The Role of Galectin-3 in Malignant Melanoma - ACS Symposium

Chapter 9

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The Role of Galectin-3 in Malignant Melanoma Gordana Radosavljevic,1 Ivan Jovanovic,1 Jelena Pantic,1 Nada Pejnovic,1 Nebojsa Arsenijevic,1 Daniel K. Hsu,2 and Miodrag L. Lukic*,1 1Center

for Molecular Medicine and Stem Cell Research, Faculty of Medicine Science, University of Kragujevac, Svetozara Markovica 69, 34000 Kragujevac, Serbia 2Department of Dermatology, School of Medicine, University of California Davis, Sacramento, California 95816, United States *E-mail: [email protected]

Mechanisms by which Galectin-3 participate in regulation of innate and acquired immune responses include adhesion of neutrophils, chemoattraction of monocytes/macrophages and activation of mast cells and T-cell survival. We have demonstrated proinflammatory effects of Galectin-3 in several experimental models of T-cell-mediated inflammatory and autoimmune diseases. Galectin-3 is also expressed in malignant cells and is involved in tumor development and progression as well as tumor immune escape. Using Galectin-3-deficient mice and malignant melanoma model we recently showed that the expression of Galectin-3 in the host cells facilitate establishment of metastasis in the lung. Mechanisms contributing to resistance to melanoma in Galectin-3-deficient mice appear to be the lower tumor cell adhesion and modulation of immune responses. Galectin-3-deficient mice had higher serum levels of IFN-gamma and IL-17 and a decrease in the percentage and total number of regulatory CD4+Foxp3+T cells compared to wild-type mice. Protective effects of Galectin-3 deficiency on metastatic melanoma spread was dependent on NK cells and associated with an enhanced cytotoxic activity of splenic NK cells in vitro and increased frequency of effective

© 2012 American Chemical Society In Galectins and Disease Implications for Targeted Therapeutics; Klyosov, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.

cytotoxic CD27highCD11bhigh NK cells as well as immature CD27highCD11blowNK cells in vivo. Thus, target inhibition of Galectin-3 expression can prevent melanoma metastasis by decreasing tumor cell adhesion and by enhancing NK cell-mediated anti-tumor immune response.


Introduction Galectins, a family of evolutionarily conserved carbohydrate-binding proteins, are defined by homologous carbohydrate recognition domains (CRDs) and affinity for β-galactosides (1, 2). Presently, 15 mammalian galectins have been identified and classified into three distinct groups based on their structures and number of CRDs they include: proto-type, chimera type and tandem repeat type galectins (2–4). There are no specific receptors for individual galectins, but they bind to a set of cell surface or extracellular matrix glycoproteins that contain suitable oligosaccharides (4). As different members of galectin family have specific distribution, expression patterns and binding ability, they exert different modulatory functions in various physiological and pathological processes (5). Galectin-3 is a unique chimera-type member of galectin family which contains three structural domains: (i.) an NH2-terminal domain with a serine phosphorylation site that participate in regulation of intracellular signaling; (ii.) collagen-like sequence, sensitive to matrix metalloproteinase MMP-2 and MMP-9-induced proteolysis; and (iii.) a COOH-terminal domain containing a single CRD with Asp-Trp-Gly-Arg amino acid sequence (NWGR) responsible for the anti-apoptotic action of Galectin-3 (6–10). Similarly to other galectins, Galectin-3 is present both inside and outside cells (11–13) and interacts with numerous intracellular and extracellular ligands. Galectin-3 upon binding to multivalent carbohydrates can form pentamers that modulate intracellular signaling cascade (14). In general, extracellular Galectin-3 acts as an adhesion molecule by cross-linking adjacent cells or cells and extracellular matrix components (15) and has chemokine-like functions in recruitment of macrophages and neutrophils (16). Intracellular Galectin-3 has been shown to exert diverse cellular functions including pre-mRNA splicing (17), regulation of cell growth and cell cycle progression and apoptosis (18). In addition, cytoplasmic Galectin-3 is anti-apoptotic, whereas nuclear and extracellular Galectin-3 is pro-apoptotic molecule (10, 19, 20). The ability of Galectin-3 to function as a potent modulator of immune responses has attracted much attention.

