Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Targeting galectin-driven regulatory circuits in cancer and fibrosis

Nature Reviews Drug Discovery volume 22, pages 295–316 (2023)Cite this article

Subjects

This article has been updated

Abstract

Galectins are a family of endogenous glycan-binding proteins that have crucial roles in a broad range of physiological and pathological processes. As a group, these proteins use both extracellular and intracellular mechanisms as well as glycan-dependent and independent pathways to reprogramme the fate and function of numerous cell types. Given their multifunctional roles in both tissue fibrosis and cancer, galectins have been identified as potential therapeutic targets for these disorders. Here, we focus on the therapeutic relevance of galectins, particularly galectin 1 (GAL1), GAL3 and GAL9 to tumour progression and fibrotic diseases. We consider an array of galectin-targeted strategies, including small-molecule carbohydrate inhibitors, natural polysaccharides and their derivatives, peptides, peptidomimetics and biological agents (notably, neutralizing monoclonal antibodies and truncated galectins) and discuss their mechanisms of action, selectivity and therapeutic potential in preclinical models of fibrosis and cancer. We also review the results of clinical trials that aim to evaluate the efficacy of galectin inhibitors in patients with idiopathic pulmonary fibrosis, nonalcoholic steatohepatitis and cancer. The rapid pace of glycobiology research, combined with the acute need for drugs to alleviate fibrotic inflammation and overcome resistance to anticancer therapies, will accelerate the translation of anti-galectin therapeutics into clinical practice.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Structural classification of galectins.
Fig. 2: Galectins reprogramme tumour, endothelial and immune landscapes in the tumour microenvironment.
Fig. 3: Small-molecule carbohydrate inhibitors.
Fig. 4: Structure of natural polysaccharides and their derivatives as galectin inhibitors.
Fig. 5: Peptides and peptidomimetics as galectin inhibitors.

Similar content being viewed by others

Change history

  • 20 February 2023

    In the version of this article originally published, in Figure 3g, compound 13, galactose units were presented without methylene groups, as are now amended in the HTML and PDF versions of the article.

References

  1. Reily, C., Stewart, T. J., Renfrow, M. B. & Novak, J. Glycosylation in health and disease. Nat. Rev. Nephrol. 15, 346–366 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Ohtsubo, K. & Marth, J. D. Glycosylation in cellular mechanisms of health and disease. Cell 126, 855–867 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Gagneux, P., Hennet, T. & Varki, A. Essentials of Glycobiology 4th edn. 79–92 (Cold Spring Harbor Laboratory Press, 2022).

  4. Dube, D. H. & Bertozzi, C. R. Glycans in cancer and inflammation — potential for therapeutics and diagnostics. Nat. Rev. Drug Discov. 4, 477–488 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Pinho, S. S. & Reis, C. A. Glycosylation in cancer: mechanisms and clinical implications. Nat. Rev. Cancer 15, 540–555 (2015).

    Article  CAS  PubMed  Google Scholar 

  6. van Kooyk, Y. & Rabinovich, G. A. Protein–glycan interactions in the control of innate and adaptive immune responses. Nat. Immunol. 9, 593–601 (2008).

    Article  PubMed  Google Scholar 

  7. McCarthy, C. et al. The role and importance of glycosylation of acute phase proteins with focus on alpha-1 antitrypsin in acute and chronic inflammatory conditions. J. Proteome Res. 13, 3131–3143 (2014).

    Article  CAS  PubMed  Google Scholar 

  8. Rabinovich, G. A. & Croci, D. O. Regulatory circuits mediated by lectin-glycan interactions in autoimmunity and cancer. Immunity 36, 322–335 (2012).

    Article  CAS  PubMed  Google Scholar 

  9. Croci, D. O. et al. Glycosylation-dependent lectin-receptor interactions preserve angiogenesis in anti-VEGF refractory tumors. Cell 156, 744–758 (2014). This study identifies the relevance of GAL1–glycan interactions as a mechanism of resistance to anti-VEGF therapies and reports the synergistic effects of anti-VEGF and anti-GAL1 mAbs in anti-angiogenic therapies.

    Article  CAS  PubMed  Google Scholar 

  10. Dewald, J. H., Colomb, F., Bobowski-Gerard, M., Groux-Degroote, S. & Delannoy, P. Role of cytokine-induced glycosylation changes in regulating cell interactions and cell signaling in inflammatory diseases and cancer. Cells 5, 43 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Cagnoni, A. J., Pérez Sáez, J. M., Rabinovich, G. A. & Mariño, K. V. Turning-off signaling by siglecs, selectins, and galectins: chemical inhibition of glycan-dependent interactions in cancer. Front. Oncol. 6, 1–21 (2016).

    Article  Google Scholar 

  12. Kirwan, A., Utratna, M., O’Dwyer, M. E., Joshi, L. & Kilcoyne, M. Glycosylation-based serum biomarkers for cancer diagnostics and prognostics. Biomed. Res. Int. 2015, 490531 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Hanić, M., Lauc, G. & Trbojević-Akmačić, I. N-glycan analysis by ultra-performance liquid chromatography and capillary gel electrophoresis with fluorescent labeling. Curr. Protoc. Protein Sci. 97, e95 (2019).

    PubMed  Google Scholar 

  14. Smith, B. A. H. & Bertozzi, C. R. The clinical impact of glycobiology: targeting selectins, siglecs and mammalian glycans. Nat. Rev. Drug Discov. 20, 217–243 (2021). This review highlights the role of selectins and siglecs as emerging glycocheckpoints and therapeutic targets.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Cerliani, J. P., Blidner, A. G., Toscano, M. A., Croci, D. O. & Rabinovich, G. A. Translating the ‘Sugar Code’ into immune and vascular signaling programs. Trends Biochem. Sci. 42, 255–273 (2017).

    Article  CAS  PubMed  Google Scholar 

  16. Toscano, M. A., Martínez Allo, V. C., Cutine, A. M., Rabinovich, G. A. & Mariño, K. V. Untangling galectin-driven regulatory circuits in autoimmune inflammation. Trends Mol. Med. 24, 348–363 (2018).

    Article  CAS  PubMed  Google Scholar 

  17. Girotti, M. R., Salatino, M., Dalotto-Moreno, T. & Rabinovich, G. A. Sweetening the hallmarks of cancer: galectins as multifunctional mediators of tumor progression. J. Exp. Med. 217, e20182041 (2020).

    Article  PubMed  Google Scholar 

  18. Navarro, P., Martínez-Bosch, N., Blidner, A. G. & Rabinovich, G. A. Impact of galectins in resistance to anticancer therapies. Clin. Cancer Res. 26, 6086–6101 (2020).

    Article  CAS  PubMed  Google Scholar 

  19. Loomba, R., Friedman, S. L. & Shulman, G. I. Mechanisms and disease consequences of nonalcoholic fatty liver disease. Cell 184, 2537–2564 (2021).

    Article  CAS  PubMed  Google Scholar 

  20. Xu, W.-D., Huang, Q. & Huang, A.-F. Emerging role of galectin family in inflammatory autoimmune diseases. Autoimmun. Rev. 20, 102847 (2021).

    Article  CAS  PubMed  Google Scholar 

  21. Slack, R. J., Mills, R. & Mackinnon, A. C. The therapeutic potential of galectin-3 inhibition in fibrotic disease. Int. J. Biochem. Cell Biol. 130, 105881 (2021).

    Article  CAS  PubMed  Google Scholar 

  22. Somogyi, V. et al. The therapy of idiopathic pulmonary fibrosis: what is next? Eur. Respir. Rev. 28, 190021 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Hirani, N. et al. Target-inhibition of galectin-3 by inhaled TD139 in patients with idiopathic pulmonary fibrosis. Eur. Respir. J. 57, 2002559 (2021). This study reports a phase I/IIa study of inhaled TD139 in healthy subjects and patients with IPF.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Mora, A. L., Rojas, M., Pardo, A. & Selman, M. Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease. Nat. Rev. Drug Discov. 16, 755–772 (2017).

    Article  CAS  PubMed  Google Scholar 

  25. Ge, X. N. et al. Regulation of eosinophilia and allergic airway inflammation by the glycan-binding protein galectin-1. Proc. Natl Acad. Sci. USA 113, E4837–E4846 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ge, X. N. et al. Allergen-induced airway remodeling is impaired in galectin-3–deficient mice. J. Immunol. 185, 1205–1214 (2010).

    Article  CAS  PubMed  Google Scholar 

  27. Morosi, L. G. et al. Control of intestinal inflammation by glycosylation-dependent lectin-driven immunoregulatory circuits. Sci. Adv. 7, eabf8630 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Martínez Allo, V. C. et al. Suppression of age-related salivary gland autoimmunity by glycosylation-dependent galectin-1driven immune inhibitory circuits. Proc. Natl Acad. Sci. USA 117, 6630–6639 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Sundblad, V. et al. Galectin-1 impacts on glucose homeostasis by modulating pancreatic insulin release. Glycobiology 31, 908–915 (2021).

    Article  CAS  PubMed  Google Scholar 

  30. Burguillos, M. A. et al. Microglia-secreted galectin-3 acts as a toll-like receptor 4 ligand and contributes to microglial activation. Cell Rep. 10, 1626–1638 (2015).

    Article  CAS  PubMed  Google Scholar 

  31. Starossom, S. C. et al. Galectin-1 deactivates classically activated microglia and protects from inflammation-induced neurodegeneration. Immunity 37, 249–263 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Seropian, I. M. et al. Galectin-1 controls cardiac inflammation and ventricular remodeling during acute myocardial infarction. Am. J. Pathol. 182, 29–40 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. MacKinnon, A. C. et al. Inhibition of galectin-3 reduces atherosclerosis in apolipoprotein E-deficient mice. Glycobiology 23, 654–663 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Roldán-Montero, R. et al. Galectin-1 prevents pathological vascular remodeling in atherosclerosis and abdominal aortic aneurysm. Sci. Adv. 8, eabm7322 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Russo, A. J. et al. Intracellular immune sensing promotes inflammation via gasdermin D-driven release of a lectin alarmin. Nat. Immunol. 22, 154–165 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ramhorst, R. E. et al. Galectin-1 confers immune privilege to human trophoblast: implications in recurrent fetal loss. Glycobiology 22, 1374–1386 (2012).

