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IL-8 Reduced Tumorigenicity of Human Ovarian Cancer In Vivo Due to Neutrophil Infiltration¹

Li-Fen Lee^2,*,, Ronald P. Hellendall, Ying Wang, J. Stephen Haskill^*,, Naofumi Mukaida^,§, Kouji Matsushima^,§ and Jenny P.-Y. Ting^3,*,

^* Departments of Biology, Microbiology-Immunology, and Obstetrics and Gynecology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599; and Department of Pharmacology and ^§ Cancer Research Institute, Kanazawa University, Kanazawa, Japan

Paclitaxel is a frontline therapy for ovarian cancer. Our laboratory has shown that paclitaxel induces IL-8, a member of the C-X-C family of chemokines, in subsets of human ovarian cancer cells. However, the critical issue concerns the biological significance of this chemokine in human ovarian cancer. To study the influence of IL-8 on tumor growth, human ovarian cancer cell lines were transfected with an expression vector for human IL-8 and tested for their ability to form tumors in nude mice. IL-8 expression by the transfected cells did not alter their growth properties in vitro. In contrast, tumor growth in vivo was significantly attenuated in animals receiving IL-8-expressing cells when compared with mice injected with control cells. As additional evidence that IL-8 is a crucial factor in tumor growth, it was noted that ovarian cell lines in which constitutive IL-8 expression is elevated did not form tumors. Injection of neutralizing Ab to IL-8 reverted the phenotype and caused tumor growth in vivo. Examination of tissue from the inoculation site revealed a dramatically elevated cellularity, containing neutrophils and macrophages, in mice receiving IL-8-expressing tumor cells. These results suggest that IL-8 production by human ovarian tumor cells can play a role in reducing the rate of tumor growth; this effect may be mediated by the increased targeting of neutrophil and other mononuclear cells to the tumor injection site. These studies indicate a role for IL-8 in ovarian cancer control and suggest that chemotherapy-induced IL-8 may have a positive role in controlling tumor growth.