important role in this process. Integrin-related cell
biological phenomena explain cancer cell migration, and recent
developments in the field have made it possible to propose that
integrins are also involved in the penetration through basement
membranes and other molecular barriers. Finally, malignant
melanoma has been used here as an example to speculate on
the function of each integrin in light of information from
different experimental models.
5 1996 Wiley-Liss,Inc.
lNTEGRlN FAMILY OF CELL AL)HESION RECEPTORS
Anchored cells use members of the integrin family for
adhesion to the structural proteins of the extracellular matrix
(Ruoslahti, 1991; Hynes, 1992 and references therein). Sixteen
a and 8 p integrin subunits can form at least 22 different,
non-covalently linked a/@type heterodimers. Fifteen of them
arc rcceptors for matrix proteins (Fig. 1). P l is thc most
promiscuous of all integrin subunits, participating in 10 diffcrent complexes. Integrins alp1 and a 2 p l are the major cell
surface collagen receptors. Both a1 and a2 subunits contain a
similar, about 200 amino acids long, ligand-binding I-domain.
The I-domain in a M integrin has been isolated and its
3-dimensional structure has been determined by X-ray crystallography (LCCet al., 1995). The revealed Mg’+-depcndcnt
ligand-binding site has been named MIDAS (Lee et al., 1995).
Collagen binding by a l p 1 and a2pl integrins is also dependent
on the presence of Mg2+ but cannot be supported by Ca2+
(Crzesiak et al., 1992). Integrin a l p 1 may prefer type IV
collagen over type I collagen, and it is a receptor for laininin-1.
Integrin a2pl can also bind laminin-1 and tenascin (Sriramarao et al., 1993). Integrin a3pl is a receptor for laminin-5,
and in different experimental modcls it has shown binding to
laminin-1, type I collagen and fibronectin. Integrins a4Pl and
a5pl are fibronectin receptors. They recognize, however,
different domains in fibronectin. The protein sequences they
bind to can be reduced to 3 or 4 amino acids; LDVP and RGD
for a 4 p l and asp1 integrins, respectively. Integrins a 6 p l and
a7pl are receptors for laminin-1. Integrin a8pl is a fibronectin
(Miiller et al., 1995) and a vitronectin reccptor, and rx9pl
intcgrin binds to tcnascin (Yokosaki et u / . , 1994). Another
integrin subunit found in many different matrix receptors is
aV. Receptors containing ciV subunit can recognize the RGD
sequence in ligand molecules. In complex with (31 or p3 it is a
receptor for both fibronectin and vitronectin. Integrin aVp3
can also bind, e.g., bone sialoprotein and thrombospondin.
Integrins ciVp.5 and aVP8 are specific for vitronectin (Nishimura et aZ., 1994) and aVP6 for fibronectin. Other intcgrintype matrix rcceptors arc a6P4, which binds members of the
laminin family and is a component of the hemidesmosomes,
and ci4p7, which is a similar fibronectin receptor to a4pl
integrin. Integrin ciIIbp3 is an RGD-dependent platelet receptor for fibrinogen, fibronectin and vitronectin.
Integrins anchor cells to their surroundings, but they are
also essential for cell migration and probably for invasion of
tumor cells (for review, see Heino, 1993; Giancotti and
Mainiero, 1994). Intracellular domains of integrin subunits are
connected to cytoskeletal proteins and signal transduction
pathways. Integrin occupancy leads to receptor targeting to
focal contacts and accumulation of cytoskeletal proteins,
whereas receptor clustering is needed for phosphorylation of
signal transduction proteins (Miyamoto et al., 1995). Activation of integrin-mediated signal transduction regulates cell
behavior, differentiation and phenotype. Expression of specific
genes, including matrix mctalloproteinases (MMPs), is partially regulated by integrin-related signals.
Integrins expressed on the cell surface are not necessarily
active ligand-binding receptors, but their action can be regulated by intracellular mechanisms. This phenomenon is called
“inside-out signaling” and is thought to take place by altering
the conformation of extracellular domains through the cytoplasmic domains (Ginsberg Pt a[., 1992).
INTEGKINS AND MMPS
MMPs are a family of zinc-dependent enzymes containing at
least 11 members, including collagenases (MMP-1, MMP-8),
gclatinascs (MMP-2, MMP-9) and stromelysins (MMP-3-7).
Two novel family members have becn described: membranetype matrix metalloproteinase (MT-MMP) and collagenase-3
(reviewed by Birkedal-Hansen, 1995). MMPs can degrade all
components of the extracellular matrix, and they are probably
essential for cancer cell invasion and formation of metastasis.
Many types of malignant cell can produce MMPs, but they
might also induce stromal cells in different tumors to produce
MMPs. The tissuc inhibitors of metalloproteinases (TIMPs)
are specific, naturally occurring inhibitors of MMPs. Several
lines of study suggest that the MMP/TIMP ratio is critical for
cell invasion (Ray and Stetler-Stevenson, 1994).
