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Tumor Necrosis Factor Stimulates Epithelial Tumor Cell Motility¹

Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut 06510 [E. M. R., E. S., M. A. D., B. M. K.]; Division of Medical Oncology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06510 [M. R.]; Department of Radiation Oncology, Long Island Jewish Medical Center, New Hyde Park, New York 11042 [I. D. G., M. B.]; and Cetus Corporation, Emeryville, California 94608 [D. L.]

Cellular motility is a critical function in embryonic development, tissue repair, and tumor invasion. We used assays of scattering (epithelial colony dispersion), cell migration, and cell invasion to study cytokine-regulated motility in epithelial and carcinoma cell lines. Tumor necrosis factor (TNF) stimulated motility in 12 of 14 cell lines in one or more assay systems. The motility-stimulating activity of TNF did not correlate with its antiproliferative activity. In lines whose migration was stimulated by both TNF and scatter factor (SF), a fibroblast-derived cytokine which stimulates epithelial cell motility, saturating concentrations of TNF plus SF induced greater migration than either agent alone. Anti-TNF monoclonal antibody blocked TNF- but not SF-stimulated motility. While various other factors (basic fibroblast growth factor, interleukin 6, interleukin 2, colony-stimulating factor 1) had little or no motility-stimulating activity, phorbol-12-myristate-13-acetate (PMA), a tumor-promoting phorbol ester, scattered and/or stimulated migration in all cell lines studied. Combinations of saturating concentrations of TNF plus PMA or of SF plus PMA induced greater migration than did any agent alone. These findings suggest that (a) carcinoma cell motility may be mediated by multiple biochemical pathways and (b) TNF stimulates epithelial motility by a mechanism different from that of SF and PMA. In vivo, TNF might enhance invasiveness of some carcinomas or stimulate epithelial wound healing.

¹ Supported in part by the USPHS (CA-50516) and the American Cancer Society (BE-7). I. D. G. and M. B. were supported by the Finkelstein Foundation. B. M. K. was supported by the USPHS (CA-47292) and Bristol-Myers Cancer Research Award 100-R063. E. M. R. is an Established Investigator of the American Heart Association.

² To whom requests for reprints should be addressed, at 132 HRT, 333 Cedar Street, Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06510.

Received 2/25/91. Accepted 7/24/91.

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