The Role of Galectin-3 in Immunoregulation Galectin-3 is expressed in many immunocompetent and inflammatory cells, either constitutively or in an inducible fashion, suggesting its pleiotropic functions in regulating innate and acquired immune response (21). Galectin-3 may regulate immune response through its ability to modulate immune cell activation, differentiation, migration and apoptosis [reviewed in (21–23)]. 156 In Galectins and Disease Implications for Targeted Therapeutics; Klyosov, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


Mechanisms by which Galectin-3 may participate in regulation of innate immune response are activation and adhesion of neutrophils (24), chemoattraction of monocytes/macrophages (16), opsonization of apoptotic neutrophils (25) and activation of mast cells (26). Further, Galectin-3 can stimulate important pathways involved in the innate immune response including oxidative burst in neutrophils (27) and mast cell degranulation (26). T cells play a central role in the acquired immune response. An important role for Galectin-3 in regulation of T-cell receptor signaling was studied by Demetriou and colleagues (28) who suggested that Galectin-3 might play an inhibitory role in T-cell activation by forming complexes with TCR glycans, therefore limiting TCR clustering necessary for initiation of TCR-mediated signaling. Several studies have demonstrated that Galectin-3 is also involved in T-cell apoptosis. For example, intracellular Galectin-3 inhibits (10), whereas extracellular Galectin-3 induces T-cell apoptosis (29). It has been suggested that although lack of Galectin-3 does not affect differentiation and maturation of dendritic cells (DCs), it greatly influences the magnitude, but not the nature of the acquired immune response (30). This view has been challenged by our data of dendritic cell phenotypes during induction of experimental autoimmune encephalomyelitis (EAE) in Gal-3 deficient mice (31). Breuilh et al. (30) showed that Galectin-3 modulates immune response during helminthic infection and that its expression in dendritic cells controls the magnitude of T-cell priming. We have shown important associations of Galectin-3 with various pathological conditions using several experimental models of T-cell-mediated inflammatory and autoimmune diseases. Our recent study in Galectin-3-deficient mice strongly indicates that Galectin-3 plays an important pro-inflammatory role in Con-A-induced hepatitis by promoting the activation of T lymphocytes, NKT cells and DCs, secretion of pro-inflammatory cytokines and prevention of M2 macrophage polarization and mononuclear cell apoptosis which result in severe liver injury (32). Galectin-3 is also involved in immune-mediated pancreatic β-cell damage and is required for MLD-STZ induced diabetes by promoting the expression of pro-inflammatory IFN-gamma, TNF-alpha and IL-17 as well as iNOS in immune and accessory effector cells (33). Interestingly, Galectin-3 may exert protective effect in obesity induced type 2 diabetes (unpublished data). Namely, we found increased body weight, amount of visceral adipose tissue and fasting blood glucose levels in Gal-3-/- mice fed high-fat diet which was accompanied with adipose tissue inflammation as reflected by increased proportion of Type 1 T and NKT lymphocytes and pro-inflammatory macrophages, and reduced percentages of CD4+CD25+FoxP3+ regulatory T cells. Also pancreatic islet inflammation with marked infiltration of mononuclear cells, higher NLRP3 inflammasome and IL-1ß expression and increased accumulation of advanced glycation endproducts (AGE) and upregulation of receptor for AGE (RAGE) was found in obese Gal-3-/- mice. These data suggest important immunoregulatory and protective roles for Gal-3 in metabolic disorders including type 2 diabetes, which could be of therapeutic importance. We showed that Galectin-3 promotes Th1- and Th17-type cytokine response in a model of autoimmune neuroinflammation (31). Recent findings also demonstrate that Galectin-3 is able to activate immune and inflammatory signaling 157 In Galectins and Disease Implications for Targeted Therapeutics; Klyosov, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


events through phosphorylation of various transcriptional factors, suggesting that Galectin-3 exerts cytokine-like regulatory actions, amplifying the inflammatory cascade in the brain (34). In addition to immunoregulatory roles in various inflammatory and autoimmune diseases, Galectin-3 is also expressed in malignant cells and is involved in tumor development and progression as well as tumor immune escape. In the current review, we focus on the role of Galectin-3 in tumor biology, as evaluated in malignant melanoma.