Cell morphology and the presence of certain matrix molecules can regulate the expression of MMPs. Recent studies
have shown that integrin-type ccll adhesion rcccptors are
mediating thc matrix-generated signals behind this phenomenon (Table I). Awidely used model to study the role of matrix
is to culture cells inside a 3-dimensional collagen gel. Under
these conditions, the expression of interstitial collagenase
(MMP-1) is induced in most cell types (Grinnell, 1994). We
have shown that in human osteogenic sarcoma-derived cell
lines the induction of MMP-1 in collagen gels is mediated by
a 2 p l integrin (Riikonen et at., 1995h). In vivo, during wound
healing, human keratinocytes exprcss MMP-1 when in contact
with type I collagen but not when located on intact basement
membranes (Saarialho-Kere et al., 1993). Similarly, cell cultured keratinocytes express MMP-1 when plated on collagen
(Sudbeck et al., 1994). Thus, the cell-collagen contact seems to
limit the collagenase expression to take place only in the
presence or its substrate. Similar integrin-mediatcd recogntion mechanisms may regulatc the exprcssion of othcr MMPs
spatiotemporally.
In rabbit synoviocytes, 2 fibronectin receptors, a4pl and
a5pl integrins, have opposite effects on the expression of 3
distinct MMPs, MMP-1, stromelysin (MMP-3), and 92 kDa
gelatinase (MMP-9). Interaction of a5pl integrin with its
target sequence in fibronectin, the RCD-containing cell adhe‘To whom corrcspondence and reprint requests should be sent, at
MediCity Research Lahoratory, University of Turku, Tykistokdtu 6A,
FIN-20520 Turku, Finland. Fax: (358) 21-633-7000.
Received: August 30, 1995 and in revised form October 25,1995
718
HEINO
sion domain, stimulates expression of these MMPs (Werb et
al., 1989). Integrin a4pl binds to another domain in fibronectin
molecules, the CS-1 containing region. This interaction suppresses production of the same MMPs (Huhtala et al., 1995).
Functional analyses of the MMP-1 gene have pointed to the
Ap-1- and PEA3-responsive DNA sequences as the sites essential for d p l integrin-generated signals (Tremble et al., 1995).
Treatment of human keratinocytes with anti-a3 or anti-pl
monoclonal antibodies, but not with other antibodies for
integrins, induces expression of MMP-9 (Larjava et al., 1993~).
Integrin a 3 p l has several putative ligand molecules, and it is
not known which one of them might be the natural regulator of
MMP-9. In human melanoma cells 72 kDa gelatinase (MMP-2)
expression can be regulated by avp3 integrin-mediated signals
(Seftor et al., 1992, 1993).
Plasminogen and plasminogen activators are components of
another proteolytic machinery suggested to have an important
function in tumor cell invasion-related matrix degradation.
Much less is known about their relationship with cell adhesion
receptors. Nip et al. (1995) suggest coordinated expression of
aVp3 integrin and urokinase-type plasminogen activator in
human melanoma cells.
INTEGRINS IN MALIGNANT MELANOMA
Cell lines cultured from primary tumors are often the only
way to study the function of specific molecules. However, the
integrin pattern in these cells sometimes varies significantly
F~GURE
1- Receptor heterodimers formed by integrin subunits
and acting as matrix receptors. Ligands: FN, fibronectin; VN,
vitronectin; LN, laminin; COL, collagen; TN, tenascin. In addition
to ligands listed here, some other matrix molecules may bind to
integrins (see text for more details).
from that in the original tumors. It is, therefore, obvious that
all of the findings must be interpreted on the basis of in vivo
observations. At the same time, it must be remembered that
alterations detected in tumors are not necessarily important
for malignant cell phenotype but might only reflect the altered
activity of transcription factors regulating a large number of
genes. Also, inflammatory cells infiltrating malignant lesions
may release cytokines regulating integrin expression (Heino et
al., 1989; Santala and Heino, 1991). Furthermore, integrin
function is regulated by intracellular signals, and the activation
or inactivation of a given receptor might be more important
than its number on the cell surface. Finally, cells are often in
different stages of tumor progression and only some of them
might be available for migration and invasion.
Melanoma was selected as an example because several
studies describe integrin expression in vivo in different stages
of the process leading from cutaneous nevus to malignant
melanoma (reviewed by Danen et al., 1995). There is some
discrepancy among the published papers, but the reports agree
about certain facts. Importantly, most lesions of malignant
melanoma seem to contain cells expressing a2p1, a3pl and
aVP3 integrins (Albelda et al., 1990; Schadendorf et al., 1993;
van Duinen et al., 1994; Danen et al., 1994), suggesting that
they might be the key players in cell invasion. Studies on
integrin expression in melanoma-derived cell lines have also
shown the correlation of a2Pl (IUein et al., 1991a, b; Etoh et
al., 1992; Danen et al., 1993) and aVp3 integrin (Gehlsen et al.,
1992) expression with aggressive phenotype. Integrins a l p l ,
a4p1, asp1 and a6pl might also be present in in vivo tumors.
