Galectin-3 Binding Protein Secreted by Breast Cancer Cells Inhibits Monocyte-Derived Fibrocyte Differentiation

Abstract

To metastasize, tumor cells often need to migrate through a layer of collagen-containing scar tissue which encapsulates the tumor. A key component of scar tissue and fibrosing diseases is the monocyte-derived fibrocyte, a collagen-secreting pro-fibrotic cell. To test the hypothesis that invasive tumor cells may block the formation of the fibrous sheath, we determined if tumor cells secrete factors that inhibit monocyte-derived fibrocyte differentiation. We found that the human metastatic breast cancer cell line MDA-MB 231 secretes activity that inhibits human monocyte-derived fibrocyte differentiation, while less aggressive breast cancer cell lines secrete less of this activity. Purification indicated that Galectin-3 Binding Protein (LGALS3BP) is the active factor. Recombinant LGALS3BP inhibits monocyte-derived fibrocyte differentiation, and immunodepletion of LGALS3BP from MDA-MB 231 conditioned media removes the monocyte-derived fibrocyte differentiation-inhibiting activity. LGALS3BP inhibits the differentiation of monocyte-derived fibrocytes from wild-type mouse spleen cells, but not from SIGN-R1−/− mouse spleen cells, suggesting that CD209/SIGN-R1 is required for the LGALS3BP effect. Galectin-3 and galectin-1, binding partners of LGALS3BP, potentiate monocyte-derived fibrocyte differentiation. In breast cancer biopsies, increased levels of tumor cell-associated LGALS3BP were observed in regions of the tumor that were invading the surrounding stroma. These findings suggest LGALS3BP and galectin-3 as new targets to treat metastatic cancer and fibrosing diseases.

Galectin-3-binding protein: A multitask glycoprotein with innate immunity functions in viral and bacterial infections

“…Early Northern blot studies showed abundant LGALS3BP mRNA signal in many normal human tissues, and especially prominent expression was seen in lung and gastrointestinal tissues. 13 This is in accordance Collagen-IV, -V, -VI Influences cell-cell or cell-matrix interaction 20 Cyclophilin C a Regulates cyclophilin C functions 16,94 DC-SIGN b,c Inhibits maturation of dendritic cells, inhibits differentiation of monocyte-derived fibrocytes, 34,60 E-cadherin-p120catenin…”

“…The study was conducted in a cancer context, and the authors proposed that the Gal‐3BP–DC‐SIGN interaction contributes to the development of tolerogenic microenvironment for Gal‐3BP‐overexpressing colorectal cancer cells . Binding of Gal‐3BP to DC‐SIGN has also been reported to suppress the differentiation of monocyte‐derived fibrocytes, further indicating that Gal‐3BP may have immunosuppressive functions.…”

Identification of distinct nanoparticles and subsets of extracellular vesicles by asymmetric flow field-flow fractionation

“…Similar to the expression in metastatic tumor cells, exosome subsets were enriched with sialylated glycoproteins, supporting the role of these structures in exosome-mediated cellular recognition. One predominant sialoglycoprotein previously identified in exosomes 25, 35 , the galectin-3-binding protein (LGALS3BP), a modulator of cell communication and immune responses 36, 37 , was highly enriched in exomeres. This ligand could mediate the specific interaction of exomeres with target cells through proteins, such as collagens, fibronectin, nidogen, galectin-3 and integrin beta-1 38,39 .…”

Glycobiology Modifications in Intratumoral Hypoxia: The Breathless Side of Glycans Interaction

“…Gal-3 has been considered a tumor-associated antigen of malignancy level in breast cancer, and is implicated in aspects, such as angiogenesis [219], adhesion [220], invasion [221], apoptosis inhibition [222], migration [223], and therapeutic resistance [224]. Chen et al, through hydrazide-based chemistry method combined with liquid chromatography tandem-mass spectrometry (LC-MS/MS), identified 72 unique N-linked glycoproteins that were significantly regulated in triple negative breast cancers, among which is LGALS3BP.…”