Epithelial cancer of the ovary spreads by implantation of tumor cells onto the mesothelial cells that line the peritoneal cavity. The aim of this study was to identify the cell-matrix interactions that mediate ovarian carcinoma cell migration toward components of the mesothelial cell-associated extracellular matrix. The human ovarian carcinoma cell lines NIH:OVCAR5 and SKOV3 were analyzed by flow cytometry for the expression of cell surface receptors. The ability of those receptors to mediate ovarian carcinoma cell migration toward fibronectin, type IV collagen, and laminin was determined. A monoclonal antibody against the β1 integrin subunit abrogated the migration of both cell lines toward the extracellular matrix proteins. Blocking antibodies against alpha integrin subunits suggest that ovarian carcinoma cell migration toward fibronectin is primarily mediated by the α5β1 integrin, type IV collagen by the α2β1 integrin, and laminin by the α6β1 integrin. These results suggest that ovarian carcinoma cell migration is regulated by multiple β1 integrin-matrix interactions. Significant reduction of cell migration was observed with a monoclonal antibody against CD44 that blocks the hyaluronan-binding site of CD44, but not with an antibody that binds at an alternate site on CD44. Intact hyaluronan and/or hyaluronan oligomers also inhibited cell migration, suggesting that the CD44-hyaluronan interaction provides an integrin-independent mechanism of control for ovarian carcinoma cell migration. These results suggest that ovarian carcinoma cell migration is regulated by both integrin-dependent mechanisms, involving the interaction of β1 integrins with extracellular matrix proteins, and an integrin-independent mechanism that involves the interaction of CD44 and hyaluronan.
Bibliographical noteFunding Information:
We thank Dr James McCarthy for providing fibronectin, Dr Leo Furcht for providing laminin and the mAb P5D2 against the β1 integrin subunit, Dr Robert C. Bast, Jr. for providing the SKOV3 cell line, and Dr Judah Folkman for providing the NIH:OVCAR5 cell line. We would also like to acknowledge the assistance of the Flow Cytometry Core Facility of the University of Minnesota Cancer Center, a comprehensive cancer center designated by the National Cancer Institute, supported in part by Grant P30 CA77598. R.C.C. was funded by a Cancer Biology Training grant from NIH/NCI (Grant # CA09138-25). The project depicted was supported by the Minnesota Medical Foundation (Grant # SMF-2078-99); the Office of the Vice President for Research and Dean of the Graduate School of the University of Minnesota; and the Department of the Army, Grant #DA/DAMD17-99-1-9564. The content of the information does not necessarily reflect the position of the Government.
- Cell migration
- Extracellular matrix
- Ovarian carcinoma