Galectin-3, the only chimera galectin found in vertebrates, is one of the best-studied galectins. It is expressed in several cell types and is involved in a broad range of physiological and ...pathological processes, such as cell adhesion, cell activation and chemoattraction, cell cycle, apoptosis, and cell growth and differentiation. However, this molecule raises special interest due to its role in regulating cancer cell activities. Galectin-3 has high affinity for β-1,6-N-acetylglucosamine branched glycans, which are formed by the action of the β1,6-N-acetylglucosaminyltransferase V (Mgat5). Mgat5-related changes in protein/lipid glycosylation on cell surface lead to alterations in the clustering of membrane proteins through lattice formation, resulting in functional advantages for tumor cells. Galectin-3 presence enhances migration and/or invasion of many tumors. Galectin-3-dependent clustering of integrins promotes ligand-induced integrin activation, leading to cell motility. Galectin-3 binding to mucin-1 increases transendothelial invasion, decreasing metastasis-free survival in an experimental metastasis model. Galectin-3 also affects endothelial cell behavior by regulating capillary tube formation. This lectin is found in the tumor stroma, suggesting a role for microenvironmental galectin-3 in tumor progression. Galectin-3 also seems to be involved in the recruitment of tumor-associated macrophages, possibly contributing to angiogenesis and tumor growth. This lectin can be a relevant factor in turning bone marrow in a sanctuary for leukemia cells, favoring resistance to therapy. Finally, galectin-3 seems to play a relevant role in orchestrating distinct cell events in tumor microenvironment and for this reason, it can be considered a target in tumor therapies. In conclusion, this review aims to describe the processes of tumor progression and metastasis involving extracellular galectin-3 and its expression and regulation.
Essential elements have functions in tumor progression by promoting protumoral cellular processes, such as proliferation, and migration, among others. Obtaining an understanding of how these elements ...relate to tumor progression processes is of great importance for research. Elemental profile studies in distant tissues, which can be modulated by tumor cells to promote metastasis, have not been sufficiently investigated. The main goal of this study is to evaluate multielemental distribution during tumor progression, focusing on tumor tissue and distant tissues that may be affected.
Tumor progression in vivo was simulated by inoculating C57BL/6 mice with Lewis Lung Carcinoma (LLC) cells. Samples of the primary tumor and distant tissues were collected during 5 weeks of tumor progression for the control and experimental (tumor-bearing) groups. The biological samples were analyzed using the synchrotron radiation X-Ray fluorescence technique. Data on the concentration of P, S, K, Ca, Mn, Fe, Cu, and Zn in the samples were obtained and statistically analyzed to evaluate the distribution of the elements during tumor progression in the primary tumor as well as distant tissues.
It was possible to observe significant changes in the concentrations' distribution of P, S, K, Ca, Mn, Fe, and Cu in distant tissues caused by the presence of tumor cells. It was also possible to detect a greater similarity between tumor tissue (which has the lung as tissue of origin) and a tissue of non-origin, such as the liver, which is an unprecedented result. Moreover, changes in the distributions of concentrations were detected and studied over time for the different tissues analyzed, such as primary tumor, liver and lung, in Control and Tumor groups.
Among other results, this paper could explore the modulation of distant tissues caused by the presence of a primary tumor. This could be achieved by the evaluation of several elements of known biological importance allowing the study of different biological processes involved in cancer. The role of essential elements as modulators of the tumor microenvironment is a relevant aspect of tumor progression and this work is a contribution to the field of tumoral metallomics.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Breast cancer continues to be a serious public health problem. The role of the hedgehog pathway in normal development of the mammary gland as well as in carcinogenesis and progression of breast ...cancer is the subject of intense investigation, revealing functional interactions with cell surface heparan sulfate. Nevertheless, its influence on breast cancer prognosis, and its relation to specific sulfation motifs in heparan sulfate have only been poorly studied in large patient cohorts. Using the public database KMplotter that includes gene expression and survival data of 3951 patients, we found that the higher expression of SHH, HHAT, PTCH1, GLI1, GLI2, and GLI3 positively influences breast cancer prognosis. Stratifying patients according to the expression of hormone receptors, histological grade, lymph node metastasis, and systemic therapy, we observed that GLI1, GLI2, and GLI3 expression, as well as co‐expression of SHH and ELP1 were associated with worse relapse‐free survival in patients with HER2‐positive tumors. Moreover, GLI1 expression in progesterone receptor‐negative tumors and GLI3 expression in grade 3 tumors correlated with poor prognosis. SHH, in a panel of cell lines representing different breast cancer subtypes, and HHAT, PTCH1, GLI1, GLI2, and GLI3 were mostly expressed in cell lines classified as HER2‐positive and basal‐like. Expression of SHH, HHAT, GLI2, and GLI3 was differentially affected by overexpression of the heparan sulfate sulfotransferases HS2ST1 and HS3ST2 in vitro. Although high HS2ST1 expression was associated with poor prognosis in KMplotter analysis, high levels of HS3ST2 were associated with a good prognosis, except for ER‐positive breast cancer. We suggest the GLI transcription factors as possible markers for the diagnosis, treatment, and prognosis of breast cancer especially in HER2‐positive tumors, but also in progesterone receptor‐negative and grade‐3 tumors. The pathway interaction and prognostic impact of specific heparan sulfate sulfotransferases provide novel perspectives regarding a therapeutical targeting of the hedgehog pathway in breast cancer.
