Abstract
Galectin-1 (Gal-1) is involved in tumoral angiogenesis, hypoxia and metastases. Actually the Gal-1 expression profile in multiple myeloma (MM) patients and its pathophysiological role in MM-induced angiogenesis and tumoral growth are unknown. In this study, we found that Gal-1 expression by MM cells was upregulated in hypoxic conditions and that stable knockdown of hypoxia inducible factor-1α significantly downregulated its expression. Therefore, we performed Gal-1 inhibition using lentivirus transfection of shRNA anti-Gal-1 in human myeloma cell lines (HMCLs), and showed that its suppression modified transcriptional profiles in both hypoxic and normoxic conditions. Interestingly, Gal-1 inhibition in MM cells downregulated proangiogenic genes, including MMP9 and CCL2, and upregulated the antiangiogenic ones SEMA3A and CXCL10. Consistently, Gal-1 suppression in MM cells significantly decreased their proangiogenic properties in vitro. This was confirmed in vivo, in two different mouse models injected with HMCLs transfected with anti-Gal-1 shRNA or the control vector. Gal-1 suppression in both models significantly reduced tumor burden and microvascular density as compared with the control mice. Moreover, Gal-1 suppression induced smaller lytic lesions on X-ray in the intratibial model. Overall, our data indicate that Gal-1 is a new potential therapeutic target in MM blocking angiogenesis.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Rabinovich GA, Toscano MA . Turning 'sweet' on immunity: galectin-glycan interactions in immune tolerance and inflammation. Nat Rev Immunol 2009; 9: 338–352.
Thijssen VL, Heusschen R, Caers J, Griffioen AW . Galectin expression in cancer diagnosis and prognosis: a systematic review. Biochim Biophys Acta 2015; 1855: 235–247.
Ito K, Stannard K, Gabutero E, Clark AM, Neo SY, Onturk S et al. Galectin-1 as a potent target for cancer therapy: role in the tumor microenvironment. Cancer Metastasis Rev 2012; 31: 763–778.
Cedeno-Laurent F, Opperman M, Barthel SR, Kuchroo VK, Dimitroff CJ . Galectin-1 triggers an immunoregulatory signature in Th cells functionally defined by IL-10 expression. J Immunol 2012; 188: 3127–3137.
Hsieh SH, Ying NW, Wu MH, Chiang WF, Hsu CL, Wong TY et al. Galectin-1, a novel ligand of neuropilin-1, activates VEGFR-2 signaling and modulates the migration of vascular endothelial cells. Oncogene 2008; 27: 3746–3753.
Thijssen VL, Barkan B, Shoji H, Aries IM, Mathieu V, Deltour L et al. Tumor cells secrete galectin-1 to enhance endothelial cell activity. Cancer Res 2010; 70: 6216–6224.
Thijssen VL, Postel R, Brandwijk RJ, Dings RP, Nesmelova I, Satijn S et al. Galectin-1 is essential in tumor angiogenesis and is a target for antiangiogenesis therapy. Proc Natl Acad Sci USA 2006; 103: 15975–15980.
Wu MH, Ying NW, Hong TM, Chiang WF, Lin YT, Chen YL . Galectin-1 induces vascular permeability through the neuropilin-1/vascular endothelial growth factor receptor-1 complex. Angiogenesis 2014; 17: 839–849.
Croci DO, Salatino M, Rubinstein N, Cerliani JP, Cavallin LE, Leung HJ et al. Disrupting galectin-1 interactions with N-glycans suppresses hypoxia-driven angiogenesis and tumorigenesis in Kaposi's sarcoma. J Exp Med 2012; 209: 1985–2000.
White NM, Masui O, Newsted D, Scorilas A, Romaschin AD, Bjarnason GA et al. Galectin-1 has potential prognostic significance and is implicated in clear cell renal cell carcinoma progression through the HIF/mTOR signaling axis. Br J Cancer 2014; 110: 1250–1259.
Le QT, Shi G, Cao H, Nelson DW, Wang Y, Chen EY et al. Galectin-1: a link between tumor hypoxia and tumor immune privilege. J Clin Oncol 2005; 23: 8932–8941.
Zhao XY, Chen TT, Xia L, Guo M, Xu Y, Yue F et al. Hypoxia inducible factor-1 mediates expression of galectin-1: the potential role in migration/invasion of colorectal cancer cells. Carcinogenesis 2010; 31: 1367–1375.
