Differential growth of IFN-beta-engineered tumor cells in nude and IFN receptor-null mice.
The purpose of this study was to investigate the therapeutic potential of interferon-beta (IFN-beta) against tumors that resist its antiproliferative effects. Mouse fibrosarcoma cells (UV-2237m-P) and their counterparts, transfected with either IFN-beta cDNA (UV-2237m-IFN-beta) or its control vector (UV-2237m-neo), were used in the study. UV-2237m-IFN-beta cells, still expressing functional IFN receptors, were resistant to the antiproliferative effects of IFN-beta. UV-2237m-P and UV-2237m-neo cells produced progressive tumors in both nude and IFN receptor-null nude (IFNAR-/-nude) mice. In contrast, growth of UV-2237m-IFN-beta cells was significantly delayed in nude mice. UV-2237m-IFN-beta tumors from nude mice contained fewer microvessels, fewer proliferating cells, and more apoptotic cells than did UV-2237m-P and UV-2237m-neo tumors. They expressed high levels of inducible nitric oxide synthase (iNOS) and were densely infiltrated by macrophages. Incubation with macrophages from nude mice, but not those from IFNAR-/- nude mice or iNOS-null/nude mice, led to more significant killing of UV-2237m-IFN-beta cells than that of control cells, which was blocked by iNOS inhibitor N-methylarginine. Similarly, more UV-2237m-IFN-beta cells were killed when they were incubated with spleen lymphocytes from nude mice. These data indicate that IFN-beta can inhibit growth of IFN-beta-resistant tumors by T cell-independent host-mediated mechanisms, including the role of macrophages, natural killer (NK) cells, and iNOS activity.
Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Fahao
F
Zhang
Juwon
J
Lee
Daren
D
Wang
Zhongyun
Z
Dong
D000818:Animals; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D005260:Female; D016899:Interferon-beta / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D017737:Macrophages, Peritoneal / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000378:metabolism; D017471:Receptors, Interferon / Q000096:biosynthesis* / Q000172:deficiency* / Q000235:genetics
D017471:Receptors, Interferon; D016899:Interferon-beta