Different papers give somewhat variable information about
their abundance, but most lesions seem to be negative in that
respect (van Duinen et al., 1994). Several studies have compared alterations in integrin expression and tumor progression. Integrin a6pl/a6p4 may be more common in nevi than in
malignant melanomas (Natali et al., 1993; van Duinen et al.,
1994; Danen et al., 1994), whereas the frequency of a4pl- and
a5pl-positive cells might increase (Danen et al., 1994). Integrin aVp3 is not expressed in nevi, unlike a3pl integrin and
probably also a2pl integrin. Expression of a2pl integrin seems
to be stronger in malignant melanoma than in melanoma in situ
(van Duinen et al., 1994; Danen et al., 1994). Expression of
aIIbp3 integrin mRNA has been reported in melanoma cell
lines (Chang et al., 1992), but the corresponding protein has
not been found in vivo (Danen et al., 1994). Similarly, a7pl
integrin is expressed in melanoma-derived cell lines (Kramer et
al., 1991), whereas less is known about its abundance in vivo.
Integrin expression in uveal melanoma seems to be very
different from that in cutaneous melanoma (ten Berge el al.,
1993). There, a 2 p l and aVp3 integrin-positive cells seem to
be rare, whereas d P l and a6p4 integrin-positive cells are
TABLE I - REGULATION OF MATKIX METAI.I.OI'KOI~IYASE GENE EXPK€SSIOK BY
IKTEGRIN-MEDlhTFD SIGNALS
Integrin
Inducer
a2pl
Type I collagen
a3pl
Anti-a3 MAb,
anti-pl MAb
Fibronectin, CS-1containing region
a4pl
a5pl
Fibronectin, RGDcontaining region
aVp3
Vitronectin, antiaVB3 MAb
Cell type
M M P ( t or 1)
sarcoma (MG-63)
Reference
(1995b)
atinocytes
fibroblasts
Human melanoma
cells (A375M)
MMP-2
f
Seftor et al. (1992)
CELL ADHESION, MATRIX DEGRADATION AND INVASION
frequently seen (ten Berge et al., 1993). It is an important
possibility that alteration in cellular integrin pattern leads to
formation of metastasis to distinct anatomical locations. This is
supported by the fact that uveal melanomas metastasize
primarily to the liver, unlike cutaneous melanomas. Furthermore, Vink et al. (1993) have measured in vitro binding of
different melanoma cell lines on cryostat sections of different
organs. They were able to show that a2pl/aVp3 integrinexpressing cells colonized only the lungs, whereas d p l / a 6 p l
integrin-positive cells colonized both lungs and extrapulmonary sites.
PUTATIVE ROLE OF INDIVIDUAL INTEGRINS
IN MELANOMA CELL INVASION
In addition to local proliferation, melanoma cells must be
able to interact with basement membranes and penetrate
through them. After that they migrate through connective
tissue stroma to reach lymph or blood vessels. A suggested role
of the different integrins in these stages has been summarized
in Figure 2.
Increasing evidence suggests that specific adhesion receptors might act in a similar way to the tumor suppressor genes,
which are down-regulated during transformation. Integrin
d p l is the major fibronectin receptor of many cell types. The
disappearance of fibronectin from the cell surface is frequently
observed during malignant transformation, and the phenomenon has been explained by impaired function (Akiyama et al.,
1990) or reduced expression of d p l integrin (Plantefaber and
Hynes, 1989). In CHO cells the forced expression of the a5
subunit inhibits the transformed phenotype (Giancotti and
Ruoslahti, 1990). Qian et al. (1994) suggest that a 4 p l integrin
might suppress the malignant behavior of mouse melanoma
cells in vivo. Integrins a4pl and a5pl are usually not detected
in nevi, and during the transformation process their expression
might be induced (Danen et aL, 1994), indicating that they are
not putative tumor suppressors in human melanoma. Integrin
a6pl is a laminin receptor and integrin 01604is a component of
A
719
hemidesmosomes in basal keratinocytes. Integrin a6 is expressed in most nevi, but according to some reports, it is seen
less frequently in malignant melanomas (Natali et al., 1993; van
Duinen et al., 1994; Danen et al., 1994). The significance of this
observation is not clear. The conclusion is that there is no in
vivo evidence that the down-regulation of some specific integrin is required for malignant growth and invasion of nevi cells.
At early stages, melanoma cells are operating in the same
molecular environment as keratinocytes. Thus, it is interesting
to know which integrins are needed by keratinocytes in wound
healing-related migration. Normal basal keratinocytes express
a2p1, a 3 p l and a6p4 integrins, but when activated a5 and aV
integrin subunits are also induced (Larjava et al., 1993b).
Indeed, the same integrin subunits are expressed in malignant
melanomas and not in nevi. Thus, expression of these 2
integrins alone might explain the increased mobility of melanoma cells.