    Article  CAS  PubMed  Google Scholar 

  37. Barondes, S. H. et al. Galectins: a family of animal β-galactoside-binding lectins. Cell 76, 597–598 (1994).

    Article  CAS  PubMed  Google Scholar 

  38. Méndez-Huergo, S. P., Blidner, A. G. & Rabinovich, G. A. Galectins: emerging regulatory checkpoints linking tumor immunity and angiogenesis. Curr. Opin. Immunol. 45, 8–15 (2017).

    Article  PubMed  Google Scholar 

  39. Vasta, G. R. Roles of galectins in infection. Nat. Rev. Microbiol. 7, 424–438 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Thiemann, S. & Baum, L. G. Galectins and immune responses — just how do they do those things they do? Annu. Rev. Immunol. 34, 243–264 (2016).

    Article  CAS  PubMed  Google Scholar 

  41. Liu, F.-T. & Rabinovich, G. A. Galectins: regulators of acute and chronic inflammation. Ann. N. Y. Acad. Sci. 1183, 158–182 (2010).

    Article  CAS  PubMed  Google Scholar 

  42. Rabinovich, G. A. & Toscano, M. A. Turning ‘sweet’ on immunity: galectin–glycan interactions in immune tolerance and inflammation. Nat. Rev. Immunol. 9, 338–352 (2009).

    Article  CAS  PubMed  Google Scholar 

  43. Hirabayashi, J., Hashidate, T., Arata, Y. & Nishi, N. Oligosaccharide specificity of galectins: a search by frontal affinity chromatography. Biochim. Biophys. Acta 1572, 1–23 (2002).

    Google Scholar 

  44. Blixt, O. et al. Printed covalent glycan array for ligand profiling of diverse glycan binding proteins. Proc. Natl Acad. Sci. USA 101, 17033 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Shimura, T. et al. Galectin-3, a novel binding partner of β-catenin. Cancer Res. 64, 6363–6367 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Yang, R.-Y., Rabinovich, G. A. & Liu, F.-T. Galectins: structure, function and therapeutic potential. Expert Rev. Mol. Med. 10, e17 (2008).

    Article  PubMed  Google Scholar 

  47. Park, J. W., Voss, P. G., Grabski, S., Wang, J. L. & Patterson, R. J. Association of galectin-1 and galectin-3 with Gemin4 in complexes containing the SMN protein. Nucleic Acids Res. 29, 3595–3602 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Liu, F.-T., Patterson, R. J. & Wang, J. L. Intracellular functions of galectins. Biochim. Biophys. Acta Gen. Subj. 1572, 263–273 (2002).

    Article  CAS  Google Scholar 

  49. Fritsch, K. et al. Galectin-3 interacts with components of the nuclear ribonucleoprotein complex. BMC Cancer 16, 502 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Chen, H.-Y. et al. Galectin-3 negatively regulates TCR-mediated CD4+ T-cell activation at the immunological synapse. Proc. Natl Acad. Sci. USA 106, 14496–14501 (2009). This study highlights the intracellular role of GAL3 in limiting TCR-dependent T cell activation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Liu, W. et al. Galectin-3 regulates intracellular trafficking of EGFR through Alix and promotes keratinocyte migration. J. Invest. Dermatol. 132, 2828–2837 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Weng, I.-C. et al. Cytosolic galectin-3 and -8 regulate antibacterial autophagy through differential recognition of host glycans on damaged phagosomes. Glycobiology 28, 392–405 (2018).

    Article  CAS  PubMed  Google Scholar 

  53. Hong, M.-H., Weng, I.-C., Li, F.-Y., Lin, W.-H. & Liu, F.-T. Intracellular galectins sense cytosolically exposed glycans as danger and mediate cellular responses. J. Biomed. Sci. 28, 16 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Nabi, I. R., Shankar, J. & Dennis, J. W. The galectin lattice at a glance. J. Cell Sci. 128, 2213–2219 (2015).

    Article  CAS  PubMed  Google Scholar 

  55. Rabinovich, G. A., Toscano, M. A., Jackson, S. S. & Vasta, G. R. Functions of cell surface galectin-glycoprotein lattices. Curr. Opin. Struct. Biol. 17, 513–520 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Blenda, A. V. et al. Galectin-9 recognizes and exhibits antimicrobial activity toward microbes expressing blood group–like antigens. J. Biol. Chem. 298, 101704 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Wu, S.-C. et al. Full-length galectin-3 is required for high affinity microbial interactions and antimicrobial activity. Front. Microbiol. 12, 731026 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Dennis, J. W. & Brewer, C. F. Density-dependent lectin-glycan interactions as a paradigm for conditional regulation by posttranslational modifications. Mol. Cell. Proteom. 12, 913–920 (2013).

    Article  CAS  Google Scholar 

  59. Nielsen, M. I. et al. Galectin binding to cells and glycoproteins with genetically modified glycosylation reveals galectin–glycan specificities in a natural context. J. Biol. Chem. 293, 20249–20262 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Johannes, L., Jacob, R. & Leffler, H. Galectins at a glance. J. Cell Sci. 131, jcs208884 (2018).

    Article  PubMed  Google Scholar 

  61. Mereiter, S., Balmaña, M., Campos, D., Gomes, J. & Reis, C. A. Glycosylation in the era of cancer-targeted therapy: where are we heading? Cancer Cell 36, 6–16 (2019).

    Article  CAS  PubMed  Google Scholar 

  62. Okoye, I. et al. Galectin-9 expression defines exhausted T cells and impaired cytotoxic NK cells in patients with virus-associated solid tumors. J. Immunother. Cancer 8, e001849 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Henderson, N. C. & Sethi, T. The regulation of inflammation by galectin-3. Immunol. Rev. 230, 160–171 (2009).

    Article  CAS  PubMed  Google Scholar 

  64. Liu, F.-T. & Rabinovich, G. A. Galectins as modulators of tumour progression. Nat. Rev. Cancer 5, 29–41 (2005).

    Article  CAS  PubMed  Google Scholar 

  65. Thijssen, V. L., Heusschen, R., Caers, J. & Griffioen, A. W. Galectin expression in cancer diagnosis and prognosis: a systematic review. Biochim. Biophys. Acta Rev. Cancer 1855, 235–247 (2015).

    Article  CAS  Google Scholar 

  66. Veschi, V. et al. Galectin-3 is a marker of favorable prognosis and a biologically relevant molecule in neuroblastic tumors. Cell Death Dis. 5, e1100 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Lahm, H. et al. Comprehensive galectin fingerprinting in a panel of 61 human tumor cell lines by RT-PCR and its implications for diagnostic and therapeutic procedures. J. Cancer Res. Clin. Oncol. 127, 375–386 (2001).

    Article  CAS  PubMed  Google Scholar 

  68. Partridge, E. A. et al. Regulation of cytokine receptors by golgi N-glycan processing and endocytosis. Science 306, 120–124 (2004). This study emphasizes the role of galectin–glycan interactions in modulating retention and endocytosis of N-glycosylated receptors.

    Article  CAS  PubMed  Google Scholar 

  69. Perrotta, R. M., Bach, C. A., Salatino, M. & Rabinovich, G. A. Reprogramming the tumor metastasis cascade by targeting galectin-driven networks. Biochem. J. 478, 597–617 (2021).

    Article  CAS  PubMed  Google Scholar 

  70. Reticker-Flynn, N. E. & Bhatia, S. N. Aberrant glycosylation promotes lung cancer metastasis through adhesion to galectins in the metastatic niche. Cancer Discov. 5, 168–181 (2015).

    Article  CAS  PubMed  Google Scholar 

  71. Nakajima, K. et al. Galectin-3 cleavage alters bone remodeling: different outcomes in breast and prostate cancer skeletal metastasis. Cancer Res. 76, 1391–1402 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Bacigalupo, M. L. et al. Galectin-1 triggers epithelial-mesenchymal transition in human hepatocellular carcinoma cells. J. Cell. Physiol. 230, 1298–1309 (2015).

    Article  CAS  PubMed  Google Scholar 

  73. Zhu, J. et al. Galectin-1 induces metastasis and epithelial-mesenchymal transition (EMT) in human ovarian cancer cells via activation of the MAPK JNK/p38 signalling pathway. Am. J. Transl. Res. 11, 3862–3878 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Nangia-Makker, P., Hogan, V. & Raz, A. Galectin-3 and cancer stemness. Glycobiology 28, 172–181 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Chong, Y. et al. Galectin-1 induces invasion and the epithelial-mesenchymal transition in human gastric cancer cells via non-canonical activation of the hedgehog signaling pathway. Oncotarget 7, 50 (2016).

    Article  Google Scholar 

  76. Zhang, P.-F. et al. Galectin-1 induces hepatocellular carcinoma EMT and sorafenib resistance by activating FAK/PI3K/AKT signaling. Cell Death Dis. 7, e2201–e2201 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Carabias, P. et al. Galectin-1 confers resistance to doxorubicin in hepatocellular carcinoma cells through modulation of P-glycoprotein expression. Cell Death Dis. 13, 79 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Orozco, C. A. et al. Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor–stroma crosstalk. Proc. Natl Acad. Sci. USA 115, 3769–3778 (2018).

    Article  Google Scholar 

  79. Shih, T.-C. et al. Targeting galectin-1 impairs castration-resistant prostate cancer progression and invasion. Clin. Cancer Res. 24, 4319–4331 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Piyush, T. et al. Interaction of galectin-3 with MUC1 on cell surface promotes EGFR dimerization and activation in human epithelial cancer cells. Cell Death Differ. 24, 1937–1947 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Mori, Y. et al. Binding of galectin-3, a β-galactoside-binding lectin, to MUC1 protein enhances phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt, promoting tumor cell malignancy. J. Biol. Chem. 290, 26125–26140 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Murugaesu, N. et al. An in vivo functional screen identifies ST6GalNAc2 sialyltransferase as a breast cancer metastasis suppressor. Cancer Discov. 4, 304–317 (2014).

    Article  CAS  PubMed  Google Scholar 

  83. Wang, L.-P., Chen, S.-W., Zhuang, S.-M., Li, H. & Song, M. Galectin-3 accelerates the progression of oral tongue squamous cell carcinoma via a Wnt/β-catenin-dependent pathway. Pathol. Oncol. Res. 19, 461–474 (2013).

