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
Open accessAbstract
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.
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- Authors
- Tarnowski, M., Grymula, K., Liu, R., Tarnowska, J., Drukala, J., Ratajczak, J., Mitchell, R. A., Ratajczak, M. Z., & Kucia, M.
- Affiliations
- Jagiellonian University (PL)
- Authors' Affiliations: 1Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky; 2Department of Physiology, Pomeranian Medical University, Szczecin, Poland; and 3Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Cracow, Poland
- Corresponding author
- Ratajczak, Mariusz Z.
- Kucia, Magda
- Venue
- Molecular Cancer Research
- Published
- 2010-10-18
- Volume
- 8
- Issue
- 10
- Pages
- 1328-1343
- ISSN
- 1541-7786 (ISSN-L)
- 1557-3125
- PMC
- PMC2974061
- OpenAlex
- W2128316913
- Cited by
- 136
- References
- 59
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 11 · 2023: 5 · 2022: 8 · 2021: 9 · 2020: 11 · 2019: 5 · 2018: 7 · 2017: 7 · 2016: 15 · 2015: 12 · 2014: 12 · 2013: 8 · 2012: 12
- FWCI
- 3.29
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r01ca106281-05)
- National Cancer Institute (R01 CA106281-01, R01 CA106281)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK074720)
- National Center for Research Resources (P20RR018733)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Macrophage Migration Inhibitory Factor
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Keywords
- macrophage migration inhibitory factor, rhabdomyosarcoma, CXCR4, CXCR7, cancer-associated fibroblasts, metastasis, tumor angiogenesis, cell adhesion, MAPK phosphorylation, Akt signaling, chemokine receptors, tumor microenvironment, autocrine and paracrine signaling
- MeSH terms
- Animals, Cell Adhesion, Cell Line, Cell Migration Inhibition, Fibroblasts, Humans, Macrophage Migration-Inhibitory Factors, Neoplasm Invasiveness, Protein Binding, Rhabdomyosarcoma, Mice, SCID, Receptors, CXCR4, Cell Line, Tumor, Mice, Receptors, CXCR
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