Integrin aV may be required for melanoma cell proliferation
in vivo (Felding-Habermann et al., 1992u), and it rescues
melanoma cells from apoptosis in 3-dimensional dermal collagen (Montgomery et al., 1994). Cell adhesion-triggered signal
transduction may regulate pathways containing Ras, mitogenactivated protein kinase (MAPK, Schlaepfer et al., 1994) and
cyclin A (Guadagno et al., 1993). It is not known whether the
proliferation of melanoma cells is modulated by the fact that
melanoma cells can use the aVP3 integrin in adhesion to, eg.,
vitronectin (Nip et aZ., 1992) and fibrinogen (FeldingHabermann et aZ., 1992). Furthermore, the p3 subunit might
not be required for in vivo tumorigeneity and formation of
metastases, but it can be replaced by pS or p6 subunits
(Boukerche et al., 1994).
Invasion through basement membranes is suggested to
require enzymes degrading at least type IV collagen. MMP-2,
MMP-3 and MMP-9 are therefore the candidate metalloproteinases to be involved in the process. Cell culture experiments
show that interaction of either a561 or aVP3 integrin with a
ligand might trigger signal transduction pathways activating
C
TRANSFORMATION MAY
RINS"
OTHER INTEGRINS MAY
BE UPREGULATED
IN DIFFERENT EXPERIMENTAL
MODELS a4pl AND a5pl INTEGRINS
HAVE PREVENTED MALIGNANT
CELL BEHAVIOUR,
WHEREAS IN MM THE NUMBER OF
a4pl AND a5pl POSITIVE CELLS MAY
INCREASE MOST LESIONS STAY NEGATIVE
MMP-2 EXPRESSION CAN BE
INDUCED BY a5pl AND aVP3
INTEGRINS
MMP-1 EXPRESSION CAN BE
REGULATED BY n2pl AND a S p l
INTEGRINS
MMP-9 EXPRESSION CAN BE
INDUCED BY a3pl INTEGRIN
INTEGRINS a 2 p l . a5pl AND nVP3
ARE INVOLVED IN CELL MIGRATION
ON COLLAGEN AND FIBRONECTIN
MOST LESIONS OF MM CONTAIN CELLS
POSmVE FOR &PI. a3pl AND aVP3 INTEGRINS
RGURE
2 -Putative functions of different integrins in (a) the control of malignant phenotype, (b) penetration through basement
membranes and (c) invasion in connective tissue stroma. MM, malignant melanoma.
720
HEINO
their expression (Werb et al., 1989; Seftor et al., 1992). In growth on laminin and collagen (Turner et al., 1989). Integrin
keratinocytes, a third integrin heterodimer, a3p1, can convey a4pl is needed in the extravasation process of many inflammatory cells, and it might have a similar function in melanoma
signals regulating MMP-9 expression (Larjava et al., 1993a).
Cell migration in dermis might require different cell adhe- cells. Indeed, a4pl integrin is frequently expressed in the
sion apparatus and the expression of different metalloprotein- metastatic lesions of melanomas (Danen et al., 1994).
ases. Integrin a 2 p l is frequently present in vivo in malignant
melanomas (Klein et al., 1991b). Interestingly, in skin malignanOPEN QUESTIONS
cies with lower tendency for invasion, like basal cell carcinoThere seems to be significant individual variation in integrin
mas, a2 integrin is down-regulated (Peltonen et al., 1989). In
culture, melanoma cells use a2pl integrin in initial adhesion to expression in different tumors, even in the ones originating
collagen (Montgomery et al., 1994) and in migration on from the same cell type. It is probable that different integrins
replace each other in the functions essential for invasion.
collagen (Etoh et al., 1992; Yoshinaga et al., 1993). Integrin may
For
that
reason, the value of analyses of integrin pattern for
a2pl is also involved in the reorganization of collagen fibrils the prognostication
of individual cancers or whether integrin
(Shiro et at., 1991; Riikonen et al., 1995b), seen in the pattern in cancer cells could be used to estimate the most
aggressive melanoma cells as the increased ability to contract probable site of metastasis is not clear.
collagenous matrices (Klein et al., 1991a). With some specific
Several lines of evidence support the importance of MMPs
cancer cell types, there is evidence suggesting the importance
in
the
invasion of malignant cells. Immunohistochemical obserof the a2pl integrin for invasive phenotype; however, in many
carcinomas a2 integrin is often down-regulated. In rhabdomyo- vations have shown MMP expression either in cancer cells or in
sarcoma cells, the forced expression of the a 2 subunit is stromal cells, generating discussion of whether MMPs are
whether they only
required for the formation of metastasis in the mouse model produced by malignant cells themselves or
induce other cells to produce MMPs. In vitro experiments
(Chan et al., 1991). In human osteogenic sarcoma (HOS) cells, reviewed in this paper show that cell interaction with matrix
transformation with both a chemical mutagen, MNNG (Dedhar can induce MMP expression. This suggests that MMP expresand Saulnier, 1990; Santala et al., 1994), and murine Kirsten sion by tumor cells might be temporally and spatially limited
sarcoma virus (Santala et al., 1994) causes induction of the a 2 and that it takes place only during the short period cells are
integrin. Forced expression of the a 2 integrin by cDNA attached to right extracellular ligands via the corresponding
transfection in HOS cells does not make the cells tumorigenic integrin-type receptors. In vivo studies planned to find evibut induces their migration on, and invasion through, type I dence to support this hypothesis should analyze single cells in
collagen (Vihinen et al., 1996). In addition to its role in cell tumors and contain simultaneous localization of specific mamigration, a2pl integrin might be an important element in the trix molecules, their receptors and MMPs. In malignant
regulation of MMP-1 expression by the collagenous matrix. In melanoma or in any other type of cancer this kind of study has
osteosarcoma cells, the number of a2 integrins on the cell not been done. Analyses of healing wounds has, however,
surface dictates the level of MMP-1 gene expression (Riikonen revealed data supporting the idea (Saarialho-Kere et al., 1993).