    Article  PubMed  Google Scholar 

  84. Seguin, L. et al. Galectin-3, a druggable vulnerability for KRAS-addicted cancers. Cancer Discov. 7, 1464–1479 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Hsu, D. K., Yang, R.-Y., Saegusa, J. & Liu, F.-T. Analysis of the intracellular role of galectins in cell growth and apoptosis. Methods Mol. Biol. 1207, 451–463 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Belanis, L., Plowman, S. J., Rotblat, B., Hancock, J. F. & Kloog, Y. Galectin-1 is a novel structural component and a major regulator of h-ras nanoclusters. Mol. Biol. Cell 19, 1404–1414 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Paz, A., Haklai, R., Elad-Sfadia, G., Ballan, E. & Kloog, Y. Galectin-1 binds oncogenic H-Ras to mediate Ras membrane anchorage and cell transformation. Oncogene 20, 7486–7493 (2001). This work documents the intracellular role of GAL1 in mediating cellular tumorigenesis by interacting with oncogenic HRAS.

    Article  CAS  PubMed  Google Scholar 

  88. Elad-Sfadia, G., Haklai, R., Balan, E. & Kloog, Y. Galectin-3 augments K-Ras activation and triggers a Ras signal that attenuates ERK but not phosphoinositide 3-kinase activity. J. Biol. Chem. 279, 34922–34930 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. Wu, K.-L. et al. Overexpression of galectin-3 enhances migration of colon cancer cells related to activation of the K-Ras–Raf–Erk1/2 pathway. J. Gastroenterol. 48, 350–359 (2013).

    Article  CAS  PubMed  Google Scholar 

  90. Menachem, A., Bodner, O., Pastor, J., Raz, A. & Kloog, Y. Inhibition of malignant thyroid carcinoma cell proliferation by Ras and galectin-3 inhibitors. Cell Death Discov. 1, 15047 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Stiasny, A. et al. The involvement of E6, p53, p16, MDM2 and Gal-3 in the clinical outcome of patients with cervical cancer. Oncol. Lett. 14, 4467–4476 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Nambiar, D. K. et al. Galectin-1–driven T cell exclusion in the tumor endothelium promotes immunotherapy resistance. J. Clin. Invest. 129, 5553–5567 (2019). This study identifies a role of GAL1 in promoting T cell exclusion and modulating resistance to anti-PD1 immunotherapy in HNSCC.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Kuo, P. et al. Galectin-1 mediates radiation-related lymphopenia and attenuates NSCLC radiation response. Clin. Cancer Res. 20, 5558–5569 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Tseng, P.-C., Chen, C.-L., Shan, Y.-S. & Lin, C.-F. An increase in galectin-3 causes cellular unresponsiveness to IFN-γ-induced signal transduction and growth inhibition in gastric cancer cells. Oncotarget 7, 15150–15160 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Carmeliet, P. & Jain, R. K. Molecular mechanisms and clinical applications of angiogenesis. Nature 473, 298–307 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Thijssen, V. L., Rabinovich, G. A. & Griffioen, A. W. Vascular galectins: regulators of tumor progression and targets for cancer therapy. Cytokine Growth Factor. Rev. 24, 547–558 (2013).

    Article  CAS  PubMed  Google Scholar 

  97. Thijssen, V. L. et al. Tumor cells secrete galectin-1 to enhance endothelial cell activity. Cancer Res. 70, 6216–6224 (2010).

    Article  CAS  PubMed  Google Scholar 

  98. Croci, D. O. et al. Disrupting galectin-1 interactions with N-glycans suppresses hypoxia-driven angiogenesis and tumorigenesis in Kaposi’s sarcoma. J. Exp. Med. 209, 1985–2000 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Astorgues-Xerri, L. et al. OTX008, a selective small-molecule inhibitor of galectin-1, downregulates cancer cell proliferation, invasion and tumour angiogenesis. Eur. J. Cancer 50, 2463–2477 (2014).

    Article  CAS  PubMed  Google Scholar 

  100. van Beijnum, J. R. et al. A key role for galectin-1 in sprouting angiogenesis revealed by novel rationally designed antibodies. Int. J. Cancer 139, 824–835 (2016).

    Article  PubMed  Google Scholar 

  101. Laderach, D. J. et al. A unique galectin signature in human prostate cancer progression suggests galectin-1 as a key target for treatment of advanced disease. Cancer Res. 73, 86–96 (2013).

    Article  CAS  PubMed  Google Scholar 

  102. Hsieh, S. H. et al. Galectin-1, a novel ligand of neuropilin-1, activates VEGFR-2 signaling and modulates the migration of vascular endothelial cells. Oncogene 27, 3746–3753 (2008).

    Article  CAS  PubMed  Google Scholar 

  103. Wu, M.-H. et al. Galectin-1 induces vascular permeability through the neuropilin-1/vascular endothelial growth factor receptor-1 complex. Angiogenesis 17, 839–849 (2014).

    Article  CAS  PubMed  Google Scholar 

  104. Wei, J., Li, D. K., Hu, X., Cheng, C. & Zhang, Y. Galectin-1–RNA interaction map reveals potential regulatory roles in angiogenesis. FEBS Lett. 595, 623–636 (2021).

    Article  CAS  PubMed  Google Scholar 

  105. Markowska, A. I., Jefferies, K. C. & Panjwani, N. Galectin-3 protein modulates cell surface expression and activation of vascular endothelial growth factor receptor 2 in human endothelial cells. J. Biol. Chem. 286, 29913–29921 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Markowska, A. I., Liu, F.-T. & Panjwani, N. Galectin-3 is an important mediator of VEGF- and bFGF-mediated angiogenic response. J. Exp. Med. 207, 1981–1993 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Nangia-Makker, P. et al. Cleavage of galectin-3 by matrix metalloproteases induces angiogenesis in breast cancer. Int. J. Cancer 127, 2530–2541 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Heusschen, R., Schulkens, I. A., van Beijnum, J., Griffioen, A. W. & Thijssen, V. L. Endothelial LGALS9 splice variant expression in endothelial cell biology and angiogenesis. Biochim. Biophys. Acta Mol. Basis Dis. 1842, 284–292 (2014).

    Article  CAS  Google Scholar 

  109. Aanhane, E. et al. Different angioregulatory activity of monovalent galectin-9 isoforms. Angiogenesis 21, 545–555 (2018).

    Article  CAS  PubMed  Google Scholar 

  110. Colomb, F. et al. Galectin-3 interacts with the cell-surface glycoprotein CD146 (MCAM, MUC18) and induces secretion of metastasis-promoting cytokines from vascular endothelial cells. J. Biol. Chem. 292, 8381–8389 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Chen, C. et al. Increased circulation of galectin-3 in cancer induces secretion of metastasis-promoting cytokines from blood vascular endothelium. Clin. Cancer Res. 19, 1693–1704 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Liebscher, L. et al. A minigene DNA vaccine encoding peptide epitopes derived from Galectin-1 has protective antitumoral effects in a model of neuroblastoma. Cancer Lett. 509, 105–114 (2021).

    Article  CAS  PubMed  Google Scholar 

  113. Shah, D. et al. A novel miR1983-TLR7-IFNβ circuit licenses NK cells to kill glioma cells, and is under the control of galectin-1. Oncoimmunology 10, 1939601 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Juszczynski, P. et al. The AP1-dependent secretion of galectin-1 by Reed-Sternberg cells fosters immune privilege in classical Hodgkin lymphoma. Proc. Natl Acad. Sci. USA 104, 13134–13139 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Croci, D. O. & Rabinovich, G. A. Linking tumor hypoxia with VEGFR2 signaling and compensatory angiogenesis: glycans make the difference. Oncoimmunology 3, e29380 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Rutkowski, M. R. et al. Microbially driven TLR5-dependent signaling governs distal malignant progression through tumor-promoting inflammation. Cancer Cell 27, 27–40 (2015).

    Article  CAS  PubMed  Google Scholar 

  117. Tiraboschi, C. et al. Combining inhibition of galectin-3 with and before a therapeutic vaccination is critical for the prostate-tumor-free outcome. J. Immunother. Cancer 8, e001535 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  118. de Mingo Pulido, Á. et al. The inhibitory receptor TIM-3 limits activation of the cGAS-STING pathway in intra-tumoral dendritic cells by suppressing extracellular DNA uptake. Immunity 54, 1154–1167 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Elola, M. T. et al. Galectins: multitask signaling molecules linking fibroblast, endothelial and immune cell programs in the tumor microenvironment. Cell. Immunol. 333, 34–45 (2018).

    Article  CAS  PubMed  Google Scholar 

  120. Ilarregui, J. M. et al. Tolerogenic signals delivered by dendritic cells to T cells through a galectin-1-driven immunoregulatory circuit involving interleukin 27 and interleukin 10. Nat. Immunol. 10, 981–991 (2009).

    Article  CAS  PubMed  Google Scholar 

  121. Tesone, A. J. et al. Satb1 overexpression drives tumor-promoting activities in cancer-associated dendritic cells. Cell Rep. 14, 1774–1786 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Sturgill, E. R. et al. Galectin-3 inhibition with belapectin combined with anti-OX40 therapy reprograms the tumor microenvironment to favor anti-tumor immunity. Oncoimmunology 10, 1892265 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  123. MacKinnon, A. C. et al. Regulation of alternative macrophage activation by galectin-3. J. Immunol. 180, 2650–2658 (2008).

    Article  CAS  PubMed  Google Scholar 

  124. Daley, D. et al. Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance. Nat. Med. 23, 556–567 (2017). This study reports the role of GAL9 as a relevant immunotherapeutic target in pancreatic adenocarcinoma by reprogramming macrophage function.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Dalotto-Moreno, T. et al. Targeting galectin-1 overcomes breast cancer-associated immunosuppression and prevents metastatic disease. Cancer Res. 73, 1107–1117 (2013).

    Article  CAS  PubMed  Google Scholar 

  126. Cagnoni, A. J. et al. Galectin-1 fosters an immunosuppressive microenvironment in colorectal cancer by reprogramming CD8+ regulatory T cells. Proc. Natl Acad. Sci. USA 118, e2102950118 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Pang, N. et al. Activated galectin-9/Tim3 promotes Treg and suppresses Th1 effector function in chronic lymphocytic leukemia. FASEB J. 35, e21556 (2021).

    Article  CAS  PubMed  Google Scholar 

  128. Rubinstein, N. et al. Targeted inhibition of galectin-1 gene expression in tumor cells results in heightened T cell-mediated rejection: a potential mechanism of tumor-immune privilege. Cancer Cell 5, 241–251 (2004). This study identifies the role of GAL1 in tumour cell evasion of immune responses in human and mouse melanoma.

