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Effect of Prostaglandin E₂-producing Nonmetastatic Lewis Lung Carcinoma Cells on the Migration of Prostaglandin E₂-responsive Metastatic Lewis Lung Carcinoma Cells¹

Departments of Research Services [M. R. Y., M. E. Y.] and Laboratory Services [H. T. W.], Edward J. Hines, Jr., Veterans Administration Hospital, Hines 60141, and Department of Pathology, Loyola University Stritch School of Medicine, Marywood, Illinois 60153 [M. R. Y., H. T. W.]

The role of prostaglandin E₂ (PGE₂) in directly stimulating metastatic spread by Lewis lung carcinoma (LLC) cells was examined with the use of an in vitro migration model for tumor dissemination. The extent to which cloned metastatic and nonmetastatic LLC cells migrated out of glass capillary tubes in vitro reflected their capacity to form pulmonary metastases in vivo. The addition of PGE₂ to metastatic LLC cells further stimulated their migration. Other cyclooxygenase products, besides PGE₂, did not stimulate the migration of metastatic LLC cells. Nonmetastatic LLC cells did not migrate out of capillary tubes, even in the presence of exogenous PGE₂. the amount of PGE₂ secreted by cloned LLC cells was quantitated by a radioimmunoassay. Nonmetastatic LLC cells secreted more PGE₂ than did the metastatic LLC cells. When the nonmetastatic LLC cells were either mixed with or placed adjacent to cloned metastatic LLC cells, the migration by the metastatic LLC cells was stimulated. The migration-stimulatory capacity of the nonmetastatic LLC cells was minimized in the presence of indomethacin, a prostaglandin synthesis inhibitor. Studies were conducted to relate these in vitro results to tumor metastasis in vivo. Injection of a mixture of metastatic and nonmetastatic LLC cells into mice s.c. resulted in a greater number of lung metastases than did injection of metastatic cells alone. This increase in metastasis formation was prevented by indomethacin. Formation of pulmonary metastases was also augmented when irradiated nonmetastatic LLC cells were injected into metastatic LLC-bearing mice. The results of our studies suggest that nonmetastatic LLC cells, by producing PGE₂, can augment in vitro migration and in vivo dissemination of metastatic LLC cells. Thus, the response of tumor cells to PGE₂, rather than simply their production of PGE₂, appears to be important in regulating tumor dissemination.

¹ This work was supported in part by the National Cancer Institute NIH Grant CA39371.

² To whom requests for reprints should be addressed, at Pathology Research (151Z2), Hines V.A. Hospital, Hines, IL 60141.

Received 10/14/86. Revised 1/ 5/87. Revised 3/31/87. Accepted 4/22/87.

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