Direct in vitro evidence and in vivo analysis of the antiangiogenesis effects of interleukin 12.
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-gamma and its inducible antiangiogenic chemokine IFN gamma-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.
Duda
D G
DG
First Department of Surgery, Tohoku University Medical School, Sendai, Japan.
Sunamura
M
M
Lozonschi
L
L
Kodama
T
T
Egawa
S
S
Matsumoto
G
G
Shimamura
H
H
Shibuya
K
K
Takeda
K
K
Matsuno
S
S
D016475:3T3 Cells; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D018664:Interleukin-12 / Q000494:pharmacology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; D016207:Cytokines; D018664:Interleukin-12