The Role of Galectin-3 in Tumors Tumor-associated Galectin-3 may play a significant role in different processes important for tumorigenesis and tumor progression through its involvement in regulation of cell proliferation, apoptosis, cell adhesion, invasion, angiogenesis and metastasis (4, 18). Presence of Galectin-3 inside cells promotes malignant cell transformation by stimulating cell growth and inhibiting apoptosis (18). Some studies suggest that increased expression of this lectin may be necessary for malignant transformation of at least some cell types, since inhibition of Galectin-3 expression in cells of human MDA-MB-435 breast cancer cells and thyroid papillary carcinoma, resulted in the loss of the malignant cell phenotype and slower tumor growth (35, 36). These findings were confirmed in experiments in which transfection of normal thyroid follicular cells by Galectin-3 cDNA induced their malignant cell transformation (37). Galectin-3 can trigger malignant cell transformation by interacting with essential components of signalling pathways such as oncogenic Ras proteins (38) since it preferentially binds to K-Ras and causes activation of phosphatidylinositol 3-kinase (PI3K) and Raf1 thus modulating gene expression at the transcriptional level (38, 39). Additional mechanism by which Galectin-3 may participate in tumorigenesis is its action on regulators of cell cycle (18, 40). It has been reported that Galectin-3 downregulates expression of cyclin E and cyclin A and upregulates expression of cell cycle inhibitors p21 (WAF1) and p27 (KIP1) (41). Other studies have shown that Galectin-3 by interacting with β-catenin enhances the expressions of cyclin D and c-myc and promotes cell cycle progression (40, 42). Human MDA-MB-435 breast cancer cells transfected with antisense Galectin-3 cDNA have reduced proliferative capacity, indicating the important role for Galectin-3 in the proliferation of malignant cells (43). Galectin-3 has a role in tumor progression by regulating apoptosis. Overexpression of intracellular Galectin-3 in aggressive form of B cell lymphomas protected these cells from apoptosis (44). Matarrese et al. (45) demonstrated that intracellular Galectin-3 maintains mitochondrial integrity and block release of pro-apoptotic factors, thereby preventing apoptotic cell death. Another mechanism by which Galectin-3 might exert anti-apoptotic action is its interaction with Bcl-2 [reviewed in (18)]. Several studies have indicated that overexpression of Galectin-3 protects malignant cells from apoptosis after the loss of cell 158 In Galectins and Disease Implications for Targeted Therapeutics; Klyosov, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


anchorage (anoikis) (41, 46) that also underlies anticancer drug resistance (45, 47), which is considered to be a hallmark of metastatic phenotype (48, 49). Outside the cell, galectin-3 plays a pivotal role in different steps of tumor progression and metastasis such as cell adhesion, promotion of survival of anchorage dependent cells, invasiveness and migration of metastatic cells (46, 50–52). Cell surface-associated Galectin-3 expressed on tumor cells stimulates homotypic cell-cell adhesion resulting in the formation of tumor emboli allowing survival of malignant cells during hematogeneous dissemination (18, 53, 54). This lectin also stimulates the binding of tumor cells to different components of extracellular matrix (heterotypic interaction), and thus accelerates tumor invasion and metastasis (18, 52). In addition, high levels of circulating Galectin-3 in cancer patients are associated with higher incidence of metastasis in distant organs (55). There are evidence that Galectin-3 may bind to a number of substrates such as Thomsen-Fridenreich antigen and transmembrane mucin protein MUC1 (56, 57). Galectin-3 has been shown to promote motility and invasiveness of malignant cells, and also to affect metastases by exerting its effect on tumor angiogenesis (18). Accumulation of Galectin-3 in lung cancer cells is associated with enhanced cell motility and invasiveness in vitro (58). In addition, Galectin-3 has a role in controlling tumor cell migration and therefore tumor cell invasion by modulating activation or expression of integrins (18, 46). Galectin-3 also participates in angiogenesis by stimulating the migration of endothelial cells in vitro (59). Beside this, it has been reported that Galectin-3 stimulates angiogenesis in vivo that resulted in breast cancer growth in nude mice. It seems that through interaction with αvβ3 integrin, this lectin mediates vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) - mediated angiogenesis (60). Finally, clinical evidence has shown that expression of Galectin-3 is altered in malignant cells (61). Overexpression of Galectin-3 in human tumors generally correlates with tumor progression and metastasis (61). However, the expression of Galectin-3 has been shown to increase (62) or decrease (63) with progression of colorectal carcinoma. Also, decreased expression of this molecule in tumor tissue has been associated with higher metastatic capacity of breast carcinoma cells (64). It seems that Galectin-3 expression is dependent on the organ or tissue, and may be modulated by tumor- or tissue specific factors (61). Additionally, Galectin-3 can modulate the effects of matrix metalloproteinases, so that activity of this lectin in various processes of tumor progression is under control of the enzymes present in the tumor microenvironment (65).

