The antiangiogenic role of the pro-inflammatory cytokine interleukin-31

// Shiri Davidi 1, * , Ella Fremder 1, * , Tal Kan 1 , Ziv Raviv 1 , Michael Timaner 1 , Nathan Karin 2 , Dov Hershkovitz 3 , Ami Arohneim 1, * , Yuval Shaked 1, * 1 Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion, Haifa, Israel 2 Department of Immunology, Rappaport Faculty of Medicine, Technion, Haifa, Israel 3 Department of Pathology, Rambam Medical Center, Haifa, Israel * These authors contributed equally to this work Correspondence to: Yuval Shaked, email: yshaked@tx.technion.ac.il Ami Aronheim, email: aronheim@tx.technion.ac.il Keywords: metastasis, angiogenesis, cancer therapy, host response Received: December 14, 2016      Accepted: January 16, 2017      Published: January 27, 2017 ABSTRACT Pro-inflammatory cytokines in the tumor microenvironment are known for their ability to either inhibit or promote cancer progression. Here we evaluated the role of Interleukin-31 (IL31), a protein belonging to the pro-inflammatory IL-6 cytokine family which has been characterized in autoimmune disease, in tumorigenesis. We show that IL31 and its receptor, IL31RA, are highly expressed in various human and mouse cancer cell lines, as well as in tumor specimens from cancer patients. MC38 murine colon carcinoma cells depleted of IL31 exhibit an increase in invasive and migratory properties in vitro , effects that are reversed by supplementing the cells with exogenous IL31. In vivo , IL31-depleted MC38 tumor cells implanted to mice grow faster than control tumors. In contrast, MC38 tumor-bearing mice infused with recombinant IL31, exhibit a significant reduction in tumor growth than control mice. Furthermore, IL31 infusion reduces the number of metastatic lesions in the lungs of mice bearing 4T1 murine metastatic breast carcinoma. Lastly, injecting tumor-bearing, chemotherapy-treated mice with a long-lived IL31-IgG fusion protein reduces tumor growth, angiogenesis and pulmonary metastasis to a greater extent than when chemotherapy is used alone. The IL31 anti-tumor activity is explained, in part, by the anti-angiogenic effects demonstrated both in vitro and in vivo highlighting the potential use of IL31 as an anti-cancer drug.