    Article  CAS  PubMed  Google Scholar 

  129. Banh, A. et al. Tumor galectin-1 mediates tumor growth and metastasis through regulation of T-cell apoptosis. Cancer Res. 71, 4423–4431 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Liu, S. D. et al. Galectin-1 tunes TCR binding and signal transduction to regulate CD8 burst size. J. Immunol. 182, 5283–5295 (2009).

    Article  CAS  PubMed  Google Scholar 

  131. Stillman, B. N. et al. Galectin-3 and galectin-1 bind distinct cell surface glycoprotein receptors to induce T cell death. J. Immunol. 176, 778–789 (2006).

    Article  CAS  PubMed  Google Scholar 

  132. Toscano, M. A. et al. Differential glycosylation of TH1, TH2 and TH-17 effector cells selectively regulates susceptibility to cell death. Nat. Immunol. 8, 825–834 (2007).

    Article  CAS  PubMed  Google Scholar 

  133. Yang, R. et al. Galectin-9 interacts with PD-1 and TIM-3 to regulate T cell death and is a target for cancer immunotherapy. Nat. Commun. 12, 832 (2021). This study unveils the role of GAL9 in cancer immunotherapy by interacting with PD1 and TIM3 immune checkpoints on T cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Cedeno-Laurent, F., Opperman, M., Barthel, S. R., Kuchroo, V. K. & Dimitroff, C. J. Galectin-1 triggers an immunoregulatory signature in Th cells functionally defined by IL-10 expression. J. Immunol. 188, 3127–3137 (2012).

    Article  CAS  PubMed  Google Scholar 

  135. Baker, G. J. et al. Natural killer cells eradicate galectin-1-deficient glioma in the absence of adaptive immunity. Cancer Res. 74, 5079–5090 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Zhang, C. et al. Galectin-9 promotes a suppressive microenvironment in human cancer by enhancing STING degradation. Oncogenesis 9, 65 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Gordon-Alonso, M., Hirsch, T., Wildmann, C. & van der Bruggen, P. Galectin-3 captures interferon-gamma in the tumor matrix reducing chemokine gradient production and T-cell tumor infiltration. Nat. Commun. 8, 793 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Demotte, N. et al. A galectin-3 ligand corrects the impaired function of human CD4 and CD8 tumor-infiltrating lymphocytes and favors tumor rejection in mice. Cancer Res. 70, 7476–7488 (2010). This study highlights the importance of targeting GAL3 to prevent T cell anergy and promote tumour rejection.

    Article  CAS  PubMed  Google Scholar 

  139. Kouo, T. et al. Galectin-3 shapes antitumor immune responses by suppressing CD8+ T cells via LAG-3 and inhibiting expansion of plasmacytoid dendritic cells. Cancer Immunol. Res. 3, 412–423 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Lau, K. S. et al. Complex N-glycan number and degree of branching cooperate to regulate cell proliferation and differentiation. Cell 129, 123–134 (2007).

    Article  CAS  PubMed  Google Scholar 

  141. Zhu, C. et al. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat. Immunol. 6, 1245–1252 (2005).

    Article  CAS  PubMed  Google Scholar 

  142. Henderson, N. C. et al. Galectin-3 regulates myofibroblast activation and hepatic fibrosis. Proc. Natl Acad. Sci. USA 103, 5060–5065 (2006). This article underscores the relevance of GAL3 as a therapeutic target in liver fibrosis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Iacobini, C. et al. Galectin-3 ablation protects mice from diet-induced NASH: a major scavenging role for galectin-3 in liver. J. Hepatol. 54, 975–983 (2011).

    Article  CAS  PubMed  Google Scholar 

  144. Hsieh, T. J. et al. Dual thio-digalactoside-binding modes of human galectins as the structural basis for the design of potent and selective inhibitors. Sci. Rep. 6, 29457 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Mackinnon, A. C. et al. Regulation of transforming growth factor-β1-driven lung fibrosis by galectin-3. Am. J. Respir. Crit. Care Med. 185, 537–546 (2012). This study validates the use of GAL3 inhibitors in lung fibrosis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Henderson, N. C. et al. Galectin-3 expression and secretion links macrophages to the promotion of renal fibrosis. Am. J. Pathol. 172, 288–298 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Argüeso, P., Mauris, J. & Uchino, Y. Galectin-3 as a regulator of the epithelial junction: Implications to wound repair and cancer. Tissue Barriers 3, e1026505–e1026505 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  148. Kasper, M. & HUghes, R. C. Immunochemical evidence for a modulation of galectin-3 (Mac-2), a carbohydrate binding protein, in pulmonary fibrosis. J. Pathol. 179, 309–316 (1996).

    Article  CAS  PubMed  Google Scholar 

  149. Fichtner-Feigl, S., Strober, W., Kawakami, K., Puri, R. K. & Kitani, A. IL-13 signaling through the IL-13α2 receptor is involved in induction of TGF-β1 production and fibrosis. Nat. Med. 12, 99–106 (2006).

    Article  CAS  PubMed  Google Scholar 

  150. Liu, J. C., Heilshorn, S. C. & Tirrell, D. A. Comparative cell response to artificial extracellular matrix proteins containing the RGD and CS5 cell-binding domains. Biomacromolecules 5, 497–504 (2004).

    Article  CAS  PubMed  Google Scholar 

  151. Rishikof, D. C., Ricupero, D. A., Kuang, P.-P., Liu, H. & Goldstein, R. H. Interleukin-4 regulates connective tissue growth factor expression in human lung fibroblasts. J. Cell. Biochem. 85, 496–504 (2002).

    Article  CAS  PubMed  Google Scholar 

  152. Jiang, Z. et al. Galectin-1 gene silencing inhibits the activation and proliferation but induces the apoptosis of hepatic stellate cells from mice with liver fibrosis. Int. J. Mol. Med. 43, 103–116 (2019).

    CAS  PubMed  Google Scholar 

  153. Hsu, Y.-A. et al. Amelioration of bleomycin-induced pulmonary fibrosis via TGF-β-induced Smad and non-Smad signaling pathways in galectin-9-deficient mice and fibroblast cells. J. Biomed. Sci. 27, 24 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Kathiriya, J. J. et al. Galectin-1 inhibition attenuates profibrotic signaling in hypoxia-induced pulmonary fibrosis. Cell Death Discov. 3, 17010 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Fujita, K. et al. Correlation between serum galectin-9 levels and liver fibrosis. J. Gastroenterol. Hepatol. 33, 492–499 (2018).

    Article  CAS  PubMed  Google Scholar 

  156. Wu, M.-H. et al. Glycosylation-dependent galectin-1/neuropilin-1 interactions promote liver fibrosis through activation of TGF-β- and PDGF-like signals in hepatic stellate cells. Sci. Rep. 7, 11006 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  157. Jin Lim, M. et al. Induction of galectin-1 by TGF-β1 accelerates fibrosis through enhancing nuclear retention of Smad2. Exp. Cell Res. 326, 125–135 (2014).

    Article  CAS  Google Scholar 

  158. Matsumoto, N. et al. A possible role of galectin-9 in the pulmonary fibrosis of patients with interstitial pneumonia. Lung 191, 191–198 (2013).

    Article  CAS  PubMed  Google Scholar 

  159. Modenutti, C. P., Capurro, J. I. B., Di Lella, S. & Martí, M. A. The structural biology of galectin-ligand recognition: current advances in modeling tools, protein engineering, and inhibitor design. Front. Chem. 7, 823 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Leffler, H. & Nilsson, U. J. In Galectins and Disease Implications for Targeted Therapeutics vol. 1115, 2–47 (American Chemical Society, 2012).

  161. Tejler, J., Salameh, B., Leffler, H. & Nilsson, U. J. Fragment-based development of triazole-substituted O-galactosyl aldoximes with fragment-induced affinity and selectivity for galectin-3. Org. Biomol. Chem. 7, 3982–3990 (2009).

    Article  CAS  PubMed  Google Scholar 

  162. Rajput, V. K., Leffler, H., Nilsson, U. J. & Mukhopadhyay, B. Synthesis and evaluation of iminocoumaryl and coumaryl derivatized glycosides as galectin antagonists. Bioorg. Med. Chem. Lett. 24, 3516–3520 (2014).

    Article  CAS  PubMed  Google Scholar 

  163. Blanchard, H., Bum-Erdene, K. & Hugo, M. W. Inhibitors of galectins and implications for structure-based design of galectin-specific therapeutics. Aust. J. Chem. 67, 1763–1779 (2014).

    Article  CAS  Google Scholar 

  164. Mackinnon, A. et al. In Carbohydrates as Drugs (eds Seeberger, P. H. & Rademacher, C.) 95–121 (Springer International Publishing, 2014).

  165. Cagnoni, A. J., Kovensky, J. & Uhrig, M. L. Design and synthesis of hydrolytically stable multivalent ligands bearing thiodigalactoside analogues for peanut lectin and human galectin-3 binding. J. Org. Chem. 79, 6456–6467 (2014).

    Article  CAS  PubMed  Google Scholar 

  166. Liu, C. et al. Identification of monosaccharide derivatives as potent, selective, and orally bioavailable inhibitors of human and mouse galectin-3. J. Med. Chem. 65, 11084–11099 (2022).

    Article  CAS  PubMed  Google Scholar 

  167. Zetterberg, F. R. et al. Monosaccharide derivatives with low-nanomolar lectin affinity and high selectivity based on combined fluorine–amide, phenyl–arginine, sulfur–π, and halogen bond interactions. ChemMedChem 13, 133–137 (2018).

    Article  CAS  PubMed  Google Scholar 

  168. Vuong, L. et al. An orally active galectin-3 antagonist inhibits lung adenocarcinoma growth and augments response to PD-L1 blockade. Cancer Res. 79, 1480–1493 (2019).

    Article  CAS  PubMed  Google Scholar 

  169. Kim, S.-J. et al. Crosstalk between WNT and STAT3 is mediated by galectin-3 in tumor progression. Gastric Cancer 24, 1050–1062 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Dahlqvist, A., Zetterberg, F. R., Leffler, H. & Nilsson, U. J. Aminopyrimidine–galactose hybrids are highly selective galectin-3 inhibitors. MedChemComm 10, 913–925 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Jalagam, P. R., Nair, S. K., Panda, M. & Regueiro-Ren, A. Small molecule inhibitors of galectin-3. Patent no. WO2019075045A1 (2022).

