Targeting Macrophage Migration Inhibitory Factor in Acute Pancreatitis and Pancreatic Cancer

Abstract

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine implicated in the pathogenesis of inflammation and cancer. It is produced by various cells and circulating MIF has been identified as a biomarker for a range of diseases. Extracellular MIF mainly binds to the cluster of differentiation 74 (CD74)/CD44 to activate downstream signaling pathways. These in turn activate immune responses, enhance inflammation and can promote cancer cell proliferation and invasion. Extracellular MIF also binds to the C-X-C chemokine receptors cooperating with or without CD74 to activate chemokine response. Intracellular MIF is involved in Toll-like receptor and inflammasome-mediated inflammatory response. Pharmacological inhibition of MIF has been shown to hold great promise in treating inflammatory diseases and cancer, including small molecule MIF inhibitors targeting the tautomerase active site of MIF and antibodies that neutralize MIF. In the current review, we discuss the role of MIF signaling pathways in inflammation and cancer and summarize the recent advances of the role of MIF in experimental and clinical exocrine pancreatic diseases. We expect to provide insights into clinical translation of MIF antagonism as a strategy for treating acute pancreatitis and pancreatic cancer.

MYC Levels Regulate Metastatic Heterogeneity in Pancreatic Adenocarcinoma

“…Similary, Mif can regulate immune cell function through binding various receptors and its tautomerase activity (71,72). To examine the role of these factors in macrophage recruitment in our system, we treated Myc_OE tumor cells with a Cxcr2 inhibitor (AZD5069) or Mif inhibitor (ISO-1) in an in vitro transwell migration assay (52,70,72,73). Compared to vehicle controls, inhibition of Cxcr2 or Mif led to 2-10 fold decrease in macrophage migration (Fig.…”

“…The cognate receptor for Cxcl3 is Cxcr2, which has previously been reported to modulate myeloid cell recruitment in prostate cancer and PDAC (59,70). Similary, Mif can regulate immune cell function through binding various receptors and its tautomerase activity (71,72). To examine the role of these factors in macrophage recruitment in our system, we treated Myc_OE tumor cells with a Cxcr2 inhibitor (AZD5069) or Mif inhibitor (ISO-1) in an in vitro transwell migration assay (52,70,72,73).…”

An Inflammatory Response Related Gene Signature Associated with Survival Outcome and Gemcitabine Response in Patients with Pancreatic Ductal Adenocarcinoma

“…Knockdown of ADM in pancreatic tumor-bearing mice significantly inhibited the recruitment of myelomonocytic cells and tumor angiogenesis ( Xu et al, 2016 ). Multiple studies have documented that elevated MIF expression was associated with increased tumor aggressiveness, reduced sensitivity to gemcitabine, and worse survival in PDAC patients ( Wen et al, 2021 ). Additionally, a previous study has identified DCBLD2 as a prognostic and diagnostic biomarker in PDAC ( Feng et al, 2021b ).…”

The Liver Pre-Metastatic Niche in Pancreatic Cancer: A Potential Opportunity for Intervention

“…Another MIF inhibitor, ISO-1, was shown to inhibit pancreatic cancer cell invasion, migration and proliferation in vitro, as well as tumor growth in vivo in an immunodeficient murine model [ 106 ]. Given the importance of MIF in PDAC pathogenesis and pre-metastatic niche formation, inhibiting its effects on pre-metastatic niche formation in the neoadjuvant or perioperative setting may prove efficacious in reducing metastases [ 107 ].…”