Direct in vitro evidence and in vivo analysis of the antiangiogenesis effects of interleukin 12

Dan Gabriel Duda, Makoto Sunamura, Lucian Lozonschi, Tomohiro Kodama, Shin Ichi Egawa, Gaku Matsumoto, Hiromune Shimamura, Kazuhiko Shibuya, Kazunori Takeda, Seiki Matsuno

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128 Citations (Scopus)


As an antitumor agent, interleukin-12 (IL-12) has been revealed to be a key regulator of the immune response, particularly that involving CTL and natural killer (NK) cells. We report herein the antiangiogenesis effect of IL-12 on human as well as murine tumors in NK-depleted severe-combined immunodeficient mice using fibroblasts genetically engineered to secrete this cytokine. Although the in vitro growth of tumor cells was not affected by the presence of IL-12, coinoculation of IL-12-secreting fibroblasts strongly inhibited tumor growth in immunodeficient mice. The neovascularization surrounding the tumor was remarkably inhibited in the area in which the IL- 12-secreting fibroblasts were implanted, resulting in the suppression of tumor growth. Lectin staining in tumor sample sections also showed a significant reduction in the number of vessels. The RNA expression of IFN-γ and its inducible antiangiogenic chemokine IFN γ-inducible protein 10 was stimulated in endothelial cells cultured with IL-12. It was also found that IL-12 down-regulated the expression of the endothelial cell mitogens vascular endothelial growth factor and basic fibroblast growth factor. The antitumor effects of IL-12 were accompanied by interesting histological changes consisting of a high degree of keratinization and apoptosis and a decrease in the proliferation rate of human tumors and extensive necrosis in the murine ones.

Original languageEnglish
Pages (from-to)1111-1116
Number of pages6
JournalCancer Research
Issue number4
Publication statusPublished - 2000 Feb 15

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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