Abstract 4841: Oxidized macrophage migration inhibitory factor (oxMIF) expressed by tumor stroma and tumor cells, contributes to tumor growth
Authors: Schinagl Alexander , Hagemann Thorsten , Douillard Patrice , Thiele Michael , Voelkel Dirk , Freissmuth Michael , Scheiflinger Friedrich , Kerschbaumer Randolf J. 
Published: May 2015

Abstract
Macrophage migration inhibitory factor (MIF) was found to be upregulated in many cancers and to act in para- and autocrine loops within the tumor microenvironment. MIF has pleiotropic effects and plays a role in tumor growth via several mechanisms. (i) MIF acts directly on tumor cells by activating signaling pathways that promote cell proliferation and cell survival. (ii) MIF facilitates invasion of the extracellular matrix and induces angiogenesis and tumor vascularization. (iii) As a proinflammatory cytokine, MIF is one of the mediators of tumor micro-inflammation. However, MIF occurs in two immunologically distinct, redox-dependent isoforms. In its reduced form (redMIF), MIF is abundantly expressed and is present even in healthy subjects. In contrast, oxidized MIF (oxMIF) is found in patients with cancer. Highly selective, fully human monoclonal antibodies that specifically target oxMIF can counter-regulate the biological functions of MIF, indicating that oxMIF is the disease-related isoform of MIF and a relevant drug target. Animal studies and in vitro studies revealed that novel human antibodies that selectively target oxMIF, inhibit proliferation by reducing phosphorylation of ERK1/2 and AKT, promote apoptosis by activating caspase 3, inhibit angiogenesis and metastasis by reducing VEGF expression and blood vessel density within the tumor, and decrease cancer-associated inflammation of the tumor by downregulating the production of proinflammatory cytokines. We used MIF wild type (wt) and MIF knockout (KO) murine pancreatic cancer cells and MIF wt and MIF KO mice with C57Bl/6 background to dissect the contribution of stromal versus tumor derived MIF to tumor progression. Transfer of a pancreatic cancer cell line expressing MIF into wt mice or MIF KO mice resulted in aggressive tumor growth, liver metastasis, and survival of approximately 30 days in both models. Similar results were obtained by transferring a MIF KO pancreatic cancer cell line into MIF wt mice. Only transfer of a MIF KO cell line into MIF KO mice led to improved overall survival of approximately 80 days and completely abrogated metastasis. In a tumor xenograft model, an intravenously applied oxMIF-specific fully human antibody was able to penetrate the cancerous tissue and was detected in the stroma and the tumor. We conclude that both tumor stroma and tumor cells are an efficient source of oxMIF to promote tumor growth and metastasis, and that anti-oxMIF antibodies are able to neutralize oxMIF in the stroma and the tumor. A phase 1 clinical study of a novel human antibody that selectively targets oxMIF is currently ongoing in patients with solid malignancies (ClinicalTrials.gov identifier: NCT01765790).
Citation Format: Alexander Schinagl, Thorsten Hagemann, Patrice Douillard, Michael Thiele, Dirk Voelkel, Michael Freissmuth, Friedrich Scheiflinger, Randolf J. Kerschbaumer. Oxidized macrophage migration inhibitory factor (oxMIF) expressed by tumor stroma and tumor cells, contributes to tumor growth. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4841. doi:10.1158/1538-7445.AM2014-4841