  172. Bolli, M. et al. Alpha-d-galactopyranoside derivatives. Patent no. WO2021038068A1 (2021).

  173. Brimert, T., Johnsson, R., Leffler, H., Nilsson, U. & Zetterberg, F. Alpha-d-galactoside inhibitors of galectins. Patent no. WO2016120403A1 (2016).

  174. Zetterberg, F. R. et al. Discovery and optimization of the first highly effective and orally available galectin-3 inhibitors for treatment of fibrotic disease. J. Med. Chem. 65, 12626–12638 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Tonev, D. et al. Gulliver-2 is an innovative, hybrid, hepatic impairment trial of the oral galectin-3 inhibitor GB1211 [abstract 3627]. Hepatology 76, S1146–S1147 (2022).

    Google Scholar 

  176. Lindmark, B. GB1211, An oral galectin-3 inhibitor, in decompensated cirrhotic patients: initial findings from the phase 2 randomized, placebo-controlled Gulliver-2 trial [abstract]. Presented at the The Liver Meeting, AASLD (2022).

  177. Tejler, J., Skogman, F., Leffler, H. & Nilsson, U. J. Synthesis of galactose-mimicking 1H-(1,2,3-triazol-1-yl)-mannosides as selective galectin-3 and 9N inhibitors. Carbohydr. Res. 342, 1869–1875 (2007).

    Article  CAS  PubMed  Google Scholar 

  178. Öberg, C. T., Leffler, H. & Nilsson, U. J. Arginine binding motifs: design and synthesis of galactose-derived arginine tweezers as galectin-3 inhibitors. J. Med. Chem. 51, 2297–2301 (2008).

    Article  PubMed  Google Scholar 

  179. Öberg, C. T., Noresson, A.-L., Leffler, H. & Nilsson, U. J. Arene–anion based arginine-binding motif on a galactose scaffold: structure–activity relationships of interactions with arginine-rich galectins. Chemistry 17, 8139–8144 (2011).

    Article  PubMed  Google Scholar 

  180. Collins, P. M., Öberg, C. T., Leffler, H., Nilsson, U. J. & Blanchard, H. Taloside inhibitors of galectin-1 and galectin-3. Chem. Biol. Drug Des. 79, 339–346 (2012).

    Article  CAS  PubMed  Google Scholar 

  181. Masuyer, G. et al. Inhibition mechanism of human galectin-7 by a novel galactose-benzylphosphate inhibitor. FEBS J. 279, 193–202 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Pal, K. B., Mahanti, M., Leffler, H. & Nilsson, U. J. A galactoside-binding protein tricked into binding unnatural pyranose derivatives: 3-deoxy-3-methyl-gulosides selectively inhibit galectin-1. Int. J. Mol. Sci. 20, 3786–3808 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Mahanti, M., Pal, K. B., Sundin, A. P., Leffler, H. & Nilsson, U. J. Epimers switch galectin-9 domain selectivity: 3N-aryl galactosides bind the C-terminal and gulosides bind the N-terminal. ACS Med. Chem. Lett. 11, 34–39 (2020).

    Article  CAS  PubMed  Google Scholar 

  184. Barondes, S. H., Cooper, D. N., Gitt, M. A. & Leffler, H. Galectins. Structure and function of a large family of animal lectins. J. Biol. Chem. 269, 20807–20810 (1994). This pioneering review provides a first definition of galectins and their glycan binding specificities and summarizes early studies on structure–function relationship.

    Article  CAS  PubMed  Google Scholar 

  185. Sörme, P. et al. Structural and thermodynamic studies on cation-Pi interactions in lectin-ligand complexes: high-affinity galectin-3 inhibitors through fine-tuning of an arginine-arene interaction. J. Am. Chem. Soc. 127, 1737–1743 (2005).

    Article  PubMed  Google Scholar 

  186. Campo, V. L., Marchiori, M. F., Rodrigues, L. C. & Dias-Baruffi, M. Synthetic glycoconjugates inhibitors of tumor-related galectin-3: an update. Glycoconj. J. 33, 853–876 (2016).

    Article  CAS  PubMed  Google Scholar 

  187. Rabinovich, G. A. et al. Synthetic lactulose amines: novel class of anticancer agents that induce tumor-cell apoptosis and inhibit galectin-mediated homotypic cell aggregation and endothelial cell morphogenesis. Glycobiology 16, 210–220 (2006).

    Article  CAS  PubMed  Google Scholar 

  188. Kishor, C., Ross, R. L. & Blanchard, H. Lactulose as a novel template for anticancer drug development targeting galectins. Chem. Biol. Drug Des. 92, 1801–1808 (2018).

    Article  CAS  PubMed  Google Scholar 

  189. Delaine, T. et al. Galectin-inhibitory thiodigalactoside ester derivatives have antimigratory effects in cultured lung and prostate cancer cells. J. Med. Chem. 51, 8109–8114 (2008).

    Article  CAS  PubMed  Google Scholar 

  190. Cumpstey, I., Carlsson, S., Leffler, H. & Nilsson, U. J. Synthesis of a phenyl thio-β-d-galactopyranoside library from 1,5-difluoro-2,4-dinitrobenzene: discovery of efficient and selective monosaccharide inhibitors of galectin-7. Org. Biomol. Chem. 3, 1922–1932 (2005).

    Article  CAS  PubMed  Google Scholar 

  191. Cumpstey, I., Salomonsson, E., Sundin, A., Leffler, H. & Nilsson, U. J. Double affinity amplification of galectin–ligand interactions through arginine–arene interactions: synthetic, thermodynamic, and computational studies with aromatic diamido thiodigalactosides. Chemistry 14, 4233–4245 (2008).

    Article  CAS  PubMed  Google Scholar 

  192. Lin, C.-I. et al. Galectin-3 targeted therapy with a small molecule inhibitor activates apoptosis and enhances both chemosensitivity and radiosensitivity in papillary thyroid cancer. Mol. Cancer Res. 7, 1655–1662 (2009).

    Article  CAS  PubMed  Google Scholar 

  193. Vašíček, T. et al. Regioselective 3-O-substitution of unprotected thiodigalactosides: direct route to galectin inhibitors. Chemistry 26, 9620–9631 (2020).

    Article  PubMed  Google Scholar 

  194. Delaine, T. et al. Galectin-3-binding glycomimetics that strongly reduce bleomycin-induced lung fibrosis and modulate intracellular glycan recognition. ChemBioChem 17, 1759–1770 (2016).

    Article  CAS  PubMed  Google Scholar 

  195. Bratteby, K. et al. In vivo veritas: 18F-radiolabeled glycomimetics allow insights into the pharmacological fate of galectin-3 inhibitors. J. Med. Chem. 63, 747–755 (2020). The pharmacokinetics for TD139 and GB1107 surrogate radiotracers is discussed, providing a rationale on different administration routes and efficacy of individual galectin inhibitors.

    Article  CAS  PubMed  Google Scholar 

  196. Hattum, H. Van et al. Tuning the preference of thiodigalactoside- and lactosamine-based ligands to galectin-3 over galectin-1. J. Med. Chem. 56, 1350–1354 (2013). This study reports the design of small molecules, based on TDG or lactosamine, with different selectivity for GAL3 and GAL1.

    Article  PubMed  Google Scholar 

  197. Rajput, V. K. et al. A selective galactose-coumarin-derived galectin-3 inhibitor demonstrates involvement of galectin-3-glycan interactions in a pulmonary fibrosis model. J. Med. Chem. 59, 8141–8147 (2016).

    Article  CAS  PubMed  Google Scholar 

  198. Xu, L. et al. Synthesis, structure–activity relationships, and in vivo evaluation of novel tetrahydropyran-based thiodisaccharide mimics as galectin-3 inhibitors. J. Med. Chem. 64, 6634–6655 (2021).

    Article  CAS  PubMed  Google Scholar 

  199. Cecioni, S., Imberty, A. & Vidal, S. Glycomimetics versus multivalent glycoconjugates for the design of high affinity lectin ligands. Chem. Rev. 115, 525–561 (2015).

    Article  CAS  PubMed  Google Scholar 

  200. André, S., Kaltner, H., Furuike, T., Nishimura, S.-I. & Gabius, H.-J. Persubstituted cyclodextrin-based glycoclusters as inhibitors of protein−carbohydrate recognition using purified plant and mammalian lectins and wild-type and lectin-gene-transfected tumor cells as targets. Bioconjug. Chem. 15, 87–98 (2004).

    Article  PubMed  Google Scholar 

  201. André, S. et al. Calix[n]arene-based glycoclusters: bioactivity of thiourea-linked galactose/lactose moieties as inhibitors of binding of medically relevant lectins to a glycoprotein and cell-surface glycoconjugates and selectivity among human adhesion/growth-regulatory G. ChemBioChem 9, 1649–1661 (2008).

    Article  PubMed  Google Scholar 

  202. Gouin, S. G. et al. Multimeric lactoside “Click Clusters” as tools to investigate the effect of linker length in specific interactions with peanut lectin, galectin-1, and -3. ChemBioChem 11, 1430–1442 (2010).

    Article  CAS  PubMed  Google Scholar 

  203. Ennist, J. H., Termuehlen, H. R., Bernhard, S. P., Fricke, M. S. & Cloninger, M. J. Chemoenzymatic synthesis of galectin binding glycopolymers. Bioconjug. Chem. 29, 4030–4039 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Böcker, S., Laaf, D. & Elling, L. Galectin binding to neo-glycoproteins: LacDiNAc conjugated BSA as ligand for human galectin-3. Biomolecules 5, 1671–1696 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  205. Zhang, H., Laaf, D., Elling, L. & Pieters, R. J. Thiodigalactoside-bovine serum albumin conjugates as high-potency inhibitors of galectin-3: an outstanding example of multivalent presentation of small molecule inhibitors. Bioconjug. Chem. 29, 1266–1275 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Guha, P. et al. Cod glycopeptide with picomolar affinity to galectin-3 suppresses T-cell apoptosis and prostate cancer metastasis. Proc. Natl Acad. Sci. USA 110, 5052–5057 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Wang, H. et al. Design and synthesis of glycoprotein-based multivalent glyco-ligands for influenza hemagglutinin and human galectin-3. Bioorg. Med. Chem. 21, 2037–2044 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Heine, V. et al. Immunoprotective neo-glycoproteins: chemoenzymatic synthesis of multivalent glycomimetics for inhibition of cancer-related galectin-3. Eur. J. Med. Chem. 220, 113500 (2021).

