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

Journal of Cell Science, Jun 1993

A.E. Faassen, D.L. Mooradian, R.T. Tranquillo, R.B. Dickinson, P.C. Letourneau, T.R. Oegema, J.B. McCarthy

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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)


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A.E. Faassen, D.L. Mooradian, R.T. Tranquillo, R.B. Dickinson, P.C. Letourneau, T.R. Oegema, J.B. McCarthy. 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, Journal of Cell Science, 1993, pp. 501-511, 105/2,