Zhou X, Li D, Wang X, Zhang B, Zhu H, Zhao J . Galectin-1 is overexpressed in CD133+ human lung adenocarcinoma cells and promotes their growth and invasiveness. Oncotarget 2015; 6: 3111–3122.
Wu MH, Hong TM, Cheng HW, Pan SH, Liang YR, Hong HC et al. Galectin-1-mediated tumor invasion and metastasis, up-regulated matrix metalloproteinase expression, and reorganized actin cytoskeletons. Mol Cancer Res 2009; 7: 311–318.
Wu MH, Hong HC, Hong TM, Chiang WF, Jin YT, Chen YL . Targeting galectin-1 in carcinoma-associated fibroblasts inhibits oral squamous cell carcinoma metastasis by downregulating MCP-1/CCL2 expression. Clin Cancer Res 2011; 17: 1306–1316.
Dalotto-Moreno T, Croci DO, Cerliani JP, Martinez-Allo VC, Dergan-Dylon S, Mendez-Huergo SP et al. Targeting galectin-1 overcomes breast cancer-associated immunosuppression and prevents metastatic disease. Cancer Res 2013; 73: 1107–1117.
D'Haene N, Sauvage S, Maris C, Adanja I, Le Mercier M, Decaestecker C et al. VEGFR1 and VEGFR2 involvement in extracellular galectin-1- and galectin-3-induced angiogenesis. PLoS One 2013; 8: e67029.
Croci DO, Cerliani JP, Dalotto-Moreno T, Mendez-Huergo SP, Mascanfroni ID, Dergan-Dylon S et al. Glycosylation-dependent lectin-receptor interactions preserve angiogenesis in anti-VEGF refractory tumors. Cell 2014; 156: 744–758.
Croci DO, Rabinovich GA . Linking tumor hypoxia with VEGFR2 signaling and compensatory angiogenesis: glycans make the difference. Oncoimmunology 2014; 3: e29380.
Palumbo A, Anderson K . Multiple myeloma. N Engl J Med 2011; 364: 1046–1060.
Roodman GD . Pathogenesis of myeloma bone disease. Leukemia 2009; 23: 435–441.
Giuliani N, Storti P, Bolzoni M, Palma BD, Bonomini S . Angiogenesis and multiple myeloma. Cancer Microenviron 2011; 4: 325–337.
Vacca A, Ribatti D . Bone marrow angiogenesis in multiple myeloma. Leukemia 2006; 20: 193–199.
Podar K, Anderson KC . The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implications. Blood 2005; 105: 1383–1395.
Barille S, Akhoundi C, Collette M, Mellerin MP, Rapp MJ, Harousseau JL et al. Metalloproteinases in multiple myeloma: production of matrix metalloproteinase-9 (MMP-9), activation of proMMP-2, and induction of MMP-1 by myeloma cells. Blood 1997; 90: 1649–1655.
Van Valckenborgh E, Bakkus M, Munaut C, Noel A St, Pierre Y, Asosingh K et al. Upregulation of matrix metalloproteinase-9 in murine 5T33 multiple myeloma cells by interaction with bone marrow endothelial cells. Int J Cancer 2002; 101: 512–518.
Vacca A, Scavelli C, Serini G, Di Pietro G, Cirulli T, Merchionne F et al. Loss of inhibitory semaphorin 3A (SEMA3A) autocrine loops in bone marrow endothelial cells of patients with multiple myeloma. Blood 2006; 108: 1661–1667.
Colla S, Tagliaferri S, Morandi F, Lunghi P, Donofrio G, Martorana D et al. The new tumor-suppressor gene inhibitor of growth family member 4 (ING4) regulates the production of proangiogenic molecules by myeloma cells and suppresses hypoxia-inducible factor-1 alpha (HIF-1alpha) activity: involvement in myeloma-induced angiogenesis. Blood 2007; 110: 4464–4475.
Kumar S, Gertz MA, Dispenzieri A, Lacy MQ, Wellik LA, Fonseca R et al. Prognostic value of bone marrow angiogenesis in patients with multiple myeloma undergoing high-dose therapy. Bone Marrow Transplant 2004; 34: 235–239.
Colla S, Storti P, Donofrio G, Todoerti K, Bolzoni M, Lazzaretti M et al. Low bone marrow oxygen tension and hypoxia-inducible factor-1alpha overexpression characterize patients with multiple myeloma: role on the transcriptional and proangiogenic profiles of CD138(+) cells. Leukemia 2010; 24: 1967–1970.