    Article  CAS  PubMed  Google Scholar 

  209. Stegmayr, J. et al. Extracellular and intracellular small-molecule galectin-3 inhibitors. Sci. Rep. 9, 1–12 (2019). Given the different function of galectins depending on their subcellular distribution, this study explores the cellular uptake of small-molecule carbohydrate GAL3 inhibitors and their function.

    Article  CAS  Google Scholar 

  210. Salameh, B. A., Cumpstey, I., Sundin, A., Leffler, H. & Nilsson, U. J. 1H-1,2,3-triazol-1-yl thiodigalactoside derivatives as high affinity galectin-3 inhibitors. Bioorg. Med. Chem. 18, 5367–5378 (2010).

    Article  CAS  PubMed  Google Scholar 

  211. Nangia-Makker, P. et al. Inhibition of human cancer cell growth and metastasis in nude mice by oral intake of modified citrus pectin. J. Natl Cancer Inst. 94, 1854–1862 (2002). This early study reports the use of MCP in modulating tumour growth and metastasis through binding to GAL3.

    Article  CAS  PubMed  Google Scholar 

  212. Chauhan, D. et al. A novel carbohydrate-based therapeutic GCS-100 overcomes bortezomib resistance and enhances dexamethasone-induced apoptosis in multiple myeloma cells. Cancer Res. 65, 8350–8358 (2005).

    Article  CAS  PubMed  Google Scholar 

  213. Yan, J. & Katz, A. PectaSol-C modified citrus pectin induces apoptosis and inhibition of proliferation in human and mouse androgen-dependent and- independent prostate cancer cells. Integr. Cancer Ther. 9, 197–203 (2010).

    Article  CAS  PubMed  Google Scholar 

  214. Klyosov, A. A. & Traber, P. G. in Galectins and Disease Implications for Targeted Therapeutics (eds Klyosov, A. A. & Traber, P. G.) 1–3 ACS Symposium series 1115 (American Chemical Society, 2013).

  215. Zhang, W., Xu, P. & Zhang, H. Pectin in cancer therapy: a review. Trends Food Sci. Technol. 44, 258–271 (2015).

    Article  CAS  Google Scholar 

  216. Banerjee, S., Parasramka, M. & Paruthy, S. B. in Polysaccharides (eds Ramawat, K. G. & Mérillon, J.-M.) 2179–2214 (Springer International Publishing, 2015).

  217. Bergman, M., Djaldetti, M., Salman, H. & Bessler, H. Effect of citrus pectin on malignant cell proliferation. Biomed. Pharmacother. 64, 44–47 (2010).

    Article  CAS  PubMed  Google Scholar 

  218. Stegmayr, J. et al. Low or no inhibitory potency of the canonical galectin carbohydrate-binding site by pectins and galactomannans. J. Biol. Chem. 291, 13318–13334 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Platt, D. & Raz, A. Modulation of the lung colonization of B16-F1 melanoma cells by citrus pectin. J. Natl Cancer Inst. 84, 438–442 (1992).

    Article  CAS  PubMed  Google Scholar 

  220. Inohara, H. & Raz, A. Effects of natural complex carbohydrate (citrus pectin) on murine melanoma cell properties related to galectin-3 functions. Glycoconj. J. 11, 527–532 (1994).

    Article  CAS  PubMed  Google Scholar 

  221. Hsieh, T. C. & Wu, J. M. Changes in cell growth, cyclin/kinase, endogenous phosphoproteins and nm23 gene expression in human prostatic JCA-1 cells treated with modified citrus pectin. Biochem. Mol. Biol. Int. 37, 833–841 (1995).

    CAS  PubMed  Google Scholar 

  222. Guess, B. W. et al. Modified citrus pectin (MCP) increases the prostate-specific antigen doubling time in men with prostate cancer: a phase II pilot study. Prostate Cancer Prostatic Dis. 6, 301–304 (2003).

    Article  CAS  PubMed  Google Scholar 

  223. Keizman, D. et al. Modified citrus pectin treatment in non-metastatic biochemically relapsed prostate cancer: results of a prospective phase II study. Nutrients 13, 4295 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Grous, J. J., Redfern, C. H., Mahadevan, D. & Schindler, J. GCS-100, a galectin-3 antagonist, in refractory solid tumors: a phase I study. J. Clin. Oncol. 24, 13023 (2006).

    Article  Google Scholar 

  225. Cotter, F. et al. Single-agent activity of GCS-100, a first-in-class galectin-3 antagonist, in elderly patients with relapsed chronic lymphocytic leukemia. J. Clin. Oncol. 27, 7006 (2009).

    Article  Google Scholar 

  226. Streetly, M. J. et al. GCS-100, a novel galectin-3 antagonist, modulates MCL-1, NOXA, and cell cycle to induce myeloma cell death. Blood 115, 3939–3948 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Ruvolo, P. P. et al. Combination of galectin inhibitor GCS-100 and BH3 mimetics eliminates both p53 wild type and p53 null AML cells. Biochim. Biophys. Acta 1863, 562–571 (2016).

    Article  CAS  PubMed  Google Scholar 

  228. Curti, B. D. et al. Enhancing clinical and immunological effects of anti-PD-1 with belapectin, a galectin-3 inhibitor. J. Immunother. Cancer 9, e002371 (2021). This article reports the synergistic effect of GAL3 and PD1 blockade in augmenting antitumour immunity and restraining tumour progression.

    Article  PubMed  PubMed Central  Google Scholar 

  229. Platt, D., Klyosov, A. A. & Zomer, E. in Carbohydrate Drug Design (eds Klyosov, A. A., Witczak, Z. J. & Platt, D.) 3–49 ACS Symposium series vol. 932 (American Chemical Society, 2006).

  230. Zomer, E., Klyosov, A. A. & Platt, D. in Glycobiology and Drug Design (ed. Klyosov, A. A.) 3–69 ACS Symposium series 1102 (American Chemical Society, 2013).

  231. Miller, M. C. et al. Binding of polysaccharides to human galectin-3 at a noncanonical site in its carbohydrate recognition domain. Glycobiology 26, 88–99 (2016).

    Article  CAS  PubMed  Google Scholar 

  232. Traber, P. G. et al. Regression of fibrosis and reversal of cirrhosis in rats by galectin inhibitors in thioacetamide-induced liver disease. PLoS ONE 8, e75361 (2013). This article evaluates GR-MD-02 (belapectin) and GM-CT-01 (Davanat) in an experimental model of liver fibrosis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Traber, P. G. & Zomer, E. Therapy of experimental NASH and fibrosis with galectin inhibitors. PLoS ONE 8, e83481 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  234. Harrison, S. A. et al. Randomised clinical study: GR-MD-02, a galectin-3 inhibitor, vs. placebo in patients having non-alcoholic steatohepatitis with advanced fibrosis. Aliment. Pharmacol. Ther. 44, 1183–1198 (2016).

    Article  CAS  PubMed  Google Scholar 

  235. Chalasani, N. et al. Effects of Belapectin, an inhibitor of galectin-3, in patients with nonalcoholic steatohepatitis with cirrhosis and portal hypertension. Gastroenterology 158, 1334–1345 (2020).

    Article  CAS  PubMed  Google Scholar 

  236. Zhang, L. et al. RN1, a novel galectin-3 inhibitor, inhibits pancreatic cancer cell growth in vitro and in vivo via blocking galectin-3 associated signaling pathways. Oncogene 36, 1297–1308 (2017).

    Article  PubMed  Google Scholar 

  237. Xue, H. et al. Selective effects of ginseng pectins on galectin-3-mediated T cell activation and apoptosis. Carbohydr. Polym. 219, 121–129 (2019).

    Article  CAS  PubMed  Google Scholar 

  238. Dings, R. P. M. & Mayo, K. H. A journey in structure-based drug discovery: from designed peptides to protein surface topomimetics as antibiotic and antiangiogenic agents. Acc. Chem. Res. 40, 1057–1065 (2007).

    Article  CAS  PubMed  Google Scholar 

  239. Mayo, K. H. in Galectins and Disease Implications for Targeted Therapeutics 3–61 ACS Symposium series 1115 (American Chemical Society, 2013).

  240. Griffioen, A. W. et al. Anginex, a designed peptide that inhibits angiogenesis. Biochem. J. 354, 233–242 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. van der Schaft, D. W. J. et al. The designer antiangiogenic peptide anginex targets tumor endothelial cells and inhibits tumor growth in animal models. FASEB J. 16, 1991–1993 (2002).

    Article  PubMed  Google Scholar 

  242. Dings, R. P. M., Yokoyama, Y., Ramakrishnan, S., Griffioen, A. W. & Mayo, K. H. The designed angiostatic peptide anginex synergistically improves chemotherapy and antiangiogenesis therapy with angiostatin. Cancer Res. 63, 382–385 (2003). This study reports the synergistic antitumour effects of Anginex, an angiostatic peptide that binds GAL1, with chemotherapy and anti-angiogenic therapy.

    CAS  PubMed  Google Scholar 

  243. Thijssen, V. L. J. L. et al. Galectin-1 is essential in tumor angiogenesis and is a target for antiangiogenesis therapy. Proc. Natl Acad. Sci. USA 103, 15975–15980 (2006). This pioneering study reports the role of GAL1 as a target of the anti-angiogenic peptide Anginex.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Brandwijk, R. J. M. G. E. et al. Cloning an artificial gene encoding angiostatic anginex: From designed peptide to functional recombinant protein. Biochem. Biophys. Res. Commun. 333, 1261–1268 (2005).

    Article  CAS  PubMed  Google Scholar 

  245. Ma, K. et al. Recombinant adeno-associated virus-delivered anginex inhibits angiogenesis and growth of HUVECs by regulating the Akt, JNK and NF-κB signaling pathways. Oncol. Rep. 35, 3505–3513 (2016).

    Article  CAS  PubMed  Google Scholar 

  246. Mayo, K. H. et al. Design of a partial peptide mimetic of anginex with antiangiogenic and anticancer activity. J. Biol. Chem. 278, 45746–45752 (2003).

    Article  CAS  PubMed  Google Scholar 

  247. Dings, R. P. M. et al. Structure-based optimization of angiostatic agent 6DBF7, an allosteric antagonist of galectin-1. J. Pharmacol. Exp. Ther. 344, 589–599 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Dings, R. P. M. et al. Antitumor agent calixarene 0118 targets human galectin-1 as an allosteric inhibitor of carbohydrate binding. J. Med. Chem. 55, 5121–5129 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Koonce, N. A., Griffin, R. J. & Dings, R. P. M. Galectin-1 inhibitor OTX008 induces tumor vessel normalization and tumor growth inhibition in human head and neck squamous cell carcinoma models. Int. J. Mol. Sci. 18, 2671–2680 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  250. Zucchetti, M. et al. Pharmacokinetics and antineoplastic activity of galectin-1-targeting OTX008 in combination with sunitinib. Cancer Chemother. Pharmacol. 72, 879–887 (2013).

