Macrophage Migration Inhibitory Factor Is Secreted by Rhabdomyosarcoma Cells, Modulates Tumor Metastasis by Binding to CXCR4 and CXCR7 Receptors and Inhibits Recruitment of Cancer-Associated Fibroblasts

Abstract

The overexpression of macrophage migration inhibitory factor (MIF) has been observed in many tumors and is implicated in oncogenic transformation and tumor progression. MIF activates CXCR2 and CD74 receptors and, as recently reported, may also bind to the stromal-derived factor-1 (SDF-1)-binding receptor CXCR4. Here, we report that human rhabdomyosarcoma (RMS) cell lines secrete MIF and that this chemokine (a) induces phosphorylation of mitogen-activated protein kinase (MAPK) p42/44 and AKT, (b) stimulates RMS cell adhesion, (c) enhances tumor vascularization, but surprisingly (d) decreases recruitment of cancer-associated fibroblasts (CAF). Because RMS cells used in our studies do not express CXCR2 and CD74 receptors, the biological effects of MIF on RMS cells depend on its interaction with CXCR4, and as we report here for the first time, MIF may also engage another SDF-1-binding receptor (CXCR7) as well. Interestingly, downregulation of MIF in RMS cells inoculated into immunodeficient mice led to formation of larger tumors that displayed higher stromal cell support. Based on these observations, we postulate that MIF is an important autocrine/paracrine factor that stimulates both CXCR4 and CXCR7 receptors to enhance the adhesiveness of RMS cells. We also envision that when locally secreted by a growing tumor, MIF prevents responsiveness of RMS to chemoattractants secreted outside the growing tumor (e.g., SDF-1) and thereby prevents release of cells into the circulation. On the other hand, despite its obvious proangiopoietic effects, MIF inhibits in CXCR2/CD74-dependent manner recruitment of CAFs to the growing tumor. Our data indicate that therapeutic inhibition of MIF in RMS may accelerate metastasis and tumor growth. Mol Cancer Res; 8(10); 1328-43. ©2010 AACR.

Expression of the CXCL12/SDF-1 Chemokine Receptor CXCR7 in Human Brain Tumours

“…Similar results were reported in angiogenesis experiments in breast and lung cancer cells (Miao et al, 2007;Goldmann et al, 2008). Macrophage migration inhibitory factor (MIF), which is secreted by rhabdomyosarcoma (RMS), is an autocrine/ paracrine factor that interacts with CXCR4 as well as with CXCR7 to enhance the adhesiveness of RMS cells (Tarnowski et al, 2010). EPCs may offer a possible biomarker for efficient of treatment and prognosis (Morita et al, 2011).…”

CXCL12 receptor preference, signal transduction, biological response and the expression of 5T4 oncofoetal glycoprotein

“…For example, syndecan has recently been shown to interact with both the CXCR4 receptor and the CXCL12 ligand (Schanz et al, 2011), and macrophage migration inhibitory factor (MIF) can bind to both CXCL12 receptors, acting as a non-cognate ligand to prevent CXCL12 driven metastasis (Tarnowski et al, 2010). Indeed a protein of similar structure to 5T4, LRRC4, has been shown to influence CXCR4 signalling kinetics and function in glioblastoma (Wu et al, 2008).…”

CXCR4 downregulation of let-7a drives chemoresistance in acute myeloid leukemia

“…The search site predicted a series of transcription factors that might be involved in the transcriptional regulation of let-7a (Table 1). The transcription factor Yin Yang 1 (YY1), ranked first in the prediction, is a member of the polycomb group and has been shown to be involved in CXCR4 signaling (25)(26)(27)(28)(29).…”