Angiostatic activity of the antitumor cytokine interleukin-21.
Interleukin-21 (IL-21) is a recently described immunoregulatory cytokine. It has been identified as a very potent immunotherapeutic agent in several cancer types in animal models, and clinical studies are ongoing. IL-21 belongs to the type I cytokine family of which other members, ie, IL-2, IL-15, and IL-4, have been shown to exert activities on vascular endothelial cells (ECs). We hypothesized that IL-21, in addition to inducing the antitumor immune response, also inhibits tumor angiogenesis. In vitro experiments showed a decrease of proliferation and sprouting of activated ECs after IL-21 treatment. We found that the IL-21 receptor is expressed on vascular ECs. Furthermore, in vivo studies in the chorioallantoic membrane of the chick embryo and in mouse tumors demonstrated that IL-21 treatment disturbs vessel architecture and negatively affects vessel outgrowth. Our results also confirm the earlier suggested angiostatic potential of IL-2 in vitro and in vivo. The angiostatic effect of IL-21 is confirmed by the decrease in expression of angiogenesis-related genes. Interestingly, IL-21 treatment of ECs leads to a decrease of Stat3 phosphorylation. Our research shows that IL-21 is a very powerful antitumor compound that combines the induction of an effective antitumor immune response with inhibition of tumor angiogenesis.
Castermans
Karolien
K
Angiogenesis Laboratory, School for Oncology and Developmental Biology, Department of Pathology, Maastricht University and University Hospital, Maastricht, The Netherlands.
Tabruyn
Sebastien P
SP
Zeng
Rong
R
van Beijnum
Judy R
JR
Eppolito
Cheryl
C
Leonard
Warren J
WJ
Shrikant
Protul A
PA
Griffioen
Arjan W
AW
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents; D001011:Aorta / Q000166:cytology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002642:Chick Embryo; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D007378:Interleukins / Q000494:pharmacology*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D053655:Receptors, Interleukin-21; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000098546:Interleukin-21
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D007378:Interleukins; D053655:Receptors, Interleukin-21; D050796:STAT3 Transcription Factor; D000098546:Interleukin-21