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Updated: Oct 4, 2025
Studying the Effects of Tumor-Secreted Paracrine Ligands on Macrophage Activation using Co-Culture with Permeable Membrane Supports
Published on: November 28, 2019
Interplay between soluble CD74 and macrophage-migration inhibitory factor drives tumor growth and influences patient
Yasunari Fukuda1, Matias A Bustos2, Sung-Nam Cho1
1Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Abstract:
Soluble forms of receptors play distinctive roles in modulating signal-transduction pathways. Soluble CD74 (sCD74) has been identified in sera of inflammatory diseases and implicated in their pathophysiology; however, few relevant data are available in the context of cancer. Here we assessed the composition and production mechanisms, as well as the clinical significance and biological properties, of sCD74 in melanoma. Serum sCD74 levels were significantly elevated in advanced melanoma patients compared with normal healthy donors, and the high ratio of sCD74 to macrophage-migration inhibitory factor (MIF) conferred significant predictive value for prolonged survival in these patients (p = 0.0035). Secretion of sCD74 was observed primarily in melanoma cell lines as well as a THP-1 line of macrophages from monocytes and primary macrophages, especially in response to interferon-γ (IFN-γ). A predominant form that showed clinical relevance was the 25-KDa sCD74, which originated from the 33-KDa isoform of CD74. The release of this sCD74 was regulated by either a disintegrin and metalloproteinase-mediated cell-surface cleavage or cysteine-protease-mediated lysosomal cleavage, depending on cell types. Both recombinant and THP-1 macrophage-released endogenous sCD74 suppressed melanoma cell growth and induced apoptosis under IFN-γ stimulatory conditions via inhibiting the MIF/CD74/AKT-survival pathway. Our findings demonstrate that the interplay between sCD74 and MIF regulates tumor progression and determines patient outcomes in advanced melanoma.
Insights
Soluble CD74 (sCD74) is elevated in advanced melanoma patients. A high sCD74 to macrophage migration inhibitory factor (MIF) ratio predicts longer survival by inhibiting the MIF/CD74/AKT pathway, impacting tumor progression.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Soluble receptors modulate signal transduction pathways.
- Soluble CD74 (sCD74) is linked to inflammatory diseases but understudied in cancer.
- Melanoma progression and patient survival require further understanding of molecular mechanisms.
Purpose of the Study:
- To investigate the composition, production, clinical significance, and biological properties of sCD74 in melanoma.
- To explore the relationship between sCD74, macrophage migration inhibitory factor (MIF), and patient outcomes.
- To elucidate the role of sCD74 in melanoma cell growth and apoptosis.
Main Methods:
- Quantification of serum sCD74 levels in advanced melanoma patients and healthy donors.
- Analysis of sCD74 production by melanoma cell lines and macrophages, stimulated with interferon-gamma (IFN-γ).
- Investigation of sCD74 cleavage mechanisms (metalloproteinase and cysteine-protease mediated).
- Assessment of recombinant and endogenous sCD74's effects on melanoma cell growth and apoptosis in vitro.
Main Results:
- Serum sCD74 levels were significantly elevated in advanced melanoma patients.
- A high ratio of sCD74 to MIF predicted prolonged survival in melanoma patients (p=0.0035).
- sCD74 was secreted by melanoma cells and macrophages, particularly upon IFN-γ stimulation.
- A 25-KDa form of sCD74, derived from the 33-KDa isoform, was clinically relevant.
- sCD74 suppressed melanoma cell growth and induced apoptosis by inhibiting the MIF/CD74/AKT pathway under IFN-γ stimulation.
Conclusions:
- sCD74 is a potential biomarker for advanced melanoma prognosis.
- The interplay between sCD74 and MIF influences melanoma tumor progression and patient outcomes.
- sCD74's inhibitory effect on the MIF/CD74/AKT pathway offers a potential therapeutic target.
