Cell surface CD44-related chondroitin sulfate proteoglycan is required for transforming growth factor-beta-stimulated mouse melanoma cell motility and invasive behavior on type I collagen
Anne E. Faassen
2
Daniel L. Mooradian
2
3
Robert T. Tranquillo
1
Richard B. Dickinson
1
Paul C. Letourneau
0
Theodore R. Oegema
3
4
James B. McCarthy
2
3
0
Cell Biology and Neuroanatomy
1
Chemical Engineering and Materials Science
2
Laboratory Medicine and Pathology
3
The Biomedical Engineering Center, Box 609 University of Minnesota Hospital and Clinics
,
321 Church St. SE, Minneapolis, MN 55455
,
USA
4
Orthopaedic Surgery and Biochemistry
*Author for correspondence
-
Cell surface CD44-related chondroitin sulfate proteoglycan is required for
SUMMARY
Tumor cell metastasis involves a complex series of
events, including the adhesion, migration and invasive
behavior of tumor cells on components of the
extracellular matrix. Multiple cell surface receptors mediate
interactions with the surrounding extracellular matrix
and thereby influence cell adhesion, motility and
invasion. We have previously described a cell surface
CD44related chondroitin sulfate proteoglycan on highly
metastatic melanoma cells. CD44-chondroitin sulfate
proteoglycan was shown to be important in melanoma
cell motility and invasive behavior on type I collagen
matrices. In our current studies, the role of cell surface
CD44-chondroitin sulfate proteoglycan in
collagenmediated mouse melanoma cell migration and invasive
behavior is further evaluated using transforming
growth factor- 1. We report that transforming growth
factor- 1 stimulates the migratory and invasive
behavior of mouse melanoma cells on type I collagen.
Transforming growth factor- 1 stimulated cell surface
CD44chondroitin sulfate proteoglycan synthesis in mouse
melanoma cells, specifically through an upregulation of
chondroitin sulfate production, while the expression of
CD44-chondroitin sulfate proteoglycan core protein was
not affected. Furthermore, transforming growth
factor1-mediated enhancement of cell polarity, migration
and invasive behavior on type I collagen gels was
markedly inhibited in the presence of -D-xyloside, an
agent that blocks chondroitin sulfate addition to the core
protein. Collectively, our findings indicate that mouse
melanoma cell surface CD44-chondroitin sulfate
proteoglycan is required for transforming growth
factor1-enhanced cell motility and invasion, and that
CD44chondroitin sulfate proteoglycan may play a role in
forming and/or maintaining a dominant leading lamella,
which is required for efficient locomotion.
INTRODUCTION
Cell migration is fundamentally important to
embryogenesis and plays a major role in many normal and
pathological processes, such as tumor cell invasion and metastasis.
Tumor cell metastasis is known to involve a complex series
of events, including the adhesion and migration of tumor
cells on extracellular matrix (ECM) components (Liotta et
al., 1983). The ECM of tissues and basement membrane
can facilitate tumor cell invasion by promoting directional
cell movement by haptotactic and contact guidance
mechanisms (McCarthy et al., 1985). While originally
considered primarily as structural components of the ECM,
several collagen types have been shown to directly mediate the
adhesion and motility of many normal and malignant cell
types (Liotta et al., 1983; Aumailley and Timpl, 1986;
Rubin et al., 1981; Dedhar et al., 1987; Herbst et al., 1988;
Chelberg et al., 1989, 1990). Understanding the mechanism
of ECM-directed cell migration and the cellular
macromolecules involved in this process will be extremely
valuable for evaluating disease processes.
We have previously demonstrated that mouse melanoma
CD44-related chondroitin sulfate proteoglycan (CSPG)
plays an important role in collagen-mediated cell motility
and invasion (Faassen et al., 1992). By blocking
K1735M4 mouse melanoma cell surface CSPG production with
p-nitrophenyl b -D-xylopyranoside (b -D-xyloside;
Schwartz, 1977), we observed a corresponding decrease in
collagen-mediated cell motility and invasive behavior,
while melanoma cell adhesion on collagen coated substrates
was not affected. These studies suggested that mouse
melanoma cell surface CSPG may be important in cell
migration, but not as a primary cell adhesion receptor. In
support of these observations, CSPGs have been implicated
in the motile behavior of various normal and transformed
cell types (Kinsella and Wight, 1986; Funderburg and
Markwald, 1986; Perris and Johansson, 1987), however, the
precise mechanisms through which CSPG mediates cell
motility have not been defined. Certain lines of evidence
suggest that CSPG disrupts cell adhesion (Culp et al., 1986;
Ruoslahti, 1988) and thereby facilitates the detachment of
the trailing edge of a migrating cell. By contrast, recent
studies have implicated melanoma cell surface CSPG in
mediating early recognition events in cell adhesion (Iida et
al., 1992) consistent with previous data localizing the large
human melanoma CSPG to cell surface microspikes
(Garrigues et al., 1986). Our current studies further evaluate the
role of CSPG in cell migration on ECM component (...truncated)