Galectins In Cancer Research Articles

Placental Galectins in Cancer: Why We Should Pay More Attention.

The first studies suggesting that abnormal expression of galectins is associated with cancer were published more than 30 years ago. Today, the role of galectins in cancer is relatively well established. We know that galectins play an active role in many types of cancer by regulating cell growth, conferring cell death resistance, or inducing local and systemic immunosuppression, allowing tumor cells to escape the host immune response. However, most of these studies have focused on very few galectins, most notably galectin-1 and galectin-3, and more recently, galectin-7 and galectin-9. Whether other galectins play a role in cancer remains unclear. This is particularly true for placental galectins, a subgroup that includes galectin-13, -14, and -16. The role of these galectins in placental development has been well described, and excellent reviews on their role during pregnancy have been published. At first sight, it was considered unlikely that placental galectins were involved in cancer. Yet, placentation and cancer progression share several cellular and molecular features, including cell invasion, immune tolerance and vascular remodeling. The development of new research tools and the concomitant increase in database repositories for high throughput gene expression data of normal and cancer tissues provide a new opportunity to examine the potential involvement of placental galectins in cancer. In this review, we discuss the possible roles of placental galectins in cancer progression and why they should be considered in cancer studies. We also address challenges associated with developing novel research tools to investigate their protumorigenic functions and design highly specific therapeutic drugs.

Inhibition of galectins in cancer: Biological challenges for their clinical application.

Galectins play relevant roles in tumor development, progression and metastasis. Accordingly, galectins are certainly enticing targets for medical intervention in cancer. To date, however, clinical trials based on galectin inhibitors reported inconclusive results. This review summarizes the galectin inhibitors currently being evaluated and discusses some of the biological challenges that need to be addressed to improve these strategies for the benefit of cancer patients.

Exploring the Role of Galectins in Cancer : In Vitro and In Vivo Approaches.

Galectins have been linked to tumorigenesis since 1975, even before this family of proteins was given its name. Since then, hundreds of papers have analyzed the role of different galectins in cancer development and progression, deciphering their involvement in many different pathological events, from the regulation of cell cycle, to angiogenesis, metastasis, and immune attack evasion. Importantly, the tumor galectin profile is often altered in many cancers and aberrant levels of some of the members of this family have been considered in diagnosis and frequently correlated with patient prognosis and clinicopathological characteristics. In this chapter, we summarize most frequent techniques employed in cancer research to interrogate the role of galectins, using Gal-1 to illustrate one member of the family and pancreatic cancer as an experimental model. We will cover from techniques employed to detect their expression (tissue and blood samples) to the most frequent tools used to change expression levels and the cell line-based in vitro studies and murine preclinical models used to explore their role in tumor progression and/or clinical translation.

Critical appraisal of epigenetic regulation of galectins in cancer.

Galectins are defined as the glycan-binding protein containing either one or two carbohydrate-binding domains and participate in various biological functions such as developmental processes, vascularisation programs, cell migration, and immune-regulation and apoptosis. Galectins are also linked to many diseases, including cancer. They are widely spread in extracellular and intracellular spaces, and their altered expression in cancer leads to tumor progression, metastasis, angiogenesis and stemness through different signalling pathways. Promoter methylation, microRNA, and histone modification constitute the epigenetic changes that regulate galectin activity in cancer. Our review discusses the concept of epigenetics in cancer and how the aforementioned factors i.e., promoter methylation, histone modification, change in miRNAs expression affect the glycomic changes in malignancies.

Galectins in Cancer and the Microenvironment: Functional Roles, Therapeutic Developments, and Perspectives.

Changes in cell growth and metabolism are affected by the surrounding environmental factors to adapt to the cell’s most appropriate growth model. However, abnormal cell metabolism is correlated with the occurrence of many diseases and is accompanied by changes in galectin (Gal) performance. Gals were found to be some of the master regulators of cell–cell interactions that reconstruct the microenvironment, and disordered expression of Gals is associated with multiple human metabolic-related diseases including cancer development. Cancer cells can interact with surrounding cells through Gals to create more suitable conditions that promote cancer cell aggressiveness. In this review, we organize the current understanding of Gals in a systematic way to dissect Gals’ effect on human disease, including how Gals’ dysregulated expression affects the tumor microenvironment’s metabolism and elucidating the mechanisms involved in Gal-mediated diseases. This information may shed light on a more precise understanding of how Gals regulate cell biology and facilitate the development of more effective therapeutic strategies for cancer treatment by targeting the Gal family.

Decoding the sweet regulation of apoptosis: the role of glycosylation and galectins in apoptotic signaling pathways.

