Role of Galectins in Multiple Myeloma

Abstract

Galectins are a family of lectins that bind β-galactose-containing glycoconjugates and are characterized by carbohydrate-recognition domains (CRDs). Galectins exploit several biological functions, including angiogenesis, regulation of immune cell activities and cell adhesion, in both physiological and pathological processes, as tumor progression. Multiple myeloma (MM) is a plasma cell (PC) malignancy characterized by the tight adhesion between tumoral PCs and bone marrow (BM) microenvironment, leading to the increase of PC survival and drug resistance, MM-induced neo-angiogenesis, immunosuppression and osteolytic bone lesions. In this review, we explore the expression profiles and the roles of galectin-1, galectin-3, galectin-8 and galectin-9 in the pathophysiology of MM. We focus on the role of these lectins in the interplay between MM and BM microenvironment cells showing their involvement in MM progression mainly through the regulation of PC survival and MM-induced angiogenesis and osteoclastogenesis. The translational impact of these pre-clinical pieces of evidence is supported by recent data that indicate galectins could be new attractive targets to block MM cell growth in vivo and by the evidence that the expression levels of LGALS1 and LGALS8, genes encoding for galectin-1 and galectin-8 respectively, correlate to MM patients' survival.

Keywords: galectin-1; galectin-3; galectin-8; galectin-9; galectins; myeloma.

Figure 1

Effect of galectins on MM cells proliferation and apoptosis induction. Galectin-1 is regulated by HIF-1α and the galectin-1/integrin β1 binding induces pro-survival cascades. The inhibition of galectin-3 by GCS-100 (reported in figure as Galectin-3/GCS-100) leads to cell cycle arrest and an activation of different pro-apoptotic signals. Galectin-9 exerts its anti-proliferative activity inducing pro-apoptotic pathways. MM, multiple myeloma; IkB, inhibitor of kappa B; ERK, Extracellular signal-regulated kinases; AKT, Protein kinase B; NOXA, Phorbol-12-myristate-13-acetate-induced protein 1; MCL-1, Induced myeloid leukemia cell differentiation protein Mcl-1; Bcl-xL, B-cell lymphoma-extralarge; NF-κB, nuclear factor-kappaB; HIF-1α, Hypoxia inducible factor-1α; H2AX, H2A histone family, member X; JNK, c-Jun N-terminal kinases.

Figure 2

Galectins in the MM BM microenvironment. Galectin-1 induces the secretion of pro-angiogenic molecules and inhibits the production of anti-angiogenic ones. Galectin-1 is present in the ECM of MM patients. Galectin-3C reduces MM cell chemotaxis and invasion and the secretion of pro-angiogenic proteins. Galectin-8 is produced by ECs and mediates the adhesion between MM PCs and ECs. Galectin-9 is secreted by OCs and could mediate the T cell activity inhibition. OCs, Osteoclasts; TIM-3, T-cell immunoglobulin and mucin-domain containing-3; MM, multiple myeloma; VEGFA, Vascular endothelial growth factor A; FGF, Fibroblast growth factor; MCP-1, Monocyte chemoattractant protein-1; MMP-9, Metalloprotease-9; Sema-3A, Semaphorin -3A; ECM, Extracellular matrix; ECs, Endothelial cells; BM, bone marrow.