Galectins as Emerging Glyco-Checkpoints and Therapeutic Targets in Glioblastoma

Abstract

Despite recent advances in diagnosis and treatment, glioblastoma (GBM) represents the most common and aggressive brain tumor in the adult population, urging identification of new rational therapeutic targets. Galectins, a family of glycan-binding proteins, are highly expressed in the tumor microenvironment (TME) and delineate prognosis and clinical outcome in patients with GBM. These endogenous lectins play key roles in different hallmarks of cancer by modulating tumor cell proliferation, oncogenic signaling, migration, vascularization and immunity. Additionally, they have emerged as mediators of resistance to different anticancer treatments, including chemotherapy, radiotherapy, immunotherapy, and antiangiogenic therapy. Particularly in GBM, galectins control tumor cell transformation and proliferation, reprogram tumor cell migration and invasion, promote vascularization, modulate cell death pathways, and shape the tumor-immune landscape by targeting myeloid, natural killer (NK), and CD8⁺ T cell compartments. Here, we discuss the role of galectins, particularly galectin-1, -3, -8, and -9, as emerging glyco-checkpoints that control different mechanisms associated with GBM progression, and discuss possible therapeutic opportunities based on inhibition of galectin-driven circuits, either alone or in combination with other treatment modalities.

Keywords: angiogenesis; central nervous system; galectins; glioblastoma; glycans; glyco-checkpoints; immunomodulation; immunotherapy; invasion.

Figure 1

Schematic representation and structural classification of galectins. Galectin family members are subdivided into three groups proto-type galectins containing one carbohydrate-recognition domain (CRD) (including Gal1, Gal2, Gal3, Gal5, Gal7, Gal10, Gal11, Gal13, Gal14, and Gal15); galectin-3, a unique chimaera-type galectin consisting of repeats of proline- and glycine-rich short stretches fused onto the CRD; and tandem-repeat-type galectins (Gal4, Gal6, Gal8, Gal9, and Gal12), which contain two distinct CRDs connected by a linker of up to 70 amino acids. Lower panels represent hypothetical lattice formations of each group. Galectin’s bindings can be monovalent, bivalent, or multivalent regarding their carbohydrate-binding activities: Proto-type one-CRD galectins often exist as dimers; galectin-3 undergoes conformational changes after binding multivalent ligands that enable its oligomerization as pentamers, and two-CRD tandem-repeat galectins have two carbohydrate-binding sites that form lattices with multivalent glycoconjugates.

Figure 2

Galectins in glioma progression and tumor-associated inflammatory responses. Representation of biological functions of galectins in glioma cells (in vitro), or in animal models (in vivo). Galectins can promote a wide range of biological functions extracellularly by clustering multiple multivalent glycoconjugates, or intracellularly by modulating several signal transduction pathways, triggering intracellular oncogenic (proliferative and/or antiapoptotic) signaling. They can also bridge two cells of the same or different types, and bridge cells to extracellular matrix proteins, promoting migration and metastasis. In addition, galectin binding to extracellular glycoconjugates can induce angiogenesis, and affects immune responses in tumor microenvironments.