Submitted September 21, 2007
Accepted April 18, 2008
Angiostatic activity of the anti-tumor cytokine interleukin-21
Karolien Castermans, Sebastien P Tabruyn, Rong Zeng, Judy R van Beijnum, Cheryl Eppolito, Warren J Leonard, Protul A Shrikant, and Arjan W Griffioen*
GROW Depts. of Pathology and Internal Medicine, Maastricht University and University Hospital, Maastricht, Netherlands
Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institute of Health, Bethesda, MD, United States
Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, United States
* Corresponding author; email: aw.griffioen{at}path.unimaas.nl.
Interleukin (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, i.e. IL-2, IL-15 and IL-4, have been shown to exert activities on vascular endothelial cells (EC). We hypothesized that IL-21, in addition to inducing the anti-tumor immune response, also inhibits tumor angiogenesis. In vitro experiments showed a decrease of proliferation and sprouting of activated EC after IL-21 treatment. We found that the IL-21 receptor is expressed on vascular EC. 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 EC leads to a decrease of Stat3 phosphorylation. Our research shows that IL-21 is a very powerful anti-tumor compound which combines the induction of an effective anti-tumor immune response with inhibition of tumor angiogenesis.
