Tumor-conditioned macrophages secrete migration-stimulating factor: a new marker for M2-polarization, influencing tumor cell motility.
Tumor-associated macrophages (TAMs) are key orchestrators of the tumor microenvironment directly affecting neoplastic cell growth, neoangiogenesis, and extracellular matrix remodeling. In turn, the tumor milieu strongly influences maturation of TAMs and shapes several of their features. To address the early macrophage (M) differentiation phase in a malignant context, we mimicked a tumor microenvironment by in vitro coculturing human blood monocytes with conditioned media from different cancer cell lines. Only 2 out of 16 tumor cell lines induced M differentiation due to secreted M-CSF isoforms, including high molecular mass species. A global gene profiling of tumor-conditioned M was performed. Comparison with other datasets (polarized M1-M, M2-M, and TAMs isolated from human tumors) highlighted the upregulation of several genes also shared by TAM and M2-polarized M. The most expressed genes were selenoprotein 1, osteoactivin, osteopontin, and, interestingly, migration-stimulating factor (MSF), a poorly studied oncofoetal isoform of fibronectin. MSF (present in fetal/cancer epithelial and stromal cells but not in healthy tissues) was never identified in M. MSF production was confirmed by immunohistochemistry in human TAMs. MSF was induced by M-CSF, IL-4, and TGFbeta but not by proinflammatory stimuli. RNA and protein analysis clearly demonstrated that it is specifically associated with the M2 polarization of M. Tumor-conditioned M-derived MSFs strongly stimulated tumor cell migration, thus contributing to the motile phenotype of neoplastic cells. In conclusion, MSF is a new molecule associated with the M2 polarization of M and expressed by TAMs. Its biological function may contribute to M-mediated promotion of cancer cell invasion and metastasis.
Department of Immunology and Inflammation, Clinical Institute Humanitas, Rozzano, Italy.
Graziella
G
Solinas
Silvia
S
Schiarea
Manuela
M
Liguori
Marco
M
Fabbri
Samantha
S
Pesce
Luca
L
Zammataro
Fabio
F
Pasqualini
Manuela
M
Nebuloni
Chiara
C
Chiabrando
Alberto
A
Mantovani
Paola
P
Allavena
D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D002454:Cell Differentiation / Q000276:immunology; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology*; D016764:Cell Polarity / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D005353:Fibronectins; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D009361:Neoplasm Invasiveness / Q000276:immunology / Q000473:pathology; D009362:Neoplasm Metastasis / Q000276:immunology / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology
D014408:Biomarkers, Tumor; D017077:Culture Media, Conditioned; D016207:Cytokines; C067625:FN1 protein, human; D005353:Fibronectins; D009363:Neoplasm Proteins