Glycosylation and glycan-binding proteins such as galectins play an important role in the control of cell death signaling. Strikingly, very little attention has been given so far to the understanding of the molecular details behind this key regulatory network. Glycans attached to the death receptors such as CD95 and TRAIL-Rs, either alone or in a complex with galectins, might promote or inhibit apoptotic signals. However, we have just started to decode the functions of galectins in the modulation of extrinsic and intrinsic apoptosis. In this work, we have discussed the current understanding of the glycosylation-galectin regulatory network in CD95- as well as TRAIL-R-induced apoptosis and therapeutic strategies based on targeting galectins in cancer.

Galectin Targeted Therapy in Oncology: Current Knowledge and Perspectives.

The incidence and mortality of cancer have increased over the past decades. Significant progress has been made in understanding the underpinnings of this disease and developing therapies. Despite this, cancer still remains a major therapeutic challenge. Current therapeutic research has targeted several aspects of the disease such as cancer development, growth, angiogenesis and metastases. Many molecular and cellular mechanisms remain unknown and current therapies have so far failed to meet their intended potential. Recent studies show that glycans, especially oligosaccharide chains, may play a role in carcinogenesis as recognition patterns for galectins. Galectins are members of the lectin family, which show high affinity for β-galactosides. The galectin–glycan conjugate plays a fundamental role in metastasis, angiogenesis, tumor immunity, proliferation and apoptosis. Galectins’ action is mediated by a structure containing at least one carbohydrate recognition domain (CRD). The potential prognostic value of galectins has been described in several neoplasms and helps clinicians predict disease outcome and determine therapeutic interventions. Currently, new therapeutic strategies involve the use of inhibitors such as competitive carbohydrates, small non-carbohydrate binding molecules and antibodies. This review outlines our current knowledge regarding the mechanism of action and potential therapy implications of galectins in cancer.

Galectin-7 in Epithelial Homeostasis and Carcinomas.

Galectins are small unglycosylated soluble lectins distributed both inside and outside the cells. They share a conserved domain for the recognition of carbohydrates (CRD). Although galectins have a common affinity for β-galatosides, they exhibit different binding preferences for complex glycans. First described twenty years ago, galectin-7 is a prototypic galectin, with a single CRD, able to form divalent homodimers. This lectin, which is mainly expressed in stratified epithelia, has been described in epithelial tissues as being involved in apoptotic responses, in proliferation and differentiation but also in cell adhesion and migration. Most members of the galectins family have been associated with cancer biology. One of the main functions of galectins in cancer is their immunomodulating potential and anti-angiogenic activity. Indeed, galectin-1 and -3, are already targeted in clinical trials. Another relevant function of galectins in tumour progression is their ability to regulate cell migration and cell adhesion. Among these galectins, galectin-7 is abnormally expressed in various cancers, most prominently in carcinomas, and is involved in cancer progression and metastasis but its precise functions in tumour biology remain poorly understood. In this issue, we will focus on the physiological functions of galectin-7 in epithelia and present the alterations of galectin-7 expression in carcinomas with the aim to describe its possible functions in tumour progression.

Biotinylated N-Acetyllactosamine- and N,N-Diacetyllactosamine-Based Oligosaccharides as Novel Ligands for Human Galectin-3.

Galectin inhibitor design is an emerging research field due to the involvement of galectins in cancer. Galectin-3, in particular, plays an important role in tumor progression. To generate inhibitors, modifications of the glycan structure can be introduced. Conjugation of hydrophobic compounds to saccharides has proven to be promising as increased binding of galectin-3 can be observed. In the present study, we report on neo-glycans carrying hydrophobic biotin as novel ligands for human galectin-3. We modified N-acetyllactosamine- and N,N-diacetyllactosamine-based tetrasaccharides at the C6-position of the terminal saccharide unit using selective enzymatic oxidation and subsequent chemical conjugation of biotinamidohexanoic acid hydrazide. These neo-glycans were much better bound by galectin-3 than the unmodified counterparts. High selectivity for galectin-3 over galectin-1 was also proven. We generated multivalent neo-glycoproteins by conjugation of neo-glycans to bovine serum albumin showing high affinity for galectin-3. Compared to non-biotinylated neo-glycoproteins, we achieved high binding levels of galectin-3 with a lesser amount of conjugated neo-glycans. Multivalent ligand presentation of neo-glycoproteins significantly increased the inhibitory potency towards galectin-3 binding to asialofetuin when compared to free monovalent glycans. Our findings show the positive impact of 6-biotinylation of tetrasaccharides on galectin-3 binding, which broadens the recent design approaches for producing high-affinity ligands.

Roles of Galectin-7 in Cancer.

Galectins are β-galactoside binding lectins that contain one or more carbohydrate recognition domains. As a consequence of sugar-binding properties, galectins exhibit a variety of interactions with glycoproteins, thus playing important roles in various pathological processes. A number of studies have shown roles of galectins in cancer. Galectin-7 is a prototype member of the galectin family implicated in epithelial stratification and cell migration. It can act as a potent dual regulator in different types of cancer. Galectin-7 may contribute either to neoplastic transformation and tumour progression through regulation of cell growth, cell cycle, angiogenesis, apoptosis and cell migration or may have a protective effect in cancer depending on the tissue type. A perusal of the literature indicates particular roles of galectin-7 in carcinomas and melanomas, while contributions await greater exploration in other types of cancers including sarcomas and leukemia. This review collectively summarizes available literature on expression and roles of galectin-7 in different cancers.

