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.
Angiogenesis Laboratory, School for Oncology and Developmental Biology, Department of Pathology, Maastricht University and University Hospital, Maastricht, The Netherlands.
Karolien
K
Castermans
Sebastien P
SP
Tabruyn
Rong
R
Zeng
Judy R
JR
van Beijnum
Cheryl
C
Eppolito
Warren J
WJ
Leonard
Protul A
PA
Shrikant
Arjan W
AW
Griffioen
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