INTERLEUKIN-1-DEPENDENT AND INTERLEUKIN-1-INDEPENDENT MOUSE MELANOMA METASTASES

Background: The adhesion of cancer cells to the endothelial lining of blood vessels, which is important for metastasis, is promoted by the a ction of interleukin 1 (IL-1) and other cytokines. Purpose: IL-1-produ cing melanoma cells were used to induce metastases in mice to test whe ther melanoma metastasis-wherever it occurs-depends on the action of I L-1. Methods: We used the following experimental designs in this study : 1) Male C57BL/6J mice were inoculated in the left cardiac ventricle with 5 x 10(4) murine B16 melanoma cells, and no treatment was given ( control animals). 2) Mice received an intraperitoneal injection of eit her saline (control animals) or recombinant human IL-1 receptor antago nist (rHuIL-1Ra) 2 hours before the injection of cancer cells; thereaf ter, they received an additional injection of saline or rHuIL-1Ra dail y for 20 days. 3) Mice received an intravenous injection of either sal ine or rHuIL-1Ra; 15 minutes later, mice that received saline were giv en either a second injection of saline (control animals) or an injecti on of bacterial lipopolysaccharide (LPS) to stimulate host IL-1 produc tion and endothelial cell activation. The mice that received rHuIL-1Ra were also given an injection of LPS at this time. Six hours later, al l mice were inoculated with cancer cells, followed by no further treat ment. In all experiments, the mice were killed 20 days after the injec tion of cancer cells, and metastases were counted in multiple organs a nd bones. Metastasis incidence values (relating to the frequency that a given site was positive for metastasis) and metastasis development i ndex values (relating to the extent of metastasis at a given site) wer e calculated. A hierarchical cluster analysis was performed to determi ne whether groups of organs exhibited characteristic changes in their metastasis development index values in response to the three treatment s given (i.e., rHuIL-1Ra, LPS, or rHuIL-1Ra plus LPS). Reported P valu es are two-sided. Results and Conclusions: Treatment with rHuIL-1Ra al one significantly (P<.05) reduced the occurrence of metastasis in the bone marrow, spleen, liver, lung, pancreas, skeletal muscle, adrenal g land, and heart, indicating that host- and/or melanoma-derived IL-1 pr omoted metastasis in these organs; treatment with rHuIL-1Ra had no eff ect on metastasis in the kidney, testis, brain, skin, and gastrointest inal tract, suggesting that metastasis in these latter organs was IL-1 independent. Treatment with LPS alone significantly (P<.05) enhanced metastasis in the same organs for which rHuIL-1Ra treatment reduced me tastasis, except for the heart and the adrenal gland. Treatment with r HuIL-1Ra 15 minutes before LPS treatment abrogated the LPS-mediated en hancement of metastasis. Two independent organ groups for which IL-1 p romoted melanoma metastasis were identified in the cluster analysis.