The antiangiogenic role of the pro-inflammatory cytokine interleukin-31
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Shiri Davidi1,*, Ella Fremder1,*, Tal Kan1, Ziv Raviv1, Michael Timaner1, Nathan Karin2, Dov Hershkovitz3, Ami Arohneim1,*, Yuval Shaked1,*
1Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion, Haifa, Israel
2Department of Immunology, Rappaport Faculty of Medicine, Technion, Haifa, Israel
3Department of Pathology, Rambam Medical Center, Haifa, Israel
*These authors contributed equally to this work
Yuval Shaked, email: email@example.com
Ami Aronheim, email: firstname.lastname@example.org
Keywords: metastasis, angiogenesis, cancer therapy, host response
Received: December 14, 2016 Accepted: January 16, 2017 Published: January 27, 2017
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.
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