Storti P, Bolzoni M, Donofrio G, Airoldi I, Guasco D, Toscani D et al. Hypoxia-inducible factor (HIF)-1alpha suppression in myeloma cells blocks tumoral growth in vivo inhibiting angiogenesis and bone destruction. Leukemia 2013; 27: 1697–1706.
Martin SK, Diamond P, Gronthos S, Peet DJ, Zannettino AC . The emerging role of hypoxia, HIF-1 and HIF-2 in multiple myeloma. Leukemia 2011; 25: 1533–1542.
Agnelli L, Mosca L, Fabris S, Lionetti M, Andronache A, Kwee I et al. A SNP microarray and FISH-based procedure to detect allelic imbalances in multiple myeloma: an integrated genomics approach reveals a wide gene dosage effect. Genes Chromosomes Cancer 2009; 48: 603–614.
Lombardi L, Poretti G, Mattioli M, Fabris S, Agnelli L, Bicciato S et al. Molecular characterization of human multiple myeloma cell lines by integrative genomics: insights into the biology of the disease. Genes Chromosomes Cancer 2007; 46: 226–238.
Agnelli L, Forcato M, Ferrari F, Tuana G, Todoerti K, Walker BA et al. The reconstruction of transcriptional networks reveals critical genes with implications for clinical outcome of multiple myeloma. Clin Cancer Res 2011; 17: 7402–7412.
Goeman JJ, le Cessie S . A goodness-of-fit test for multinomial logistic regression. Biometrics 2006; 62: 980–985.
Storti P, Donofrio G, Colla S, Airoldi I, Bolzoni M, Agnelli L et al. HOXB7 expression by myeloma cells regulates their pro-angiogenic properties in multiple myeloma patients. Leukemia 2011; 25: 527–537.
D'Souza S, del Prete D, Jin S, Sun Q, Huston AJ, Kostov FE et al. Gfi1 expressed in bone marrow stromal cells is a novel osteoblast suppressor in patients with multiple myeloma bone disease. Blood 2011; 118: 6871–6880.
Mirandola L, Yu Y, Chui K, Jenkins MR, Cobos E, John CM et al. Galectin-3C inhibits tumor growth and increases the anticancer activity of bortezomib in a murine model of human multiple myeloma. PLoS One 2011; 6: e21811.
Streetly MJ, Maharaj L, Joel S, Schey SA, Gribben JG, Cotter FE . GCS-100, a novel galectin-3 antagonist, modulates MCL-1, NOXA, and cell cycle to induce myeloma cell death. Blood 2010; 115: 3939–3948.
Kobayashi T, Kuroda J, Ashihara E, Oomizu S, Terui Y, Taniyama A et al. Galectin-9 exhibits anti-myeloma activity through JNK and p38 MAP kinase pathways. Leukemia 2010; 24: 843–850.
Shaughnessy JD Jr, Zhan F, Burington BE, Huang Y, Colla S, Hanamura I et al. A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. Blood 2007; 109: 2276–2284.
Chen L, Wang S, Zhou Y, Wu X, Entin I, Epstein J et al. Identification of early growth response protein 1 (EGR-1) as a novel target for JUN-induced apoptosis in multiple myeloma. Blood 2010; 115: 61–70.
Kaiser MF, Johnson DC, Wu P, Walker BA, Brioli A, Mirabella F et al. Global methylation analysis identifies prognostically important epigenetically inactivated tumor suppressor genes in multiple myeloma. Blood 2013; 122: 219–226.
Cedeno-Laurent F, Watanabe R, Teague JE, Kupper TS, Clark RA, Dimitroff CJ . Galectin-1 inhibits the viability, proliferation, and Th1 cytokine production of nonmalignant T cells in patie xnts with leukemic cutaneous T-cell lymphoma. Blood 2012; 119: 3534–3538.
Zacarias Fluck MF, Hess L, Salatino M, Croci DO, Stupirski JC, Di Masso RJ et al. The aggressiveness of murine lymphomas selected in vivo by growth rate correlates with galectin-1 expression and response to cyclophosphamide. Cancer Immunol Immunother 2012; 61: 469–480.
Ouyang J, Plutschow A, Pogge von Strandmann E, Reiners KS, Ponader S, Rabinovich GA et al. Galectin-1 serum levels reflect tumor burden and adverse clinical features in classical Hodgkin lymphoma. Blood 2013; 121: 3431–3433.
Abroun S, Otsuyama K, Shamsasenjan K, Islam A, Amin J, Iqbal MS et al. Galectin-1 supports the survival of CD45RA(-) primary myeloma cells in vitro. Br J Haematol 2008; 142: 754–765.
