Tumor-Conditioned Macrophages Secrete Migration-Stimulating Factor: A New Marker for M2-Polarization, Influencing Tumor Cell Motility

Department of Immunology and Inflammation, Clinical Institute Humanitas, Rozzano, Italy.
The Journal of Immunology (Impact Factor: 4.92). 07/2010; 185(1):642-52. DOI: 10.4049/jimmunol.1000413
Source: PubMed


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.

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    • "It is mainly expressed on M␸s, but also by dendritic cells (DCs) and non-vascular endothelial cells. Some M␸-subpopulations, including TAMs, strongly express MR [15] [16], and in one study, gene expression of MR was increased 44-fold in human monocytes after in vitro differentiation into TAMs [17]. Interestingly, a recent paper stated that MR, in addition to being an M2/TAM-marker, could also be directly implicated in mediating immune suppression within the tumor microenvironment [18]. "
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    • "According to a previous study, the M1-type is characterized by the surface marker CD11b+F4/80lowLy-6C+CD206-, whereas the M2-type is characterized by the surface marker CD11b+F4/80highLy-6C-/lowLy-6G-CD206+ [8]. Moreover, migration stimulating factor, a whole new marker for M2-type differentiation, was identified in recent research [9]. Previous studies have also shown that the M2-type is the dominant form of TAM [10,11]. "
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