et al., 1995b). MMP-1 can be essential for invasion for 2
Finally, an important hypothesis is that invasion of cancer
reasons: (i) Type I collagen is a major component of dermis cells can be prevented by treatment with molecules blocking
and collagen fibrils might form a molecular barrier preventing integrin-mediated cellular functions. There is some experimencell movement. MMP-1, in addition to leukocyte MMP-8 and tal data supporting this possibility (Humphries et al., 1986;
the newly described collagenase-3, is the only known enzyme Trikha et al., 1994). In the future, a more detailed picture
degrading type I collagen. (zi) Degradation of type I collagen about the mechanisms of invasion will help to target new
by MMP-1 leads also to its denaturation and reveals new molecules to critical points in the process.
binding sites for other integrin heterodimers, like aVp3. Signal
transduction by another integrin heterodimer, d p l , might
ACKNOWLEDGEMENTS
also regulate MMP-1 expression (Werb et al., 1989).
The lesions of malignant melanoma may also contain cells
This research has been supported by the Sigrid JusClius
positive for alp1 and a4pl integrins (Schadendorf et al., 1993; Foundation, the Technology Development Centre in Finland
Danen et al., 1994). The first one is a laminin and a collagen ( T E E S ) , the Academy of Finland, the Finnish Cancer
receptor, though its significance for cells is not known. In Association, and the Finnish Cancer Union. I thank Dr. V.-M.
cultured PC 12 cells, it plays an important role in neurite Kahari for critically reading the manuscript.
REFERENCES
AKIYAMA,
S.K., LARJAVA,
H. and YAMADA,
K.M., Differences in the
biosynthesis and localization of the fibronectin receptor in normal and
transformed cultured human cells. Cancer Res., 50,1601-1607 (1990).
ALBELDA,
S.M., MEITE, S.A., ELDER,D.E., STEWART,
R., DAMIANOVICH, L., HERLYN,
M. and BUCK,C.A., Integrin distribution in malignant melanoma: association of the p3 subunit with tumor progression.
Cancer Res., 50,6757-6764 (1990).
BIRKEDAL-HANSEN,
H., Proteolytic remodeling of extracellular matrix.
Cur. Opin. Cell Biol., 7,728-735 (1995).
BOUKERCHE,
H., BENCHAIBI,
M., BERTHIER-VERGNES,
O., LIZARD,G.,
M. and MCGREGOR,
J.L., Two human melanoma
BAILLY,
M., BAILLY,
cell-line variants with enhanced in vivo tumor growth and metastatic
capacity do not ex ress the p3 integrin subunit. Europ. J. Biochem.,
220,485-491 (1994y
CHAN,B.M.C., MATSUURA,
N., TAKADA,Y., ZETTER,B.R. and
HEMLER,
M., In vitro and in vivo consequences of VLA-2 expression on
rhabdomyosarcoma cells. Science, 251,1600-1602 (1991).
CHANG,Y.S., CHEN,Y.Q., TIMAR,J., NELSON,K.K., GROSS, I.M.,
FITZGERALD,
L.A., DIGLIO,C.A. and HONN,K.V., Increased expres-
sion of uIIbp3 integrin in subpopulations of murine melanoma cells
with high lung-colonizing ability. Znt. J. Cancer, 51,445-451 (1992).
DANEN,E.H., TEN BERGE, P.J., VAN MUIJEN,G.N., VAN HOFGROOTENBOER,
A.E. and BROCKER,
E.B., Emergence of u5pl fibronectin and uVp3 vitronectin receptor expression in melanocytic tumour
progression. Histopathology, 24,249-256 (1994).
DANEN,E.H., VAN MUIJEN,G.N. and RUITER,D.J., Role of integrins
as signal transducing cell adhesion molecules in human cutaneous
melanoma. Cancer Sum., 24,43-65 (1995).
DANEN,E.H., VAN MUIJEN,G.N., VAN DE WIEL VAN mMENADE, E.,
JANSEN,
K.F., RUITER,D.J. and FIGDOR,
C.G., Regulation of integrinmediated adhesion to laminin and collagen in human melanocytes and
in non-metastatic and highly metastatic human melanoma cells. Int. J.