Galectins in cancer: carcinogenesis, diagnosis and therapy.

A major breakthrough in the field of medical oncology has been the discovery of galectins and their role in cancer development, progression and metastasis. In this review article we have condensed the results of a number of studies published over the past decade in an effort to shed some light on the unique role played by the galectin family of proteins in neoplasia, and how this knowledge may alter the approach to cancer diagnosis as well as therapy in the future. In this review we have also emphasized the potential use of galectin inhibitors or modulators in the treatment of cancer and how this novel treatment modality may affect patient outcomes in the future. Based on current pre-clinical models we believe the use of galectin inhibitors/modulators will play a significant role in cancer treatment in the future. Early clinical studies are underway to evaluate the utility of these promising agents in cancer patients.

Intracellular galectins in cancer cells: Potential new targets for therapy

Dysregulation of galectin expression is frequently observed in cancer tissues. Such an abnormal expression pattern often correlates with aggressiveness and relapse in many types of cancer. Because galectins have the ability to modulate functions that are important for cell survival, migration and metastasis, they also represent attractive targets for cancer therapy. This has been well-exploited for extracellular galectins, which bind glycoconjugates expressed on the surface of cancer cells. Although the existence of intracellular functions of galectins has been known for many years, an increasing number of studies indicate that these proteins can also alter tumor progression through their interaction with intracellular ligands. In fact, in some instances, the interactions of galectins with their intracellular ligands seem to occur independently of their carbohydrate recognition domain. Such findings call for a change in the basic assumptions, or paradigms, concerning the activity of galectins in cancer and may force us to revisit our strategies to develop galectin antagonists for the treatment of cancer.

New Roles for Galectins in Brain Tumors-From Prognostic Markers to Therapeutic Targets

Despite advances in diagnosis and treatment, brain tumors continue to be the leading cause of cancer-related death in patients under 35 years of age, demonstrating the need for better prognostic and therapeutic targets. Galectins, a family of mammalian carbohydrate binding proteins, are involved in many processes important for tumor survival and dissemination, including proliferation, apoptosis, transcriptional regulation, intracellular signaling, cell adhesion, and cell migration. Several galectins are expressed in human brain, with many galectins demonstrating altered expression during tumor progression. Thus, galectins and the functions regulated by this family of proteins are potential targets for the diagnosis and treatment of brain cancer. This review highlights the roles of galectins in cancer and specifically, the developing field of galectins in brain cancer.

Expression of galectins in cancer: a critical review.

A large body of literature has examined and described galectin expression in cancer. Discrepancies have been observed in the reported data, which hampered clear understanding of the expression profiles. This relates to the use of different types of methods that evaluate either global or specific gene expression in heterogeneous cancer tissue samples, type of antibodies used in immunohistochemistry and procedures of comparison of gene expression. In this manuscript, we review the main data concerning expression of galectins in human cancer. Only galectin-1 and galectin-3, the most abundant and examined galectins, will be examined here.

90K (Mac-2 BP) and galectins in tumor progression and metastasis.

Galectins and their ligands have been implicated in cell transformation and cancer metastasis, and found to have prognostic value. Mac-2 BP, also known as 90K, is a highly glycosylated, secreted protein extensively studied in human cancer, which binds galectin-1, galectin-3 and galectin-7. High expression levels of 90K are associated with a shorter survival, the occurrence of metastasis or a reduced response to chemotherapy in patients with different types of malignancy. The mechanisms underlying the prognostic significance of 90K and galectins in cancer are far from being understood, although they may be related to the ability of these proteins to interact and, to some extent, modulate cell-cell and cell-matrix adhesion and apoptosis. The resulting scenario is even more complex, as data have been presented that all these proteins might be associated with either a positive or a negative outcome of the patients. It is hypothesised that different galectins and galectin ligands with overlapping or opposite functions, expressed in different tumors during the different steps of the metastatic cascade might play a crucial role in tumor progression.

Introduction to galectins.

Good evidence suggest roles of galectins in cancer, immunity and inflammation, and development, but a unifying picture of their biological function is lacking. Instead galectins appear to have a particularly diverse, bewildering but intriguing array of activities both inside and outside cells--"clear truths and mysteries are inextricably twined". Fortunately this has not discouraged but rather enthused a large number of good galectin researchers, some of which have contributed to this special issue of Glycoconjugate Journal to provide a personal, critical status of the field. Here we will give a brief introduction to the galectins as a protein family with some comments on nomenclature.