The relevance of glycan-binding protein in immune tolerance and inflammation has been well established, mainly by studies of C-type lectins, siglecs and galectins both in experimental models and patient samples. Galectins, a family of evolutionarily conserved lectins, are characterized by sequence homology in the carbohydrate-recognition domain (CRD), atypical secretion via an ER-Golgi-independent pathway and the ability to recognize β-galactoside-containing saccharides. Galectin-1 (Gal-1), a prototype member of this family displays mainly anti-inflammatory and immunosuppressive activities, although, similar to many cytokines and growth factors, it may also trigger paradoxical pro-inflammatory effects under certain circumstances. These dual effects could be associated to tissue-, time- or context-dependent regulation of galectin expression and function, including particular pathophysiologic settings and/or environmental conditions influencing the structure of this lectin, as well as the availability of glycosylated ligands in immune cells during the course of inflammatory responses. Here, we discuss the tissue-specific role of Gal-1 as a master regulator of inflammatory responses across different pathophysiologic settings, highlighting its potential role as a therapeutic target. Further studies designed at analyzing the intrinsic and extrinsic pathways that control Gal-1 expression and function in different tissue microenvironments may contribute to design tailored therapeutic strategies aimed at positively or negatively modulate this glycan-binding protein in pathologic inflammatory conditions.
The role of active antitumor immunity in hormone receptor–positive (HR+) breast cancer has been historically underlooked. The aim of this study was to determine the contribution of the immune system to antiprogestin-induced tumor growth inhibition using a hormone-dependent breast cancer model. BALB/c-GFP+ bone marrow (BM) cells were transplanted into immunodeficient NSG mice to generate an immunocompetent NSG/BM-GFP+ (NSG-R) mouse model. Treatment with the antiprogestin mifepristone (MFP) inhibited growth of 59–2-HI tumors with similar kinetics in both animal models. Interestingly, MFP treatment reshaped the tumor microenvironment, enhancing the production of proinflammatory cytokines and chemokines. Tumors in MFP-treated immunocompetent mice showed increased infiltration of F4/80+ macrophages, natural killer, and CD8 T cells, displaying a central memory phenotype. Mechanistically, MFP induced immunogenic cell death (ICD) in vivo and in vitro, as depicted by the expression and subcellular localization of the alarmins calreticulin and HMGB-1 and the induction of an ICD gene program. Moreover, MFP-treated tumor cells efficiently activated immature dendritic cells, evidenced by enhanced expression of MHC-II and CD86, and induced a memory T-cell response, attenuating tumor onset and growth after re-challenge. Finally, MFP treatment increased the sensitivity of HR+ 59–2-HI tumor to PD-L1 blockade, suggesting that antiprogestins may improve immunotherapy response rates. These results contribute to a better understanding of the mechanisms underlying the antitumor effect of hormonal treatment and the rational design of therapeutic combinations based on endocrine and immunomodulatory agents in HR+ breast cancer. Significance: Antiprogestin therapy induces immunogenic tumor cell death in PRA-overexpressing tumors, eliciting an adaptive immune memory response that protects mice from future tumor recurrence and increases sensitivity to PD-L1 blockade.
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.
Development of improved drug and gene delivery systems directly into the lungs is highly desirable given the important burden of respiratory diseases. We aimed to evaluate the safety and efficacy of liposomes composed of photopolymerized lipids [1,2-bis-(tricosa-10,12-diynoyl)-sn-glycero-3-phosphocholine] associated with amino acids as vectors for gene delivery into the lungs of healthy animals. Lipopolymer vesicles, in particular, are more stable than other types of liposomes. In this study, lipopolymers were associated with l-arginine, l-tryptophan, or l-cysteine. We hypothesized that the addition of these amino acids would enhance the efficacy of gene delivery to the lungs by the lipopolymers. l-Arginine showed the highest association efficiency due to its positive charge and better surface interactions. None of the formulations caused inflammation or altered lung mechanics, suggesting that these lipopolymers can be safely administered as aerosols. All formulations were able to induce eGFP mRNA expression in lung tissue, but the addition of amino acids reduced delivery efficacy when compared with the simple lipopolymer particle. These results indicate that this system could be further explored for gene or drug delivery targeting lung diseases.