Cancer, 54,315-321 (1993).
DEDHAR,S. and SAULNIER,
R., Alterations in integrin receptor
expression on chemically transformed human cells: specific enhancement of laminin and collagen receptor complexes. J. Cell Biol., 110,
481-489 (1990).
ETOH, T., BYERS,H.R. and MIHM, M.C., Integrin expression in
CELL ADHESION, MATRIX DEGRADATION AND INVASION
721
NATALI,P.G., NICOTRA,M.R., BARTOLAZZI,
A., CAVALIERE,
R. and
malignant melanoma and their role in cell attachment and migration
BIGOTTI,A., Integrin expression in cutaneous malignant melanoma:
on extracellular matrix proteins. J. Dermatol., 19,841-846 (1992).
FELDING-HABERMANN,
B., MUELLER,B.M., ROMERDAHL,
C.A. and association of the 013/pl heterodimer with tumor progression. Int. J.
Cancer, 54,68-72 (1993).
CHERESH,
D.A., Involvement of integrin a V gene expression in human
melanoma tumorigenicity. J. clin. Invest., 89,2018-2022 (1992~).
NIP, J., RABBANI,
S.A., SHIBATA,H.R. and BRODT,P., Coordinated
FELDING-HEBERMANN,
B., RUGGERI,Z.M. and CHERESH,D.A., Dis- expression of the vitronectin receptor and the urokinase-type plasminotinct biological consequences of integrin aVf33-mediated melanoma gen activator in metastatic melanoma cells. J. clin. Invest., 95, 2096cell adhesion to fibrinogen and its plasmic fragments. J. Bid. Chem., 2103 (1995).
267,507&5077 (199%).
NIP, J., SHIBATA,
H., LOSKUTOFF,
D.J., CHERESH,
D.A. and BRODT,P.,
GEHLSEN,K.R., DAVIS,G.E. and SRIRAMARAO,
P., Integrin expression Human melanoma cells derived from lymphatic metastases use intein human melanoma cells with differing invasive and metastatic grin 01Vp3 to adhere to lymph node vitronectin. J. clin. Invest., 90,
14061413 (1992).
properties. Clin. ap.Metastasis, 10, 111-120 (1992).
S.L., SHEPPARD,D. and PYTELA,R., Integrin aVp8.
G I A N C O ~F.G.
I , and MAINIERO,
F., Integrin-mediated adhesion and NISHIMURA,
signaling in tumorigenesis. Biochem. biophys. Acta., 1198,47-64 (1994). Interaction with vitronectin and functional divergence of the p8
cytoplasmic domain. J. biol. Chem., 269,28708-28715 (1994).
GIANCOTTI,F.G. and RUOSLAHTI,
E., Elevated levels of the d p l
J., LARJAVA,
H., JAAKKOLA,
S., GRALNICK,
H., AKIYAMA,
fibronectin receptor suppress the transformed phenotype of Chinese PELTONEN,
S.K., YAMADA,S.S., YAMADA,K. and UITTO, J., Localization of
hamster ovary cells. Cell, 60,849-859 (1990).
integrin receptors for fibronectin, collagen, and laminin in human skin.
GINSBERG,
M.H., Du, X. and PLOW,E.F., Inside-out integrin signal- J. clzn. Invest., 84,1916-1923 (1989).
ling. Cum. Opin. Cell. Biol., 4,766-771 (1992).
PLANTEFABER,
L.C. and HYNES,R.O., Changes in integrin receptors
GRINNELL,
F., Fibroblasts, myofibroblasts, and wound contraction. J. on oncogenically transformed cells. Cell, 56,281-290 (1989).
CeNBiol., 124,401404 (1994).
QIAN,F., VAUX,D.L. and WEISSMAN,
I.L., Expression of the integrin
GRZESIAK,
J.J., DAVIS,G.E., KIRCHHOFER,
D. and PIERSCHBACHER,a4pl on melanoma cells can inhibit the invasive stage of metastasis
M.D., Regulation of a2pl-mediated fibroblast migration on type I formation. Cell, 77,335-347 (1994).
colla en by shifts in the concentrations of extracellular Mg2+and Caz+.
RAY,J.M. and STETLER-STEVENSON,
W.G., TIMP-2 expression moduJ. CeiBivl., 117,1109-1117 (1992).
lates human melanoma cell adhesion and motility. Ann. N.Y. Acad.
GUADAGNO,
T.M., OHTSUBO,
M., ROBERTS,
J.M. and ASSOIAN,
R.K., A Sci., 732,233-247 (1994).
link between cyclin A expression and adhesion-dependent cell cycle
RIIKONEN,
T., KOIVISTO,
L., VIHINEN,P. and HEINO,J., Transforming
progression. Science, 262,1572-1574 (1993).
factor-p induces collagen gel contraction by increasing the
HEINO,J., Integrin-type extracellular matrix receptors in cancer and growth
expression of 012f3l integrin in osteogenic cells. J. bivl. Chem., 270,
inflammation. Ann. Med., 25,335-342 (1993).