    Article  CAS  PubMed  Google Scholar 

  251. Rezai, K. et al. Abstract 33: OTX008 pharmacokinetics (PK) during the first-in-man phase I study in patients with advanced solid tumors. Cancer Res. 73 (Suppl. 8), 33 (2013).

    Article  Google Scholar 

  252. Leung, Z. et al. Galectin-1 promotes hepatocellular carcinoma and the combined therapeutic effect of OTX008 galectin-1 inhibitor and sorafenib in tumor cells. J. Exp. Clin. Cancer Res. 38, 423 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  253. Gheysen, L. et al. New treatment strategy targeting galectin-1 against thyroid cancer. Cells 10, 1112–1120 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Dings, R. P. M. et al. Polycationic calixarene PTX013, a potent cytotoxic agent against tumors and drug resistant cancer. Invest. New Drugs 31, 1142–1150 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Läppchen, T. et al. Novel analogs of antitumor agent calixarene 0118: synthesis, cytotoxicity, click labeling with 2-[18F]fluoroethylazide, and in vivo evaluation. Eur. J. Med. Chem. 89, 279–295 (2015).

    Article  PubMed  Google Scholar 

  256. Blanchard, H., Bum-Erdene, K., Bohari, M. H. & Yu, X. Galectin-1 inhibitors and their potential therapeutic applications: a patent review. Expert. Opin. Ther. Pat. 26, 537–554 (2016).

    Article  CAS  PubMed  Google Scholar 

  257. Miller, M. C. et al. Targeting the CRD F-face of human galectin-3 and allosterically modulating glycan binding by angiostatic PTX008 and a structurally optimized derivative. ChemMedChem 16, 713–723 (2021).

    Article  CAS  PubMed  Google Scholar 

  258. Zou, J., Glinsky, V. V., Landon, L. A., Matthews, L. & Deutscher, S. L. Peptides specific to the galectin-3 carbohydrate recognition domain inhibit metastasis-associated cancer cell adhesion. Carcinogenesis 26, 309–318 (2005).

    Article  CAS  PubMed  Google Scholar 

  259. Geng, Q., Sun, X., Gong, T. & Zhang, Z.-R. Peptide–drug conjugate linked via a disulfide bond for kidney targeted drug delivery. Bioconjug. Chem. 23, 1200–1210 (2012).

    Article  CAS  PubMed  Google Scholar 

  260. Kopansky, E., Shamay, Y. & David, A. Peptide-directed HPMA copolymer-doxorubicin conjugates as targeted therapeutics for colorectal cancer. J. Drug Target. 19, 933–943 (2011).

    Article  CAS  PubMed  Google Scholar 

  261. Yang, Y. et al. Targeting prostate carcinoma by G3-C12 peptide conjugated N-(2-hydroxypropyl)methacrylamide copolymers. Mol. Pharm. 11, 3251–3260 (2014).

    Article  CAS  PubMed  Google Scholar 

  262. Yang, Y. et al. Treatment of prostate carcinoma with (galectin-3)-targeted HPMA copolymer-(G3-C12)-5-fluorouracil conjugates. Biomaterials 33, 2260–2271 (2012).

    Article  CAS  PubMed  Google Scholar 

  263. Liu, T. & Huang, Q. Biodegradable brush-type copolymer modified with targeting peptide as a nanoscopic platform for targeting drug delivery to treat castration-resistant prostate cancer. Int. J. Pharm. 511, 1002–1011 (2016).

    Article  CAS  PubMed  Google Scholar 

  264. Kanda, A., Noda, K., Saito, W. & Ishida, S. Aflibercept traps galectin-1, an angiogenic factor associated with diabetic retinopathy. Sci. Rep. 5, 17946 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  265. Danhier, F., Messaoudi, K., Lemaire, L., Benoit, J.-P. & Lagarce, F. Combined anti-Galectin-1 and anti-EGFR siRNA-loaded chitosan-lipid nanocapsules decrease temozolomide resistance in glioblastoma: In vivo evaluation. Int. J. Pharm. 481, 154–161 (2015). This study highlights the impact of combining GAL1 and EGFR siRNA in the treatment of patients with glioblastoma resistant to temozolomide.

    Article  CAS  PubMed  Google Scholar 

  266. Storti, P. et al. Galectin-1 suppression delineates a new strategy to inhibit myeloma-induced angiogenesis and tumoral growth in vivo. Leukemia 30, 2351–2363 (2016).

    Article  CAS  PubMed  Google Scholar 

  267. Tsai, Y.-T. et al. A DNA Aptamer targeting galectin-1 as a novel immunotherapeutic strategy for lung cancer. Mol. Ther. Nucleic Acids 18, 991–998 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  268. Zuckerman, J. E. & Davis, M. E. Clinical experiences with systemically administered siRNA-based therapeutics in cancer. Nat. Rev. Drug Discov. 14, 843–856 (2015).

    Article  CAS  PubMed  Google Scholar 

  269. Ribas, A. & Wolchok, J. D. Cancer immunotherapy using checkpoint blockade. Science 359, 1350–1355 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  270. Nelson, A. L., Dhimolea, E. & Reichert, J. M. Development trends for human monoclonal antibody therapeutics. Nat. Rev. Drug Discov. 9, 767–774 (2010).

    Article  CAS  PubMed  Google Scholar 

  271. Ouyang, J. et al. Viral induction and targeted inhibition of galectin-1 in EBV+ posttransplant lymphoproliferative disorders. Blood 117, 4315–4322 (2011).

    Article  CAS  PubMed  Google Scholar 

  272. Pérez Sáez, J. M. et al. Characterization of a neutralizing anti-human galectin-1 monoclonal antibody with angioregulatory and immunomodulatory activities. Angiogenesis 24, 1–5 (2021). This study highlights the dual immunomodulatory and angioregulatory activities of a GAL1-neutralizing mAb.

    Article  PubMed  Google Scholar 

  273. Femel, J. et al. Vaccination against galectin-1 promotes cytotoxic T-cell infiltration in melanoma and reduces tumor burden. Cancer Immunol. Immunother. 71, 2029–2040 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  274. Rao, T. D. et al. Expression of the carboxy-terminal portion of MUC16/CA125 induces transformation and tumor invasion. PLoS ONE 10, e0126633 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  275. Stasenko, M. et al. Targeting galectin-3 with a high-affinity antibody for inhibition of high-grade serous ovarian cancer and other MUC16/CA-125-expressing malignancies. Sci. Rep. 11, 3718 (2021). This study reports the therapeutic relevance of a GAL3 blocking mAb in high-grade serous ovarian cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  276. Sun, D. et al. Anti-Gal-3 antibodies and methods of use. International Patent Application. Patent no. WO/2021/146218 A1 (2021).

  277. Lee, M., Filipovic, A. & Henry, C. J. Combinatorial inhibition of galectin-9 and CHK1 represent a novel treatment strategy for T-cell acute lymphoblastic leukemia. Blood 138, 4400 (2021).

    Article  Google Scholar 

  278. Mirandola, L. et al. Galectin-3 inhibition suppresses drug resistance, motility, invasion and angiogenic potential in ovarian cancer. Gynecol. Oncol. 135, 573–579 (2014).

    Article  CAS  PubMed  Google Scholar 

  279. John, C. M., Leffler, H., Kahl-Knutsson, B., Svensson, I. & Jarvis, G. A. Truncated galectin-3 inhibits tumor growth and metastasis in orthotopic nude mouse model of human breast cancer. Clin. Cancer Res. 9, 2374 (2003).

    CAS  PubMed  Google Scholar 

  280. Mirandola, L. et al. Galectin-3C inhibits tumor growth and increases the anticancer activity of bortezomib in a murine model of human multiple myeloma. PLoS ONE 6, e21811 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  281. St-Gelais, J., Denavit, V. & Giguère, D. Efficient synthesis of a galectin inhibitor clinical candidate (TD139) using a Payne rearrangement/azidation reaction cascade. Org. Biomol. Chem. 18, 3903–3907 (2020).

    Article  CAS  PubMed  Google Scholar 

  282. Stowell, S. R. et al. Ligand reduces galectin-1 sensitivity to oxidative inactivation by enhancing dimer formation. J. Biol. Chem. 284, 4989–4999 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  283. Guardia, C. M. et al. Structural basis of redox-dependent modulation of galectin-1 dynamics and function. Glycobiology 24, 428–441 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  284. Di Lella, S. et al. When galectins recognize glycans: from biochemistry to physiology and back again. Biochemistry 50, 7842–7857 (2011).

    Article  PubMed  Google Scholar 

  285. Salomonsson, E., Thijssen, V. L., Griffioen, A. W., Nilsson, U. J. & Leffler, H. The anti-angiogenic peptide anginex greatly enhances galectin-1 binding affinity for glycoproteins. J. Biol. Chem. 286, 13801–13804 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  286. Gohil, S. H., Iorgulescu, J. B., Braun, D. A., Keskin, D. B. & Livak, K. J. Applying high-dimensional single-cell technologies to the analysis of cancer immunotherapy. Nat. Rev. Clin. Oncol. 18, 244–256 (2021).

    Article  PubMed  Google Scholar 

  287. Kearney, C. J. et al. SUGAR-seq enables simultaneous detection of glycans, epitopes, and the transcriptome in single cells. Sci. Adv. 7, eabe3610 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  288. Peixoto, A., Miranda, A., Santos, L. L. & Ferreira, J. A. A roadmap for translational cancer glycoimmunology at single cell resolution. J. Exp. Clin. Cancer Res. 41, 143 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  289. Matthews, S. E. in Calixarenes and Beyond (eds Neri, P., Sessler, J. L. & Wang, M.-X.) 559–600 (Springer International Publishing, 2016).

  290. Glinsky, V. V. & Raz, A. Modified citrus pectin anti-metastatic properties: one bullet, multiple targets. Carbohydr. Res. 344, 1788–1791 (2009).

    Article  CAS  PubMed  Google Scholar 

  291. Zhang, T. et al. Macromolecular assemblies of complex polysaccharides with galectin-3 and their synergistic effects on function. Biochem. J. 474, 3849–3868 (2017).