Aims:In this work, we developed and characterized liposomal formulations that encapsulate Lcysteine to study their further application in drug delivery and amino acid supplementation. The lipids used were 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC). Methodology: Encapsulation efficiency and amino acid release were determined. For biophysical characterization of the three formulations, the size, surface charge and surface packing were also studied. Cell viability was analyzed with MTT reagent after treatments with formulations ir order to study efficiency of these systems in induce changes in metabolism. Results: Results showed that L-cysteine interacts at the polar head level and that this interaction stabilizes the surface charge and prevents aggregation. We also determined the influence on cell metabolism in all formulations. The presence of L-cysteine in the DSPC formulation induced deeper Perrotta et al.; BBJ, 12(4): 1-11, 2016; Article no.BBJ.24723 2 changes in metabolism, evidencing that this formulation provides better transport of this amino acid. Conclusion: Liposomes developed herein are well suited for the application in the delivery of L-cysteine. Particularly, they can encapsulate nearly all the L-cysteine and can retain it for 6 hours. Also, L-cysteine stabilized liposomes, preventing their aggregation. L-cysteine encapsulated in the DSPC formulation induced deeper changes in cell metabolism, causing a decrease in metabolic activity; this was probably due to a higher entry, thus a better liposome-mediated transport. Considering that the smaller the particle, the better the circulation, we believe that the stabilization of the vesicle by L-cysteine may allow these transporters to have higher circulation times. Based on the above, we conclude that the DSPC formulation is the best suited for further application in L-cysteine delivery. Original Research Article
Endogenous lectins play key roles in cell homeostasis by decoding the information encrypted in glycans present on the cell surface or extracellular matrix. Galectins, a family of soluble lectins, have emerged as central regulators of innate and adaptive immune responses. In this article, we review seminal work demonstrating the immunoregulatory roles of Galectin-1 (Gal-1), a proto-type member of the galectin family, and highlight central mechanisms that control its functions in cancer and autoimmune inflammation. Understanding the cellular pathways that control Gal-1 expression and function in tumor and inflammatory microenvironments will set the bases for the design of rational therapies based on positive or negative modulation of this endogenous lectin in cancer and autoimmune diseases.
Galectins decode glycan-containing information in a number of cell receptors adjusting signaling thresholds and modulating cellular functions. Upon specific binding to cell surface glycans these lectins control receptor clustering, endocytosis and signaling, influencing many physiological and pathological conditions. In particular, galectin-1 (Gal1), a 14kD prototype galectin, binds to terminal N-acetyllactosamine residues on glycosylated proteins in the absence of α2-6 sialic acid capping (Gal1 permissive glycophenotype). In early studies, our group demonstrated that tumors usurp the Gal1 pathway to evade immune surveillance and to promote aberrant angiogenesis, influencing sensitivity to anti-VEGF therapy. Here we aim to explore the glycosylation signature of HER2+ breast cancer cells and to investigate the effects of tumor-derived Gal1 on RTK activation and resistance to trastuzumab (TZ). We first selected three HER2+ human breast cancer cell lines with different response to TZ: JIMT-1 (resistant-TZR), BT-474 and SK-BR-3 (sensitive-TZS). To identify specific glycan structures, we used a panel of biotinylated plant lectins with different carbohydrate specificities. We found that TZS cell lines exhibited a Gal-1 restrictive glycophenotype characterized by high α2,6 sialic acid capping. Profiling of N-type glycans (WAX-HPLC) confirmed that TZSs cell lines exhibit higher frequency of α2,6 sialic acid residues compared to TZR JIMT-1. This effect was further substantiated by RT-PCR analysis of specific glycosyltransferases responsible of Gal1 ligands biosynthesis. These results were supported by analysis of raw data from public databases arrays (GSE62327) showing that patients who presented complete response to TZ exhibited higher levels of ST6GAL1, a glycosyltransferase responsible for α2-6 sialic acid capping. In accordance with the glycophenotype, TZR cell line bound and expressed higher levels of Gal1 when compared to TZS cell lines by Western blot, RT-PCR and ELISA of conditioned medium, suggesting a positive autocrine loop that could modulate cell behavior. Moreover, in silico analysis of raw data from the Long HER Study (GSE44272) revealed that patients with poor response to TZ expressed higher levels of Gal1 mRNA than long-term responders, reinforcing our hypothesis from a clinical standpoint. Finally, in order to elucidate Gal1 implications in TZ resistance, we knocked down Gal1 in JIMT-1 cell line using shRNA strategies. Remarkably, absence of Gal1 expression sensitized JIMT-1 cells to TZ-inhibition in vitro, and the resistant phenotype was further reestablished by addition of human recombinant Gal1. In summary, our study suggests that individual HER2+ human breast cancer cells display particular “glycosylation signatures” which, in association with Gal1 expression pattern, may control resistance to anti-HER2 targeted therapy and may predict breast cancer clinical outcome. Citation Format: Ramiro M. Perrotta, Tomás Dalotto-Moreno, Alejandro Cagnoni, Karina Mariño, Gabriel Rabinovich, Mariana Salatino. Glycosylation of HER2+ human breast cancer cells control sensitivity to trastuzumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1840.
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