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.
Highlights
One of the main obstacles in clinical oncology is the development of resistance to therapy leading to tumor re-growth and even spread
We found that IL31 and IL31RA are expressed by several types of tumor cells from both mouse and human origins
Recent studies have emphasized that following therapy, dramatic changes occur in the tumor microenvironment that may contribute to tumor regrowth and metastasis [1]
Summary
One of the main obstacles in clinical oncology is the development of resistance to therapy leading to tumor re-growth and even spread. Blocking the colonization or function of these host cells using antiangiogenic drugs improves therapy outcome, and delays recurrence [6,7,8] These host cellular effects are accompanied by a substantial upregulation of growth factors, enzymes, chemokines and cytokines [7, 9, 10]. Naïve mice implanted with cultured tumor cells together with macrophages obtained from PTX-treated mice exhibited increased tumor www.impactjournals.com/oncotarget lymphangiogenesis, in a similar manner to tumor-bearing mice treated with PTX [13] These collective studies demonstrate that the host response to chemotherapy results in a substantial increase in various BMDCs and factors that affect the tumor microenvironment and negate the drug anti-tumor activity [1]
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