Under nonpathological conditions, the extracellular nucleotide concentration remains constant and low (nM range) because of a close balance between ATP release and ATP consumption. This balance is ...completely altered in cancer disease. Adenine and uridine nucleotides are found in the extracellular space of tumors in high millimolar (mM) concentrations acting as extracellular signaling molecules. In general, although uridine nucleotides may be involved in different tumor cell responses, purinergic signaling in cancer is preferentially focused on adenine nucleotides and nucleosides. Extracellular ATP can bind to specific receptors (P receptors) triggering different responses, or it can be hydrolyzed by ectoenzymes bound to cell membranes to render the final product adenosine. The latter pathway plays an important role in the increase of adenosine in tumor microenvironment. In this study, we will focus on extracellular ATP and adenosine, their effects acting as ligands of specific receptors, activating ectoenzymes, and promoting epithelial–mesenchymal transition, migration, and invasion in cancer cells. Finding the roles that these nucleotides play in tumor microenvironment may be important to design new intervention strategies in cancer therapies.
Under pathological conditions, such as cancer, there is an increase in extracellular ATP levels. Also, there is an upregulation of the expression of ectoenzymes that sequentially promote ATP hydrolysis and adenosine accumulation. They can activate specific P receptors that have a role in epithelial–mesenchymal transition, cell migration, and invasion.
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•In mouse models, intracellular ALCAM depletion reduces tumor growth.•Circulating ALCAM emerges as a potential biomarker for tumor progression.•ALCAM alternative splicing regulates ...cell adhesion by introducing proteolytic susceptibility.•Expression of ALCAM-Iso2 isoform increases with progression in particular tumors.•ALCAM is a cancer stem cell marker in several tumors.
Activated Leukocyte Cell Adhesion Molecule (ALCAM/CD166) is a glycoprotein involved in homotypic and heterotypic cell adhesion. ALCAM can be proteolytically cleaved at the cell surface by metalloproteases, which generate shedding of its ectodomain. In various tumors, ALCAM is overexpressed and serves as a valuable prognostic marker of disease progression. Moreover, CD166 has been identified as a putative cancer stem cell marker in particular cancers. Herein, we summarize biochemical aspects of ALCAM, including structure, proteolytic shedding, alternative splicing, and specific ligands, and integrate this information with biological functions of this glycoprotein including cell adhesion, migration and invasion. In addition, we discuss different patterns of ALCAM expression in distinct tumor types and its contribution to tumor progression. Finally, we highlight the role of ALCAM as a cancer stem cell marker and introduce current clinical trials associated with this molecule. Future studies are needed to define the value of shed ALCAM in biofluids or ALCAM isoform expression as prognostic biomarkers in tumor progression.
Galectins, a family of evolutionarily conserved glycan-binding proteins, play key roles in diverse biological processes including tissue repair, adipogenesis, immune cell homeostasis, angiogenesis, ...and pathogen recognition. Dysregulation of galectins and their ligands has been observed in a wide range of pathologic conditions including cancer, autoimmune inflammation, infection, fibrosis, and metabolic disorders. Through protein–glycan or protein–protein interactions, these endogenous lectins can shape the initiation, perpetuation, and resolution of these processes, suggesting their potential roles in disease monitoring and treatment. However, despite considerable progress, a full understanding of the biology and therapeutic potential of galectins has not been reached due to their diversity, multiplicity of cell targets, and receptor promiscuity. In this article, we discuss the multiple galectin-binding partners present in different cell types, focusing on their contributions to selected physiologic and pathologic settings. Understanding the molecular bases of galectin–ligand interactions, particularly their glycan-dependency, the biochemical nature of selected receptors, and underlying signaling events, might contribute to designing rational therapeutic strategies to control a broad range of pathologic conditions.
