Gelectin-1 is a new potential therapeutic target in multiple myeloma

Galectin-1 (Gal-1) is a lectin, involved in several processes related to cancer, including immunosuppression, angiogenesis, hypoxia, and metastases. Currently, the role of Gal-1 in multiple myeloma (MM) pathophysiology and in MM-induced angiogenesis is unknown. Firstly, we found that Gal-1 was expressed by malignant plasma cells in the bone marrow microenvironment. Moreover, our data demonstrated that Gal-1 expression was up-regulated in MM cells by hypoxia treatment (1% of O2).Furthermore, the stable knock-down of Hypoxia Inducible Factor-1α, the master regulator of oxygen homeostasis, in human myeloma cell lines (HMCLs) markedly down-regulated Gal-1 expression. Thereafter, we found that the stable inhibition of Gal-1 by lentiviral vector short hairpin RNA (shRNA) anti-Gal-1 did not affect the proliferation and survival of MM cells, but significantly modified their transcriptional profiles, both in normoxic and hypoxic conditions. Notably, Gal-1 inhibition in MM cells significantly down-regulated genes involved in promoting tumor angiogenesis such as CCL2 and MMP9, and up-regulated some putative anti-angiogenic genes, including SEMA3A and CXCL10. In line with these observations, we found that Gal-1 suppression significantly decreased the pro-angiogenic proprieties of HMCLs, assessed by in vitro angiogenesis assay. Finally, we found that NOD-SCID mice, injected subcutaneously with HMCLs carrying a stable infection with lentiviral vector shRNA anti-Gal-1, showed a reduction in tumor volume and a significant reduction in the plasmacytomas microvascular density, compared to mice inoculated with HMCLs carrying a stable infection with the control vector. In a different set of experiments, a HMCL JJN3 infected with shRNA anti-Gal-1 and with control vector were injected in NIH-III SCID mice, an intratibial mouse model. We found that the anti-Gal-1 group developed tumors reduced in length, thickness, width and volume size and, in addition, developed fewer and smaller lytic lesions on x-ray compared to the control group. Overall, our data indicate that Gal-1 exerts a role in MM pathophysiology and in MM-induced angiogenesis and its inhibition in MM cells significantly reduced tumor growth in vivo, suggesting that Gal-1 is a new potential therapeutic target in MM.