Reprogramming the tumor metastasis cascade by targeting galectin-driven networks

Abstract

A sequence of interconnected events known as the metastatic cascade promotes tumor progression by regulating cellular and molecular interactions between tumor, stromal, endothelial, and immune cells both locally and systemically. Recently, a new concept has emerged to better describe this process by defining four attributes that metastatic cells should undergo. Every individual hallmark represents a unique trait of a metastatic cell that impacts directly in the outcome of the metastasis process. These critical features, known as the hallmarks of metastasis, include motility and invasion, modulation of the microenvironment, cell plasticity and colonization. They are hierarchically regulated at different levels by several factors, including galectins, a highly conserved family of β-galactoside-binding proteins abundantly expressed in tumor microenvironments and sites of metastasis. In this review, we discuss the role of galectins in modulating each hallmark of metastasis, highlighting novel therapeutic opportunities for treating the metastatic disease.

Galectins as Emerging Glyco-Checkpoints and Therapeutic Targets in Glioblastoma

“…Galectins are abundantly expressed in the TME, where they play essential roles by linking tumor, stromal, and immunological compartments [ 24 , 41 ]. They have been proposed to play key roles in virtually all hallmarks of cancer and metastasis [ 42 , 43 ]. This includes galectin-mediated programs that assist tumors in sustaining proliferation driven by oncogenic signaling circuits [ 44 , 45 ], evading growth suppressors [ 46 , 47 ], fostering inflammation [ 48 , 49 , 50 ], activating invasion processes such as epithelial–mesenchymal transition (EMT) and early dissemination [ 51 , 52 , 53 ], inducing angiogenesis [ 33 , 54 , 55 , 56 ], developing resistance to cell death [ 57 , 58 ], and avoiding immune destruction [ 59 , 60 , 61 , 62 , 63 ].…”

Functions and Inhibition of Galectin-7, an Emerging Target in Cellular Pathophysiology

“…Hanahan and Weinberg defined hallmarks of most cancers which describe the biological capabilities essential for carcinogenesis [ 31 ]. There are a number of papers published regarding the subject of cancer (development) and the roles of (targeting) galectins, and even galectin-7 in particular [ 13 , 30 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 ]. Nevertheless, our goal for this section is to provide the reader with a brief overview of the presence and roles of galectin-7 in most cancers/cancer types by covering mostly recent publications.…”

“…The approach of carbohydrate-derived small-molecule inhibitors to target the CRD of galectins is mainly based on the use of chemically modified natural galectin ligands, such as the disaccharides lactose (Lac) or N -acetyllactosamine (LacNAc). As the development of these inhibitors involves a full understanding of the biochemistry of galectin–glycan interactions, efforts are being made to generate galectin inhibitors that target individual members (particularly galectins-1, -3 and -7) of the family with higher affinity and selectivity [ 50 ]. Most of the current inhibitors only block extracellular functions of a given galectin and neglect intracellular functions [ 36 ], except for galectin-3 for which Stegmayr and co-workers were able to synthesize and evaluate the roles of intracellular and extracellular galectin-3 inhibitors [ 94 ].…”

“…In addition, they should display improved pharmacological properties, have better resistance against glycosidase hydrolysis, and bind more strongly and more selectively to galectin-7 [ 2 ]. In particular, the poor selectivity of current small-molecule inhibitors remains an important obstacle to overcome, due to the high similarity of the CRD structures among the different galectins [ 50 ]. Hence, developing specific galectin-7 inhibitors that will selectively target the intracellular or extracellular functions of galectin-7 could be a strategy to inhibit not all, but specific galectin-7–mediated processes [ 13 ].…”

Galectin-8, cytokines, and the storm

“…Galectins, including Gal-8, emerge as key regulators of primary tumor growth and metastasis [24][25][26][27][28][29][30][31]. Amplification of LGALS8 and increased Gal-8 expression is observed in various cancerous tissues [32][33][34][35] including breast, prostate, and lung [32][33][34][36][37][38] and is often associated with poor prognosis [32].…”