Deletion of galectin-3 in the host attenuates metastasis of murine melanoma by modulating tumor adhesion and NK cell activity

Abstract

Galectin-3, a β galactoside-binding lectin, plays an important role in the processes relevant to tumorigenesis such as malignant cell transformation, invasion and metastasis. We have investigated whether deletion of Galectin-3 in the host affects the metastasis of B16F1 malignant melanoma. Galectin-3-deficient (Gal-3(-/-)) mice are more resistant to metastatic malignant melanoma as evaluated by number and size of metastatic colonies in the lung. In vitro assays showed lower number of attached malignant cells in the tissue section derived from Gal-3(-/-) mice. Furthermore, lack of Galectin-3 correlates with higher serum levels of IFN-γ and IL-17 in tumor bearing hosts. Interestingly, spleens of Gal-3(-/-) mice have lower number of Foxp3(+) T cells after injection of B16F1 melanoma cells. Finally, we found that while CD8(+) T cell and adherent cell cytotoxicity were similar, there was greater cytotoxic activity of splenic NK cells of Gal-3(-/-) mice compared with "wild-type" (Gal-3( +/+ )) mice. Despite the reduction in total number of CD3ε(-)NK1.1(+), Gal-3(-/-) mice constitutively have a significantly higher percentage of effective cytotoxic CD27(high)CD11b(high) NK cells as well as the percentage of immature CD27(high)CD11b(low) NK cells. In contrast, CD27(low)CD11b(high) less functionally exhausted NK cells and NK cells bearing inhibitory KLRG1 receptor were more numerous in Gal-3( +/+ ) mice. It appears that lack of Galectin-3 affects tumor metastasis by at least two independent mechanisms: by a decrease in binding of melanoma cells onto target tissue and by enhanced NK-mediated anti-tumor response suggesting that Galectin-3 may be considered as therapeutic target.

Intracellular galectins in cancer cells: Potential new targets for therapy

“…Specifically, galectin-3 reduces glioma cell migration (121). In general, however, galectin-3 (107) is mostly associated with increased invasive behavior in most cancer cell types tested (94,95,117,(122)(123)(124)(125)(126), supporting the view that targeting this galectin might be a promising avenue for the treatment of many types of cancer. Whether this is also true for other galectins has to be determined.…”

The Two Faces of Galectin-3: Roles in Various Pathological Conditions

“…+ T cells in wild type mice, but not in Galectin-3-deficient mice (86). Thus, our findings suggest that hostderived Galectin-3 could lead to an increase in the number and percentage of Treg cells, which promotes the formation of an immunosuppressive tumour network and can be one of the main facilitative mechanisms important for tumour metastasis.…”

“…In an experimental model of B16-F1 murine melanoma, we demonstrated that Galectin-3-deficient mice were more resistant to metastatic melanoma, as evidenced by markedly reduced number and size of lung metastatic colonies compared with wild type mice. In addition, by in vitro assay we noticed lower numbers of attached malignant cells in lung tissue sections of Galectin-3-deficient mice, suggesting that hostderived Galectin-3 plays a pivotal role in tumour cell adhesion to the metastatic target (86). Recently, it has been shown that Galectin-3, which is expressed in lungs (especially on the vascular endothelium), cooperates with poly-N-acetyl-lactosamine on N-glycans on B16-F1 murine melanoma cells, as a ligand for Galectin-3 (87).…”

“…Our data support a link between Galectin-3 and the cytotoxic capacity of NK cells, but not that of CD8 + T cells. In fact, we demonstrated that lack of Galectin-3 is associated with enhanced tumouricidal activity of NK cells directed against B16-F1 melanoma cells (86 (86). It is believed that Galectin-3 interferes with binding to regulatory molecules on the cancer cell that serve as ligands for receptors of NK cells (96).…”

“…We observed higher serum levels of IFN-γ and IL-17 in tumour-bearing hosts in Galectin-3 deficiency, which was not accompanied by differences in the number of CD4 + and CD8 + T cells in the spleen. This does not exclude the possibility that the number of tumour-specific Th1 cells and cytotoxic CD8 + T cells is different (86). Reported data suggest that Galectin-3 suppresses IFN-γ production by antigen-specific CD8 + T cells in vitro (95).…”