Gastrointestinal cancer is a group of tumors that affect multiple sites of the digestive system, including the stomach, liver, colon and pancreas. These cancers are very aggressive and rapidly ...metastasize, thus identifying effective targets is crucial for treatment. Galectin-1(Gal-1) belongs to a family of glycan-binding proteins, or lectins, with the ability to cross-link specific glycoconjugates. A variety of biological activities have been attributed to Gal-1 at different steps of tumor progression. Herein, we summarize the current literature regarding the roles of Gal-1 in gastrointestinal malignancies. Accumulating evidence shows that Gal-1 is drastically up-regulated in human gastric cancer, hepatocellular carcinoma, colorectal cancer and pancreatic ductal adenocarcinoma tissues, both in tumor epithelial and tumor-associated stromal cells. Moreover, Gal-1 makes a crucial contribution to the pathogenesis of gastrointestinal malignancies, favoring tumor development, aggressiveness, metastasis, immunosuppression and angiogenesis. We also highlight that alterations in Gal-1-specific glycoepitopes may be relevant for gastrointestinal cancer progression. Despite the findings obtained so far, further functional studies are still required. Elucidating the precise molecular mechanisms modulated by Gal-1 underlying gastrointestinal tumor progression, might lead to the development of novel Gal-1-based diagnostic methods and/or therapies.
Galectin-8 (Gal-8), a ‘tandem-repeat’-type galectin, has been described as a modulator of cellular functions including adhesion, spreading, growth arrest, apoptosis, pathogen recognition, autophagy, ...and immunomodulation. We have previously shown that activated leukocyte cell adhesion molecule (ALCAM), also known as CD166, serves as a receptor for endogenous Gal-8. ALCAM is a member of the immunoglobulin superfamily involved in cell-cell adhesion through homophilic (ALCAM-ALCAM) and heterophilic (i.e. ALCAM-CD6) interactions in different tissues. Here we investigated the physiologic relevance of ALCAM-Gal-8 association and glycosylation-dependent mechanisms governing these interactions. We found that silencing of ALCAM in MDA-MB-231 triple negative breast cancer cells decreases cell adhesion and migration onto Gal-8-coated surfaces in a glycan-dependent fashion. Remarkably, either Gal-8 or ALCAM silencing also disrupted cell-cell adhesion, and led to reduced tumor growth in a murine model of triple negative breast cancer. Moreover, structural characterization of endogenous ALCAM N-glycosylation showed abundant permissive structures for Gal-8 binding. Importantly, we also found that cell sialylation controls Gal-8-mediated cell adhesion. Altogether, these findings demonstrate a central role of either ALCAM or Gal-8 (or both) in controlling triple negative breast cancer.
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•ALCAM silencing decreases in vitro cell adhesion and migration onto Gal-8.•Surface ALCAM establishes glycan-dependent cell interactions with Gal-8.•Either Gal-8 or ALCAM silencing attenuates cell-cell aggregation.•In mouse xenografts, Gal-8 and ALCAM silencing synergistically slow down tumor growth.
Galectins are a taxonomically widespread family of glycan-binding proteins, defined by at least one conserved carbohydrate-recognition domain with a canonical amino acid sequence and affinity for ...β-galactosides. Because of their anti-adhesive as well as pro-adhesive extracellular functions, galectins appear to be a novel class of adhesion-modulating proteins collectively known as matricellular proteins (which include thrombospondin, SPARC, tenascin, hevin, and disintegrins). Accordingly, galectins can display de-adhesive effects when presented as soluble proteins to cells in a strong adhesive state. In this context, the de-adhesive properties of galectins should be considered as physiologically relevant as the proadhesive effects of these glycan-binding proteins. This article focuses on the roles of mammalian galectins in cell adhesion, spreading, and migration, and the crossregulation of these functions. Although careful attention should be paid when examining individual galectin functions due to overlapping distributions, these intriguing glycan-binding proteins offer promising possibilities for the treatment and intervention of a wide variety of pathological processes, including cancer, inflammation, and autoimmunity.
