Galectin‐3 disruption impaired tumoral angiogenesis by reducing VEGF secretion from TGFβ1‐induced macrophages

Abstract

In order to study the role of galectin-3 in tumor angiogenesis associated with tumor-associated macrophages (TAM) and tumor parenchyma, the galectin-3 expression was reconstituted in Tm1 melanoma cell line that lacks this protein. Galectin-3-expressing cells (Tm1G3) and mock-vector transfected cells (Tm1N3) were injected into wild-type (WT) and galectin-3 knockout (KO) C57Bl/6 mice. Tumors originated from Tm1G3 were larger in tumor volume with enlarged functional vessels, decreased necrotic areas, and increased vascular endothelial growth factor (VEGF) protein levels. Galectin-3-nonexpressing-cells injected into WT and KO showed increased levels of transforming growth factor beta 1 (TGFβ1) and, in WT animals this feature was also accompanied by increased VEGFR2 expression and its phosphorylation. In KO animals, tumors derived from galectin-3-expressing cells were infiltrated by CD68+-cells, whereas in tumors derived from galectin-3-nonexpressing-cells, CD68+ cells failed to infiltrate tumors and accumulated in the periphery of the tumor mass. In vitro studies showed that Tm1G3 secreted more VEGF than Tm1N3 cells. In the latter case, TGFβ1 induced VEGF production. Basal secretion of VEGF was higher in WT-bone marrow-derived macrophages (BMDM) than in KO-BMDM. TGFβ1 induced secretion of VEGF only in WT-BMDM. Tm1G3-induced tumors had the Arginase I mRNA increased, which upregulated alternative macrophage (M2)/TAM induction. M2 stimuli, such as interleukin-4 (IL4) and TGFβ1, increased Arginase I protein levels and galectin-3 expression in WT- BMDM, but not in cells from KO mice. Hence, we report that galectin-3 disruption in tumor stroma and parenchyma decreases angiogenesis through interfering with the responses of macrophages to the interdependent VEGF and TGFβ1 signaling pathways.

Galectin-3 as a Next-Generation Biomarker for Detecting Early Stage of Various Diseases

“…Gal-3 is secreted into tumor stroma and plays an important role of tumor microenvironment contributing to the tumor progression. Gal-3 also affects the tumor angiogenesis by regulating vascular endothelial growth factor [135].…”

Extracellular Galectin-3 in Tumor Progression and Metastasis

“…The last four are important steps of the metastatic process, in which extracellular, rather than intracellular galectin-3, plays a prominent role in both tumor cells and stromal cells present in the tumor microenvironment (19, 26–28). …”

Galectin-3 Regulates the Expression of Tumor Glycosaminoglycans and Increases the Metastatic Potential of Breast Cancer

“…In another report, Gal-3 silencing in colonic epithelial cells was shown to decrease the transcriptional activity of AP-1 and SP-1 [15][16][17][18][19][20]. Moreover, a decreased expression of ARSB was associated with an increase in the invasiveness of human melanoma cells by reducing Gal-3 binding to C4S [21]. us, the interaction of Gal-3 with glycosylated components of the tumor microenvironment, such as GAGs, may form a physical and functional scaffold having an important role in cancer biology [14,22].…”

“…ese data suggested that Gal-3 plays a central role, at least in part, in the structural organization of tissues acting as a physical barrier to control cell dissemination. Indeed, a decreased expression of Gal-3 is usually observed during breast cancer progression, while cells embolized in the tumor vasculature present high levels of Gal-3, which indicates that Gal-3 maintains the cohesion between the tumor cells until they find a fertile soil to establish a future metastatic seed [21,[24][25][26]. Although the role of Gal-3 in the maintenance of a tumorigenic phenotype by breast carcinoma cells has been previously demonstrated [27], its role in the tumor biology of breast cancer progression and metastasis is still controversial.…”