The Role of Galectin-3 in Human Melanoma Human melanoma is the most aggressive form of skin cancer that originates in malignant melanocytes. Malignant transformation of melanocytes is multistep process that involves activation of multiple oncogenes (e.g. N-Ras and BRAF) and the inactivation of tumor suppressor genes (e.g. PTEN and p16IKN4A), resulting in "unplanned" proliferation of melanoma cells which also become immortal and able to invade and metastasize to other tissues (66–68). 159 In Galectins and Disease Implications for Targeted Therapeutics; Klyosov, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


Although the data from studies describing the role of Galectin-3 in the pathogenesis of malignant melanoma are conflicting, the general conclusion is that Galectin-3 could modulate melanoma progression and metastasis. It was demonstrated that expression of Galectin-3 is upregulated in primary and metastatic melanoma lesions compared with benign nevi, suggesting that its overexpression correlates with metastatic progression of human melanoma and poor clinical outcome (69). Further, melanocytes accumulation of Galectin-3, particularly in the nucleus, is associated with melanoma progression. It seems that this translocation of Galectin-3 to nucleus of malignant melanocytes results in a more aggressive tumor behavior, as it acts as a survival factor and renders melanocytes resistant to apoptosis induced by anoikis and chemotherapeutic agents (69). Similarly, Galectin-3 expression was shown to be higher in malignant compared to benign tumor lesions (70). The nuclecytoplasmic pattern of Galectin-3 expression is associated with probability of malignant phenotype and poor prognostic impact on patient’s outcome (70). There are data that expression of Galectin-3 also correlates with lymphatic invasion and distant metastasis, suggesting its pivotal role in lymphogenous metastasis (71). Furthermore, some studies have reported that serum level of Galectin-3 is higher in patients with advanced melanoma (55, 72). Studies using xenograft melanoma model in nude mice with human melanoma cell lines have shown that Galectin-3 expression was lower in metastatic melanoma lesions than in thin primary lesions which was inversely correlated with tumor aggressiveness (73). Given the role of Galectin-3 in adhesion interactions, it seems that the progressive decrease of Galectin-3 levels may act as a trigger for metastatic dissemination of melanocytes (73). The results from clinical study demonstrated higher Galectin-3 expression in thin primary melanomas compared to benign nevi, and a progressive fall in Galectin-3 expression between thin primary melanomas, thicker melanomas and metastatic lesions, suggesting that Galectin-3 might be a marker for melanoma progression (74). Metastatic phenotype of melanoma is associated with high invasive potential, ability of melanocytes to survive and to colonize distant organs, effective tumor angiogenesis and high plasticity of melanocytes (68, 75). For example, highly aggressive melanocytes have the capacity to produce "vasculogenic mimicry" (vasculogenic channels lined by melanoma cells) by expressing endotheliumand epithelium-associated markers, and to form a vasculogenic-like network in vitro (76). The study using human melanoma cell lines has demonstrated that Galectin-3 exerts pro-tumorigenic and pro-metastatic properties by promoting tumor angiogenesis and melanoma cell "vasculogenic mimicry" (77). Galectin-3 might play an important role in tumor immunity by regulating the survival of immune cells in tumor microenvironment. It has been demonstrated that expression of Galectin-3 in human melanoma biopsies correlated with apoptosis of tumor-associated lymphocytes (78), therefore contributing to tumor immune escape. The existing information suggests that Galectin-3 might be a potential therapeutic target in treatment of malignant tumors. 160 In Galectins and Disease Implications for Targeted Therapeutics; Klyosov, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


