Galectins and gliomas

Abstract

Malignant gliomas, especially glioblastomas, are associated with a dismal prognosis. Despite advances in diagnosis and treatment, glioblastoma patients still have a median survival expectancy of only 14 months. This poor prognosis can be at least partly explained by the fact that glioma cells diffusely infiltrate the brain parenchyma and exhibit decreased levels of apoptosis, and thus resistance to cytotoxic drugs. Galectins are a family of mammalian beta-galactoside-binding proteins characterized by a shared characteristic amino acid sequence. They are expressed differentially in normal vs. neoplastic tissues and are known to play important roles in several biological processes such as cell proliferation, death and migration. This review focuses on the role played by galectins, especially galectin-1 and galectin-3, in glioma biology. The involvement of these galectins in different steps of glioma malignant progression such as migration, angiogenesis or chemoresistance makes them potentially good targets for the development of new drugs to combat these malignant tumors.

Figure 1

Galectins, integrins and cell migration. The interaction of galectins with integrins modulates cell migration as well as other processes. Galectin‐1 (Gal‐1) interacts with the β1 integrin subunit inducing the phosphorylation of FAK, which modulates cell migration (85). Binding of Gal‐1 to integrin is involved in cell adhesion (83). Moreover, Gal‐1 was shown to regulate the expression of the protein ADAM‐15 that is involved in integrin‐mediated adhesion (12). Gal‐1 also induces growth inhibition via its interaction with α5β1 (26). This interaction results in the inhibition of the Ras–MEK–ERK pathway and the consecutive transactivation of Sp1, which induces p27 transcription (26). In addition, Gal‐1 is involved in the PKCε/vimentin controlled trafficking of integrin β1, a process that is important for cell migration (28). However, it is not known with which molecule(s) Gal‐1 is interacting, or in which intra‐ or extracellular location this interaction is taking place in order to initiate this signaling. Finally, Gal‐1 is also involved in cell motility via the Gal‐1‐induced expression of RhoA and the alteration of the polimerization of the actin cytoskeleton (11) Once again, the receptor to which Gal‐1 bind to initiate this signaling is not known. Galectin‐3 (Ga‐3) regulates cell adhesion via binding to α1β1 (94). Gal‐3 also forms a complex with α3β1 and the proteoglycan NG2 (31). This interaction regulates endothelial cell motility and angiogenesis. Finally, Gal‐3 has been shown to regulate the expression of integrin α6β1 and actin cytoskeleton organization (20). However, it is not known with which molecule(s) Gal‐3 is interacting to initiate this signaling. Galectin‐8 (Gal‐8) interacts with several integrins including α1β1, α3β1, α5β1 and α6β1. These interactions are involved in cell adhesion and apoptosis (40). Abbreviations: ERK = extracellular signal‐regulated kinase; FAK = focal adhesion kinase; MEK = MAP kinase/extracellular signal‐regulated kinase kinase (MAPK/ERK Kinase); PKCε = protein kinase C epsilon.

Figure 2

Presumed role of galectins in angiogenesis and chemoresistance. Necrotic foci in glioblastoma are typically surrounded by hypercellular zones referred to as pseudopalisades (104). It has been shown that pseudopalisades are hypoxic and express high amounts of the transcription factor hypoxia‐inducible factor 1 (HIF‐1) (104). Galectin‐3 (Gal‐3) expression is stimulated by hypoxia via HIF‐1 (132) and stimulates angiogenesis in vitro and in vivo (89). Gal‐3 has also been shown to interact with NG2 proteoglycan, a component of microvasculature pericytes, which stimulates endothelial cell motility and morphogenesis (130). In addition, Gal‐3 is involved in chemoresistance, a process that is increased in hypoxic conditions (30). Galectin‐1 (Gal‐1) expression is also stimulated in hypoxic conditions (67), however, it is not known if this is HIF‐1‐dependent. Recent evidence indicates that Gal‐1 plays an important role in angiogenesis and in chemo‐ and radioresistance 64, 120. These effects of Gal‐1 can be explained at least partly by the fact that Gal‐1 modulates the unfolded protein response (UPR), a process that is involved in resistance and angiogenesis 64, 65. Moreover, Gal‐1 was shown to control the expression level of the UPR‐regulated protein ORP150, which is responsible for vascular endothelial growth factor (VEGF) maturation and secretion (65).