Molecular Mechanisms Underlying the Role of Galectin-8 as a Regulator of Cancer Growth and Metastasis

Galectin-8 (Gal-8) is a member of the galectin family of animal lectins that regulate a myriad of biological processes including cell growth, cell transformation, embryogenesis, apoptosis, cell adhesion and immune responses. Gal-8 expression increases in several, though not all, cancerous tissues including lung, bladder, kidney, prostate, and breast tissues. Based on its prevalence, an estimated ~500,000 newly diagnosed cancer patients/year are expected to possess an amplified Gal-8 gene. Yet, the molecular mechanisms underlying its role in cancer growth and metastasis remain incompletely understood. Here we describe potential modes of action of Gal-8 that might account for its central role in cancer biology. The evidence, gathered thus far, implicates Gal-8 as a driver of a ‘vicious cycle,’ whereby cancer cells that overexpress and secrete Gal-8, benefit from its potential to promote their own growth; potentiate epithelial mesenchymal transition, and induce secretion of metastasis-promoting agents at the metastatic niche that induce further recruitment and seeding of cancer cells. Further in-depth studies related to its mode of action, are expected to support ongoing efforts aimed at implementing Gal-8-targeted therapies for the treatment of cancer patients. A. Introduction Galectin-8 (Gal-8) (1) is a member of the galectin family of animal lectins (2) that regulate a myriad of biological processes including cell growth, cell transformation, embryogenesis, apoptosis, cell adhesion and immune responses [reviewed in (3–7)]. It is a 34 kDa protein, made of two carbohydrate recognition domains (CRDs) of about 140 amino acid each, joined by a linker peptide of various lengths. The two CRDs share ~40% sequence identity and exhibit differential glycan binding specificities (1, 8, 9). The N-terminal CRD (Gal-8N), has unique sugar binding residues that recognize a broader spectrum of glycans compared to the Cterminal CRD (Gal-8C), and exhibits preferential binding towards anionic sugars including 3′-O-sulfate/3′-O-sialylated lactose (10). Recent crystallographic study highlighted preference of Gal-8N towards recognizing neolacto-series over lacto-series glycosphingolipids implying specific roles for Gal-8 over other galectins (11). While lacking a signal peptide suitable for ER/Golgi-mediated secretion, Gal-8, like other galectins, is externalized by an atypical secretory mechanism (12). Atypical secretion (13–15) is not a unique property of galectins, because a number of other cytoplasmic proteins like thioredoxin (16), IL-1β (17) and basic FGF (18) lack a signal sequence, yet are externalized and function extracellularly. Gal-8 is widely expressed in a large number of tissues including lung, liver, kidney, spleen, hind limb, and cardiac muscle (1, 19, 20). Low levels of expression were detected in intestine, colon, fat, and thymus and almost no expression was detected in hematopoietic cells. These results indicate that although Gal-8 is a fairly abundant protein, it is not ubiquitously expressed. Gal-8 is a cytoplasmic protein. However, similar to other galectins (21–23), it is not uniformly spread within the cell. Instead, it shows a microclustering pattern reminiscent of that seen with proteins associated with mitochondria, the Golgi or trans-Golgi membranes (1, 20, 24–26). Nuclear expression of Gal-8 is evident as well (27). Expression of Gal-8 seems to be developmentally regulated. Very low levels of expression were noted in whole embryos (1), while high levels of expression were noted in adult tissues. Hence, Gal-8, like other galectins (28–31), can be implicated as a regulator of cell growth, embryogenesis and development. Upon secretion, Gal-8 acts as an extracellular matrix protein equipotent to fibronectin in promoting cell adhesion by ligation and clustering a selective subset of cell surface integrins and CD44 (19, 32, 33). This allows local signals emitted by secreted Gal8 to specify territories available for cell adhesion and migration (19, 33–35). Aside from its role as an extracellular regulator of cell functions, Gal-8, like other members of the galectin family (5), has intracellular functions. In particular, Gal-8-mediated recognition of intracellular vesicles, damaged following bacterial infection, targets these vesicles for autophagy, thus providing a unique form of intracellular antimicrobial defense elicited by Gal-8 (36). Altogether, the biological effects of Gal-8 resemble the mode of action of other galectins in a number of aspects; nonetheless, several features of Gal-8 single it out from the entire galectin family. These unique features, mainly its role as a regulator of cancer growth and MINIREVIEW doi: 10.4052/tigg.1742.1SE (Article for special issue on Galectins)