The Role of Galectin-3 in Murine B16-F1 Melanoma Metastasis A series of experimental and clinical evidence indicate that Galectin-3 on the surface of tumor cells as well as circulating Galectin-3 have regulatory roles in tumor progression and metastasis, but the role of Galectin-3 in regulating anti-tumor immunity and metastatic process in vivo still remains a puzzle. Using Galectin-3-deficient mice we recently provided evidence that expression of Galectin-3 in the host also facilitate establishment of metastasis in B16-F1 malignant melanoma model (79). In fact, Galectin-3 deficient mice were significantly protected against the development of metastatic melanoma reflected by decreased number and size of melanoma colonies in the lung. Based on these findings, we suggest that expression of Galectin-3 on the host cells could be critical for promoting lung tumorigenesis as well as metastasis. Similar conclusion has been drown from the study of NNK-induced lung tumorogenesis in Galectin-3 deficient mice (80). Additionally, we demonstrated that one of the mechanisms contributing to resistance of Galectin-3-deficient mice is lower tumor cell adhesion. In this context, our results from in vitro assays showed that deletion of Galectin-3 decreased number of attached malignant cells in lung tissue sections (79). We assume that endothelial Galectin-3 may be pivotal for the adhesion of tumor cells through its interaction with numerous carbohydrate ligands expressed on tumor cells (54, 81, 82), thus participating in the formation of metastatic foci in target tissue (83). Recent study demonstrated that Galectin-3 by segregation of CD8 from TCR molecule (84) caused anergy of tumor-specific cytotoxic T lymphocytes (CTLs), suggesting that Galectin-3 in tumor microenvironment could impair T-cell mediated anti-tumor immunity in vivo (85). Our study showed that deletion of Galectin-3 in the C57BL/6 mice inhibited formation of metastasis by modifying anti-melanoma immune response (79). We found that Galectin-3-deficient mice had higher serum levels of IFN-gamma and IL-17 compared to wild-type C57BL/6 (WT) mice. Further, injection of melanoma cells resulted in a significant increase in the percentage and total number of regulatory CD4+Foxp3+T cells in WT mice, but not in Galectin-3-deficient mice. Most importantly, we noticed that protective effects of Galectin-3 deficiency on metastatic melanoma spread was dependent on NK cells and associated with an enhanced cytotoxic activity of splenic NK cells in vitro and increased frequency of effective cytotoxic CD27highCD11bhighNK cells as well as immature CD27highCD11blowNK cells in the spleen. On the other side, we showed that WT mice had increased percentage of CD27lowCD11bhigh less functionally exhausted NK cells as well as NK cells bearing inhibitory KLRG1 receptor (79). We postulated that metastatic melanoma spread in WT mice was mainly associated with decreased cytotoxic capacity of NK cells most probably due to increased expansion of suppressive CD4+Foxp3+ T regulatory cells in spleens. Also, an inverse correlation between NK cell activity and expansion of regulatory T cells has been demonstrated in cancer patients (86), indicating that regulatory T cells might hamper NK cell function (87, 88). Our findings indicate that expression of Galectin-3 on the host cells may facilitate melanoma metastasis by affecting tumor cell adhesion and by modulating 161 In Galectins and Disease Implications for Targeted Therapeutics; Klyosov, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.

mainly innate anti-tumor immune response (79). Thus, target inhibition of Galectin-3 expression can prevent melanoma metastasis by decreasing tumor cell adhesion and by enhancing NK cell-mediated anti-tumor immune response.


Effects of Galectin-3 Inhibition in Vitro Given the important roles for Galectin-3 in modulating numerous processes relevant for tumorogenesis and tumor progression, this lectin could be considered as one of molecular targets in the therapy of malignant diseases. Inhibitory effects by certain Galectin-3 inhibitors on growth and metastasis in cancer cell lines have been demonstrated. Thus, treatment of B16-F1 and UV237 with a monoclonal antibody against tumor cell surface lectins before their intravenous injection strongly inhibits experimental lung metastasis of melanoma and fibrosarcoma cells (89). The Galectin-3C is a soluble recombinant galectin that binds carbohydrates and competes with endogenous Galectin-3 for carbohydrate binding sites. It has been shown that Galectin-3C significantly decreased the tumor growth and metastasis of breast MDA-MB-535 carcinoma in a mouse orthotopic model (90). The pH-modified citrus pectin (MCP), a competitive inhibitor for natural ligands of Galectin-3, has been shown to affect homotypic aggregation of B16-F1 melanoma cells (91, 92), angiogenesis and tumor cells adhesion to endothelial cells in vitro (93). In addition, injection of B16-F1 melanoma cells with MCP resulted in a marked decrease of experimental metastasis in the lung tissue (92). Recently, Galectin-3 has sparked interest for developing synthetic selective inhibitors. Thus, thiodigalactoside diester Td131_1 preferentially binds and inhibits Galectin-3, because it has a high affinity and specificity for this lectin due to the specific interactions of its two ester moieties with Arg144 and Arg186 of Galectin-3 (94). Data from Lin et al (95) demonstrated that treatment of papillary thyroid cancer cell lines and human ex vivo papillary thyroid cancer with Td131_1 results in their enhanced sensitivity to chemotherapeutic drug such as doxorubicin. It seems that Td131_1 activates apoptosis and improves the sensitivity of papillary thyroid cancer cells to radiotherapy and to chemotherapy in a synergistic fashion, suggesting that Galectin-3 inhibitor is a promising agent for advanced tumors that are refractory to conventional therapies. Interestingly, pre-treatment of C57BL/6 mice with selective inhibitor of Galectin-3 (TD139) led to attenuation of liver injury in Concanavalin A-induced hepatitis model in vivo (32). These observations clearly indicate that blockade of Galectin-3 might result in therapeutic benefits in cancer metastasis as well as in autoimmune and inflammatory diseases.

Acknowledgments This study is supported by grants: ON175069, ON175071 and ON175103 from Ministry of Education and Science, and from the Faculty of Medical Science, University of Kragujevac (project JP 01/10), Serbia. 162 In Galectins and Disease Implications for Targeted Therapeutics; Klyosov, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.

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