Li Y, Zheng Y, Li T, Wang Q, Qian J, Lu Y et al. Chemokines CCL2, 3, 14 stimulate macrophage bone marrow homing, proliferation, and polarization in multiple myeloma. Oncotarget 2015; 6: 24218–24229.
Stifter S . The role of nuclear factor kappaB on angiogenesis regulation through monocyte chemotactic protein-1 in myeloma. Med Hypotheses 2006; 66: 384–386.
Acevedo LM, Barillas S, Weis SM, Gothert JR, Cheresh DA . Semaphorin 3A suppresses VEGF-mediated angiogenesis yet acts as a vascular permeability factor. Blood 2008; 111: 2674–2680.
Keeley EC, Mehrad B, Strieter RM . Chemokines as mediators of neovascularization. Arterioscler Thromb Vasc Biol 2008; 28: 1928–1936.
Barash U, Zohar Y, Wildbaum G, Beider K, Nagler A, Karin N et al. Heparanase enhances myeloma progression via CXCL10 downregulation. Leukemia 2014; 28: 2178–2187.
Giuliani N, Bonomini S, Romagnani P, Lazzaretti M, Morandi F, Colla S et al. CXCR3 and its binding chemokines in myeloma cells: expression of isoforms and potential relationships with myeloma cell proliferation and survival. Haematologica 2006; 91: 1489–1497.
Le Mercier M, Mathieu V, Haibe-Kains B, Bontempi G, Mijatovic T, Decaestecker C et al. Knocking down galectin 1 in human hs683 glioblastoma cells impairs both angiogenesis and endoplasmic reticulum stress responses. J Neuropathol Exp Neurol 2008; 67: 456–469.
Lee YP, Schwarz EM, Davies M, Jo M, Gates J, Zhang X et al. Use of zoledronate to treat osteoblastic versus osteolytic lesions in a severe-combined-immunodeficient mouse model. Cancer Res 2002; 62: 5564–5570.
Hayashi M, Nakashima T, Taniguchi M, Kodama T, Kumanogoh A, Takayanagi H . Osteoprotection by semaphorin 3A. Nature 2012; 485: 69–74.
Miller MC, Klyosov A, Mayo KH . The alpha-galactomannan Davanat binds galectin-1 at a site different from the conventional galectin carbohydrate binding domain. Glycobiology 2009; 19: 1034–1045.
Astorgues-Xerri L, Riveiro ME, Tijeras-Raballand A, Serova M, Rabinovich GA, Bieche I et al. OTX008, a selective small-molecule inhibitor of galectin-1, downregulates cancer cell proliferation, invasion and tumour angiogenesis. Eur J Cancer 2014; 50: 2463–2477.
Zucchetti M, Bonezzi K, Frapolli R, Sala F, Borsotti P, Zangarini M et al. Pharmacokinetics and antineoplastic activity of galectin-1-targeting OTX008 in combination with sunitinib. Cancer Chemother Pharmacol 2013; 72: 879–887.
Acknowledgements
This work was supported in part by a grant from the Associazione Italiana per la Ricerca sul Cancro (AIRC) IG2014 no. 15531 (to NG) and IG13018 (to IA). This work was also supported by a fellowship Fondazione Italiana per la Ricerca sul Cancro id. 18152 (MB) and two fellowship by ParmAIL (Associazione italiana contro le leucemie-linfomi e myeloma, Parma) (VM and DG). We thank Dirce Gennari for her technical support.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies this paper on the Leukemia website
Supplementary information
Rights and permissions
About this article
Cite this article
Storti, P., Marchica, V., Airoldi, I. et al. Galectin-1 suppression delineates a new strategy to inhibit myeloma-induced angiogenesis and tumoral growth in vivo. Leukemia 30, 2351–2363 (2016). https://doi.org/10.1038/leu.2016.137
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/leu.2016.137
This article is cited by
-
Galectin-1 promotes angiogenesis and chondrogenesis during antler regeneration
Cellular & Molecular Biology Letters (2023)
-
Targeting galectin-driven regulatory circuits in cancer and fibrosis
Nature Reviews Drug Discovery (2023)
-
Transcriptional profiling of circulating tumor cells in multiple myeloma: a new model to understand disease dissemination
Leukemia (2020)
-
Treatment of B-cell precursor acute lymphoblastic leukemia with the Galectin-1 inhibitor PTX008
Journal of Experimental & Clinical Cancer Research (2018)
-
Proteomic characterization of human multiple myeloma bone marrow extracellular matrix
Leukemia (2017)