LGALS3BP, lectin galactoside-binding soluble 3 binding protein, induces vascular endothelial growth factor in human breast cancer cells and promotes angiogenesis

Abstract

Elevated serum or tissue levels of lectin galactoside-binding soluble 3 binding protein (LGALS3BP) have been associated with short survival and development of metastasis in a variety of human cancers. However, the role of LGALS3BP, particularly in the context of tumor-host relationships, is still missing. Here, we show that LGALS3BP knockdown in MDA-MB-231 human breast cancer cells leads to a decreased adhesion to fibronectin, a reduced transendothelial migration and, more importantly, a reduced expression of vascular endothelial growth factor (VEGF). Production of VEGF, that was restored by exposure of silenced cells to recombinant LGALS3BP, required an intact PI3k/Akt signaling. Furthermore, we show that LGALS3BP was able to directly stimulate HUVEC tubulogenesis in a VEGF-independent, galectin-3-dependent manner. Immunohistochemical analysis of human breast cancer tissues revealed a correlation among LGALS3BP expression, VEGF expression, and blood vessel density. We propose that in addition to its prometastatic role, LGALS3BP secreted by breast cancer cells functions critically as a pro-angiogenic factor through a dual mechanism, i.e by induction of tumor VEGF and stimulation of endothelial cell tubulogenesis.

Inhibition of Tumor Growth and Angiogenesis by SP-2, an Anti–Lectin, Galactoside-Binding Soluble 3 Binding Protein (LGALS3BP) Antibody

“…Recently, SP-2 was found to reduce LGALS3BP-induced tube formation in Matrigel by endothelial cells (8). In the present study, we tested the ability of SP-2 to inhibit LGALS3BP-stimulated angiogenesis and tumor growth.…”

“…The generation of MDA-MB-231 and IR-8 cells silenced for LGALS3BP (shLGALS3BP) or not (shCTR), was performed in 2012 as previously described (8). For collection of the conditioned medium, cells were grown until 80% confluent, washed with PBS, and cultured in serum-free medium for additional 24 to 48 hours.…”

“…Despite these evidences, little is known regarding the mechanism(s) underlying LGALS3BP activity in cancer. Recently, we identified LGALS3BP as a novel proangiogenic factor capable of inducing VEGF in human breast cancer cells and promoting angiogenesis by a direct stimulation of endothelial cells (8).…”

Lectin Galactoside-binding Soluble 3 Binding Protein (LGALS3BP) Is a Tumor-associated Immunomodulatory Ligand for CD33-related Siglecs

“…Although initial studies rapidly associated LGALS3BP with immunomodulatory effects (57,58), the exact mechanism remained unclear. Recent studies focused more on tumor cells and transmission of signals into the tumor cell (59,60). For example, binding of LGALS3BP to integrins on tumor cells activate the Akt and Raf-Erk pathways, which was associated with increased survival, proliferation, motility, and migration of cancer cell lines (59).…”

“…For example, binding of LGALS3BP to integrins on tumor cells activate the Akt and Raf-Erk pathways, which was associated with increased survival, proliferation, motility, and migration of cancer cell lines (59). LGALS3BP has also been shown to induce VEGF expression in cancer cells and is associated with increased angiogenesis (60,61). Moreover, LGALS3BP has been described to increase IL-6 expression in stromal cells in neuroblastoma models by binding to galectin-3 (62).…”