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ClasSOMfier is a software package to classify atoms into a given number of disconnected groups (or clusters) and detect lattice defects, such as vacancies, interstitials, ...dislocations, voids and grain boundaries. Each cluster is formed by atoms whose atomic environment can be described by a common pattern. Unlike many methods available in the literature, where these patterns are given in advance and are associated with known lattice structures (i.e. fcc, bcc or hcp), this code implements a Kohonen network, which is based on unsupervised learning and where no information about the atomic environment has to be given in advance. ClasSOMfier accelerates the application of machine learning for cluster analysis by providing an efficient and fast code in Fortran with a user-friendly interface in Python.
Angiogenesis, the growth of new capillaries from preexisting blood vessels, is a complex process involving endothelial cell (EC) activation, disruption of vascular basement membranes, and migration ...and proliferation of ECs. Glycan‐mediated recognition has been proposed to play an instrumental role in mediating cell‐cell and cell‐matrix interactions. Ga‐lectins (Gal), a family of glycan‐binding proteins with affinity for β‐galactosides and a conserved sequence motif, can decipher glycan‐containing information and mediate cell‐cell communication. Galectin‐8 (Gal‐8), a member of this family, is a bivalent “tandem‐repeat”‐type galectin, which possesses 2 CRDs connected by a linker peptide. Here, we show that Gal‐8 is endowed with proangiogeneic properties. Functional assays revealed a critical role for this lectin in the regulation of capillary‐tube formation and EC migration. Moreover, Matrigel, either supplemented with Gal‐8 or vascular endothelial growth factor (VEGF), injected in mice resulted in induction of in vivo angiogenesis. Remarkably, Gal‐8 was expressed both in the cytoplasm and nucleus in ECs of normal and tumor vessels. Furthermore, CD166 activated leukocyte cell adhesion molecule (ALCAM) was identified as a specific Gal‐8‐binding partner in normal vascular ECs. Collectively, these data provide the first evidence demonstrating an essential role for Gal‐8 in the regulation of angiogenesis with critical implications in tumor biology.—CCárdenasrdenas Delgado, V. M., Nugnes, L. G., Colombo, L. L., Troncoso, M. F., Fernández, M. M., Malchiodi, E. L., Frahm, I., Croci, D. O., Compagno, D., Rabinovich, G. A., Wolfenstein‐Todel, C., Elola, M. T. Modulation of endothelial cell migration and angiogenesis: a novel function for the “tandem‐repeat” lectin galectin‐8. FASEB J. 25, 242–254 (2011). www.fasebj.org
Abstract Galectin-1 (Gal-1), a member of a highly conserved family of animal lectins, binds to the common disaccharide Galβ(1-4)-GlcNAc on both N - and O -glycans decorating cell surface ...glycoconjugates. Current evidence supports a role for Gal-1 in the pathophysiology of multiple sclerosis (MS), one of the most prevalent chronic inflammatory diseases. Previous studies showed that Gal-1 exerts neuroprotective effects by promoting microglial deactivation in a model of autoimmune neuroinflammation and induces axonal regeneration in spinal cord injury. Seeking a model that could link demyelination, oligodendrocyte (OLG) responses and microglial activation, here we used a lysolecithin (LPC)-induced demyelination model to evaluate the ability of Gal-1 to preserve myelin without taking part in T-cell modulation. Gal-1 treatment after LPC-induced demyelination promoted a significant decrease in the demyelinated area and fostered more efficient remyelination, concomitantly with an attenuated oligodendroglial progenitor response reflecting less severe myelination damage. These results were accompanied by a decrease in the area of microglial activation with a shift toward an M2-polarized microglial phenotype and diminished astroglial activation. In vitro studies further showed that, mechanistically, Gal-1 targets activated microglia, promoting an increase in their myelin phagocytic capacity and their shift toward an M2 phenotype, and leads to oligodendroglial differentiation. Therefore, this study supports the use of Gal-1 as a potential treatment for demyelinating diseases such as MS.
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