376-382 (1995a).
HEINO,J., IGNOTZ,
R.A., HEMLER,M.E., CROUSE,C. and MASSAGUB, RIIKONEN,
T., WESTERMARCK,
J., KOIVISTO,
L., BROBERG,
A., KAHARI,
J., Regulation of cell adhesion receptors by TGF-p. Concomitant V.-M.
and HEINO,J., 012pl integrin is a positive regulator of collageregulation of integrins that share a common pl-subunit. J. biol. Chem., nase (MMP-1)
and collagen al(1) gene expressi0n.J. bivl. Chem., 270,
264,380-388 (1989).
13548-13552 (19956).
HUHTALA,
P., HUMPHRIES,
M.J., MCCARTHY,J.B., TREMBLE,
P.M., RUOSLAHTI,
E., Integrins. J. clin. Invest., 87,l-5 (1991).
WERB,Z. and DAMSKY,
C.H., Cooperative signalling by a5pl and a4pl
integrins regulates metalloproteinase gene expression in fibroblasts SAARIALHO-KERE,
U.K., KOVACS,S.O., PENTLAND,
A.P., OLERUD,
adhering to fibronectin. J. Cell Bid., 129,867-879 (1995).
J.E., WELGUS,H.G. and PARKS,W.C., Cell-matrix interactions modulate
interstitial
collagenase
expression
by
human
keratinocytes
actively
HUMPHRIES,
M.J., OLDEN,K. and YAMADA,
K.M., A synthetic peptide
from fibronectin inhibits experimental metastasis of murine melanoma involved in wound healing. J. clin. Invest., 92,2858-2866 (1993).
cells. Science, 233,467-470 (1986).
SANTALA,
P. and HEINO,J., Regulation of integrin-type cell adhesion
HYNES,R.O., Integrins: versatility, modulation, and signaling in cell receptors by cytokines. J. biol. Chem., 266,23505-23509 (1991).
adhesion. Cell, 69,ll-25 (1992).
SANTALA,
P., LARJAVA,
H., NISSINEN,
L., RIIKONEN,
T., M~ATTA,A.
KLEIN,C.E., DRESSEL,D., STEINMAYER,
T., MAUCH,C., ECKES,B., and HEINO,J., Suppressed collagen synthesis and induced expression
KRIEG,T., BANKERT,R.B. and WEBER,L., Integrin a2pl is upregu- of a2pl integrin-type collagen rece tor in tumorigenic osteosarcoma
lated in fibroblasts and highly aggressive melanoma cells in three- cells. J. biol. Chem., 269,1276-1283 5994).
dimensional collagen lattices and mediates the reorganization of SCHADENDORF,
D., GAWLIK,C., HANEY,U., OSTMEIER,
H., SUTER,L.
collagen I fibrils.J. Cell Biol., 115,1427-1436 (1991a).
and CZARNETSKI,
B.M., Tumour progression and metastatic behaviour
KLEIN,C.E., STEINMAYER,
T., KAUFMANN,
D., WEBER,L. and B R ~ K E R , in vivo correlates with inte rin expression on melanocytic tumours. J.
E.-B. Identification of a melanoma progression antigen as integrin Pathol., 170,429-434 (19937.
VLA-2. J. invest. Dermatol., 96,281-284 (1991b).
SCHLAEPFER,
D.D., HANKS,S.K., HUNTER,
T. and VAN DER GEER,P.,
KRAMER,
R.H., Vu, M.P., CHENG,Y.F., RAMOS,D.M., TIMPL,
R. and Integrin-mediated signal transduction linked to Ras pathway by GRB2
WALEH,N., Laminin-binding integrin a7pl: functional characteriza- binding to focal adhesion kinase. Nature (Lond.), 372,786-791 (1994).
tion and expression in normal and malignant melanocytes. Cell Regul., SEFTOR,R.E.B., SEFTOR,E.A., GEHLSEN,K.R., STETLER-STEVENSON,
2,805-817 (1991).
E. and HENDRIX,
M.J.C., Role of the
W.G., BROWN,
P.D., RUOSLAHTI,
LARJAVA,H., LYONS,J.G., SALO,T., MAKELA, M., KOIVISTO,L., 01Vp3 integrin in human melanoma cell invasion. Proc. nat Acad. Sci.
BIRKEDAL-HANSEN,
H., AKIYAMA,
S.K., YAMADA,
K.M. and HEINO,J., (Wash.), 89,1557-1561 (1992).
Anti-integrin antibodies induce type IV collagenase expression in SEFTOR,R.E.B., SEFTOR,E.A., STETLER-STEVENSON,
W.G. and HENkeratinocytes. J. cell. Physiof., 157,190-200 (1993a).
DRIX, M.J.C., The 72 kDa type IV collagenase is modulated via
LARJAVA,
H., SALO,T., HAAPASALMI,
K., KRAMER,R. and HEINO,J., differential expression of aVp3 and a5pl integrins during melanoma
Expression of integrins and basement membrane components by cell invasion. CancerRes., 53,3411-3415 (1993).
wound keratinocytes. J. clin. Invest., 92,1425-1435 (19936).