    Article  CAS  PubMed  Google Scholar 

  292. Nanthakumar, C. B. et al. Dissecting fibrosis: therapeutic insights from the small-molecule toolbox. Nat. Rev. Drug Discov. 14, 693–720 (2015).

    Article  CAS  PubMed  Google Scholar 

  293. Miller, M. C., Klyosov, A. & Mayo, K. H. The α-galactomannan Davanat binds galectin-1 at a site different from the conventional galectin carbohydrate binding domain. Glycobiology 19, 1034–1045 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  294. Miller, M. C., Klyosov, A. A. & Mayo, K. H. Structural features for α-galactomannan binding to galectin-1. Glycobiology 22, 543–551 (2012).

    Article  CAS  PubMed  Google Scholar 

  295. Leclere, L. et al. Heat-modified citrus pectin induces apoptosis-like cell death and autophagy in HepG2 and A549 cancer cells. PLoS ONE 10, e0115831 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  296. Li, L. et al. The effect of the size of fluorescent dextran on its endocytic pathway. Cell Biol. Int. 39, 531–539 (2015).

    Article  CAS  PubMed  Google Scholar 

  297. Pilch, J. et al. The anti-angiogenic peptide anginex disrupts the cell membrane. J. Mol. Biol. 356, 876–885 (2006).

    Article  CAS  PubMed  Google Scholar 

  298. RodrÍguez, E., Schetters, S. T. T. & van Kooyk, Y. The tumour glyco-code as a novel immune checkpoint for immunotherapy. Nat. Rev. Immunol. 18, 204–211 (2018).

    Article  PubMed  Google Scholar 

  299. Farrants, H. et al. Chemogenetic control of nanobodies. Nat. Methods 17, 279–282 (2020).

    Article  CAS  PubMed  Google Scholar 

  300. Hockl, P. F. et al. Glyco-nano-oncology: novel therapeutic opportunities by combining small and sweet. Pharmacol. Res. 109, 45–54 (2016).

    Article  CAS  PubMed  Google Scholar 

  301. Zhong, X., Qian, X., Chen, G. & Song, X. The role of galectin-3 in heart failure and cardiovascular disease. Clin. Exp. Pharmacol. Physiol. 46, 197–203 (2019).

    Article  CAS  PubMed  Google Scholar 

  302. Lau, E. S. et al. Galectin-3 inhibition with modified citrus pectin in hypertension. JACC Basic Transl. Sci. 6, 12–21 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  303. Chen, W.-S., Cao, Z., Leffler, H., Nilsson, U. J. & Panjwani, N. Galectin-3 inhibition by a small-molecule inhibitor reduces both pathological corneal neovascularization and fibrosis. Invest. Ophthalmol. Vis. Sci. 58, 9–20 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  304. Al-Obaidi, N. et al. Galectin-1 is a new fibrosis protein in type 1 and type 2 diabetes. FASEB J. 33, 373–387 (2019).

    Article  CAS  PubMed  Google Scholar 

  305. Neelamegham, S. et al. Updates to the symbol nomenclature for glycans guidelines. Glycobiology 29, 620–624 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  306. Stowell, S. R. et al. Galectin-1, -2, and -3 exhibit differential recognition of sialylated glycans and blood group antigens. J. Biol. Chem. 283, 10109–10123 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  307. Kopitz, J., von Reitzenstein, C., Burchert, M., Cantz, M. & Gabius, H.-J. Galectin-1 is a major receptor for ganglioside GM1, a product of the growth-controlling activity of a cell surface ganglioside sialidase, on human neuroblastoma cells in culture*. J. Biol. Chem. 273, 11205–11211 (1998).

    Article  CAS  PubMed  Google Scholar 

  308. Boscher, C. et al. Galectin-3 protein regulates mobility of N-cadherin and GM1 ganglioside at cell-cell junctions of mammary carcinoma cells. J. Biol. Chem. 287, 32940–32952 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Work in the authors’ laboratories is supported by grants from the Agency for Promotion of Science, Technology and Innovation (PICT 2015-0564 and 2018-2766 to K.V.M., PICT 2018-0955 to A.J.C., PICT 2019-0532 to D.O.C. and PICT 2017-0494 and PICT 2020-01552 to G.A.R.) as well as NIH grant CA221208 to G.A.R. The authors are also thankful for generous support from Sales Foundation, Bunge & Born Foundation, Williams Foundation and Richard Lounsbery Foundation, as well as donations from Ferioli-Ostry and Caraballo families to G.A.R. They thank H. Rosenberg for critical reading of the manuscript.

Author information

Authors and Affiliations

  1. Laboratorio de Glicómica Funcional y Molecular, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina

    Karina V. Mariño & Alejandro J. Cagnoni

  2. Laboratorio de Glicomedicina, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina

    Alejandro J. Cagnoni & Gabriel A. Rabinovich

  3. Laboratorio de Glicobiología y Biología Vascular, Instituto de Histología y Embriología de Mendoza (IHEM), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET); Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Cuyo, Mendoza, Argentina

    Diego O. Croci

  4. Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina

    Gabriel A. Rabinovich

Authors
  1. Karina V. Mariño
    View author publications

    Search author on:PubMed Google Scholar

  2. Alejandro J. Cagnoni
    View author publications

    Search author on:PubMed Google Scholar

  3. Diego O. Croci
    View author publications

    Search author on:PubMed Google Scholar

  4. Gabriel A. Rabinovich
    View author publications

    Search author on:PubMed Google Scholar

Contributions

All authors contributed data for the article, made substantial contributions to discussions of the content, wrote the article, and reviewed and edited the article before its submission.

Corresponding author

Correspondence to Gabriel A. Rabinovich.

Ethics declarations

Competing interests

G.A.R. and D.O.C. are co-inventors in the US Patent 10294295B2: ‘Methods for modulating angiogenesis of cancers refractory to anti-VEGF treatment’.

Peer review

Peer review information

Nature Reviews Drug Discovery thanks Gerardo Vasta and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

ADME(T)

Acronym for the study of absorption, distribution, metabolism, excretion and (toxicity), key processes in drug pharmacokinetics.

Antennae

Branches of the core N-glycan structure (Manα1–3(Manα1–6)Manβ1–4GlcNAcβ1–4GlcNAcβ1–Asn-X-Ser/Thr) initiated by the action of N-acetylglucosaminyltransferases, resulting in mono-, di-, tri- and tetra-antennary complex N-glycans.

Cluster glycoside effect

Increased binding activity observed in multivalent versus monovalent interactions on a per mole or valence-corrected basis, previously known as ‘avidity’. Multivalent interactions are typically stronger than the sum of individual monovalent interactions.

Child–Pugh

Classification that assesses liver function and prognosis in patients with cirrhosis. Based on a score that includes serum albumin and serum bilirubin levels, ascites and encephalopathy, it includes three classes (A, B, C). Classes B and C are the most severe forms of hepatic dysfunction, with life expectancy of 4–14 years (B) and 1–3 years (C).

Cyclodextrins

Cyclic oligosaccharides composed of α(1–4)-linked d-glucopyranose units that bear a hydrophilic outer surface and a hydrophobic central cavity.

Doxorubicin

Anthracycline antibiotic with broad use as a chemotherapeutic agent.

F-face of the GAL3 β-sandwich

All members of the galectin family, including GAL3, present a conserved carbohydrate recognition domain with an 11-stranded, β-sandwich fold that presents two faces: the six β-stranded S-face (key for interaction with β/α-galactosides), and an opposing F-face (five β-strands) where some larger polysaccharides can interact.

Glycoconjugates

Macromolecules that contain carbohydrates in their structure. Carbohydrates can be covalently linked to proteins or lipids.

Glycodendrimers

Radially symmetrical, carbohydrate-based repetitively branched molecules with well-defined, homogeneous and monodisperse structure.

Idiopathic pulmonary fibrosis

(IPF). A chronic, progressive inflammatory lung disease that causes fibrosis.

Mucin 1

Glycoconjugate that belongs to the family of large, highly glycosylated proteins that contain tandem repeats of amino acids rich in serine and threonine (mucins). These Ser/Thr residues can be O-glycosylated with the monosaccharide N-acetylgalactosamine (GalNAc) and further elongated (O-GalNAc glycans). This modification is characteristic of mucins and is therefore termed mucin-type O-glycosylation. Mucins can be secreted or be transmembrane proteins.

N-acetyllactosamine

(LacNAc). A Galβ(1–3)GlcNAc (type 1) or Galβ(1–4)GlcNAc (type 2) disaccharide.

Nonalcoholic steatohepatitis

(NASH). An inflammatory condition in which patients build up an excess of fat in the liver, leading to damage of this organ. This pathology is not related to alcohol consumption and results in progressive fibrosis that can lead to cirrhosis and hepatocellular carcinoma.

Neoglycoproteins

Synthetic or modified glycoproteins. This term typically refers to natural proteins that have been modified by the addition of structurally well-defined glycans.

Small interfering RNA

(siRNA). A class of double-stranded RNA molecules, usually about 20–25 nucleotides in length, designed to target a specific mRNA for degradation. Thus, siRNA prevents the production of specific proteins based on the nucleotide sequences of their corresponding mRNA. The process is called RNA interference (RNAi).

Sorafenib

An anticancer agent that inhibits multiple kinases and affects the vascular endothelial growth factor (VEGF), Raf–Ras and FMS-like tyrosine kinase 3 (FLT3) pathways.

Thomsen–Friedenreich antigen

(Tf antigen). The core 1 O-GalNAc glycan Galβ(1–3)GalNAc, also known as TF(a), T antigen, Thomsen–Friedenreich disaccharide and/or CD176. In some publications the definition of Tf antigen includes the covalently bound Ser/Thr (α-linkage).

Topomimetic

Agent with stereostructural elements that imitate the topographical features of proteins or peptides.

Tumour-associated carbohydrate antigens

(TACAs). Glycan structures that are frequently found in tumour cells as a consequence of malignancy. They include under- or overexpression of naturally occurring glycans, but also neo-expression of specific carbohydrate structures.

Valency

Number of individual structural units connected to a core structure in a multivalent ligand.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mariño, K.V., Cagnoni, A.J., Croci, D.O. et al. Targeting galectin-driven regulatory circuits in cancer and fibrosis. Nat Rev Drug Discov 22, 295–316 (2023). https://doi.org/10.1038/s41573-023-00636-2

Download citation

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41573-023-00636-2

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer