Flt-3 Ligand Inhibits Growth of Human Ovarian Tumors Engrafted in Severe Combined Immunodeficient Mice

• Published in: Gynecologic oncology 2000-06, Vol.77 (3), p.377-382
• Main Authors: Silver, David F., Hempling, Ronald E., Piver, M.Steven, Repasky, Elizabeth A.
• Format: Article
• Language: English
• Subjects: Animals; Cell Division; cytokine; Female; Flt3 ligand; Humans; Killer Cells, Natural - immunology; Membrane Proteins - pharmacology; Mice; Mice, SCID; natural killer cells; ovarian cancer; Ovarian Neoplasms - immunology; Ovarian Neoplasms - pathology; severe combined immunodeficient (SCID) mice; Spleen - immunology; Transplantation, Heterologous
• ISSN: 0090-8258; 1095-6859
• DOI: 10.1006/gyno.2000.5782

Objective. The current study evaluated the effects of Flt-3 ligand (FL) on the growth of human malignant ovarian tumors engrafted in severe combined immunodeficient (SCID) mice with particular attention directed at FL's effect on the host natural killer (NK) cell response against ovarian cancer xenografts. Methods. Equal portions of surgical specimen-derived human ovarian carcinomas were engrafted subcutaneously (SC) into SCID mice. Mice were placed into one of two treatment groups 7 days after the day of implantation. Group 1 received placebo injections SC from Day 1 to Day 20 and group 2 received FL at 10 μg/day SC from Day 1 to Day 20. NK cell depletion was performed on three additional mice from group 2 starting on Day 0 using anti-asialo GM1. Serial tumor volumes were measured. On Day 21, mice from each group were sacrificed, and tumors and spleens were evaluated. Data analysis included χ2 tests, Student t tests, and analyses of variance when appropriate. Results. FL resulted in tumor growth delay compared with control (P = 0.036). When NK cell activity was depleted prior to FL administration, no tumor growth delay was observed. Spleens from FL-treated mice were larger (P < 0.01) with expanded white pulp compared with controls. Histologic examination of tumor sections from FL-treated mice revealed regions of solid tumor growth with glandular architecture similar to that seen in control tumors; however, there was an obvious increase in regions composed largely of dense fibrosis in the FL-treated tumors. NK cells and other infiltrating cells could be detected in clusters among tumors from mice treated with FL whereas these cells were only occasionally detected in sections of control tumors. Conclusion. FL treatment resulted in an antitumor response against human ovarian cancer engrafted in SCID mice and this inhibition appears to be largely host NK cell mediated. The tumor inhibition seen in this model is similar to that previously seen using syngeneic tumors grown in an immunocompetent animal model. Results from this model can potentially be extrapolated to treatment of human ovarian cancer patients.