SHIRO,J.A., CHAN,B.M.C., ROSWIT,W.T., KASSNER,
P.D., PENTLAND,
LEE, J.-O., RIEU, P., ARNAOUT,M.A. and LIDDINGTON,
R., Crystal A.P., HEMLER,M.E., EISEN,A.Z. and KUPPER,T.S., Integrin 012pl
structure of the A domain from the 01 subunit of integrin CR3 (VLA-2) mediates reorganization and contraction of collagen matrices
by human cells. Cell, 67, 403-410 (1991).
(CDllbICD18). Cell, 80,631-638 (1995).
P., MENDLER,
M. and BOURDON,
M.A., Endothelial cell
MIYAMOTO,
S., AKIYAMA,S.K. and YAMADA,
K., Synergistic roles for SRIRAMARAO,
receptor occupancy and ag regation in integrin transmembrane func- attachment and spreading on human tenascin is mediated by a2pl and
aVp3 integrins.J. Cell Sci., 105,1001-1012 (1993).
tion. Science, 267,883-885 t1995).
B.D.. PARKS.W.C.. WELGUS.H.G. and PENTLAND.
A.P..
MONTGOMERY,
A.M.P., REISFELD,R.A. and CHERESH,D.A., Integrin SUDBECK.
aVp3 rescues melanoma cells from apoptosis in three-dimensional Col1agen:stimulated inductionof keratinocyte collagenase is mediated
via tyrosine kinase and protein kinase C activities. J. bid. Chem., 269,
dermal collagen. Proc. nat. Acad. Sci. (Wash.), 91,8856-8860 (1994).
MULLER,U., BOSSY,B., VENSTROM,
K. and REICHARDT,
L.F., Integrin 30022-30029 (1994).
a8pl promotes attachment, cell spreading, and neurite outgrowth on TEN BERGE,P.J., DANEN,E.H., VAN MUIJEN,G.N., JAGER,M.J. and
RUITER,D.J., Integrin expression in uveal melanoma differs from
fibronectin. Mol. B i d Cell, 6,433448 (1995).
722
HEINO
cutaneous melanoma. Invest. Ophthalmoi. Ks. Sci., 34, 3635-3640
(1993).
TREMBLE,
P., DAMSKY,
C.H. and WERB,Z., Components of the nuclear
signaling cascade that regulate collagenase gene ex ression in response to integrin-derived signals. J. Cell Biol., 129,1787-1720 (1995).
TRIKHA,M., DE CLERCK,
Y.A. and MARKLAND,
F.S., Contortrostatin,
a snake venom disintegrin, inhibits p l integrin-mediated human
metastatic melanoma cell adhesion and blocks experimental metastasis. CancerRes., 54,4993-4998 (1994).
TURNER,
D.C., FLIER,L.A. and CRABONEITO,S., Identification of a
cell-surface protein involved in PC12 cell-substratum adhesion and
neurite outgrowth on laminin and collagen. J. Neuroscience, 9, 32873296 (1989).
VAN DUINEN,
C.M., VAN DEN BROEK,L.J., VERMEER,
B.J., FLEUREN,
G.J. and BRUIJN,
J.A., The distribution of cellular adhesion molecules
in pigmented skin lesions. Cancer, 73,2131-2139 (1994).
VIHINEN,
P., RIIKONEN,
T., LAINE,A. AND HEINO,J., Integrin a2pl in
tumorigenic human osteosarcoma cell lines regulates cell adhesion,
migration and invasion by interaction with type I collagen. Cell Growth
Difl, (1996) (in press).
VINK, J., THOMAS,L., ETOH, T., BRUIJN,J.A., MIHM, M.C., JR.,
S. and BYERS,H.R., Role of pl integrins in organ
GATTONI-CELLI,
specific adhesion of melanoma cells in vitro. Lab. Invest., 68, 192-203
(1993).
WERB, Z., TREMBLE,P.M., BEHRENDTSEN,
O., CROWLEY,E. and
DAMSKY,
C.H., Signal transduction through the fibronectin receptor
induces collagenase and stromelysin gene expression. J. Cell Biol., 109,
877-889 (1989).
WOESSNER,
J.R., JR., The family of matrix metalloproteinases. Ann.
N.Y. Acad. Sci., 732,ll-21 (1994).
YOKOSAKI,Y., PALMER,E.L., PRIETO,A.L., CROSSIN,
K.L., BOURDON,
M.A., PYTELA,R. and SHEPPARD,
D., The integrin a9pl mediates cell
attachment to a non-RGD site in the third fibronectin type I11 repeat
of tenascin. J. biol. Chem., 269,26691-26696 (1994).
YOSHINAGA,
I.G., VINK,J., DEKKER,S.K., MIHM,M.C., JR. and BYERS,
H.R., Role of a3pl and a2pl integrins in melanoma cell migration.
Melanoma Res., 3,435-441 (1993).
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