The hedgehog pathway plays an important role during mammary gland development and breast cancer pathogenesis. In this study, we establish general and subtype‐specific prognostic values for selected hedgehog pathway constituents in breast cancer, and provide a link to heparan sulfate. The pathway interaction and prognostic impact of specific heparan sulfate sulfotransferases provide novel perspectives regarding a therapeutical targeting of the hedgehog pathway in breast cancer.
Heparan sulfate 3‐O‐sulfotransferase 2 (HS3ST2), an enzyme mediating 3‐O‐sulfation of heparan sulfate (HS), is silenced by hypermethylation in breast cancer. As HS has an important co‐receptor ...function for numerous signal transduction pathways, the phenotypical changes due to HS3ST2 reexpression were investigated in vitro using high and low invasive breast cancer cell lines. Compared to controls, highly invasive HS3ST2‐expressing MDA‐MB‐231 cells showed enhanced Matrigel invasiveness, transendothelial migration and motility. Affymetrix screening and confirmatory real‐time PCR and Western blotting analysis revealed increased expression of several matrix metalloproteinases, cadherin‐11, E‐cadherin and CEACAM‐1, while protease inhibitor and annexin A10 expression were decreased. Low invasive HS3ST2 ‐expressing MCF‐7 cells became even less invasive, with no change in gelatinolytic MMP activity. HS3ST2 expression increased HS‐dependent basal and FGF2‐specific signaling through the constitutively active p44/42 MAPK pathway in MDA‐MB‐231 cells. Increased MAPK activation was accompanied by upregulation of ß‐catenin in MDA‐MB‐231, and of the transcription factor Tcf4 in both cell lines. Dysregulation of Tcf4‐regulated ion transporters and increased cytosolic acidification were observed in HS3ST2‐expressing MDA‐MB‐231 cells, which is a possible underlying cause of increased chemosensitivity towards doxorubicine and paclitaxel in these cells. This study provides the first in vitro evidence of the involvement of HS3ST2 in breast cancer cell invasion and chemosensitivity.
What's New?
Heparan sulfate is present in all cell types and tissues and is involved in the modulation of cell adhesion, proliferation, and motility. While HS3ST2—an enzyme mediating 3‐O‐sulfation of heparan sulfate—is known to be epigenetically silenced in breast cancer, its mechanistic role has yet to be characterized. This study reveals a novel role of HS3ST2 in modulating breast cancer cell invasiveness and chemoresistance via MAP kinase‐ and Tcf7l2/Tcf4‐dependent regulation of protease and cadherin expression. The findings demonstrate the importance of specific sulfation patterns in heparan sulfate and pave the way for new heparinoid‐based therapeutic approaches.
Nanoporous gold (NPG) structures were prepared on the surface of a gold microelectrode (Au-μE) by an anodization-reduction method. Cyclic voltammetry and field emission scanning electron microscopy ...were used to study the electrochemical properties and the morphology of the nanostructured film. Voltammetry showed an improved sensitivity for dopamine (DA) oxidation at this microelectrode when compared to a bare gold microelectrode, with a peak near 0.2 V (vs. Ag/AgCl) at a scan rate of 0.1 V s
−1
. This is due to the increased surface area and roughness. Square wave voltammetry shows a response that is linear in the 0.1–10 μmol L
−1
DA concentration range, with a 30 nmol L
-1
detection limit and a sensitivity of 1.18 mA (μmol L
−1
)
−1
cm
−2
. The sensor is not interfered by ascorbic acid. The reproducibility, repeatability, long-term stability and real sample analysis (spiked urine) were assessed, and acceptable performance was achieved. The “proof-of-concept” detection of dopamine release was demonstrated by using scanning electrochemical microscopy (SECM) with the aim of future applications for single cell analysis.
Graphical abstract
A reproducible electrochemical approach was proposed to fabricate an NPG-microelectrode for DA detection, with enhanced sensitivity and selectivity. Besides, a proof-of-concept detection of DA release was also demonstrated by using SECM.
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•Design of a continuous process for the valorization of Sargassum muticum seaweed.•Proposal of an alternative process without anaerobic digestion of biomass.•Cash flow analysis to ...evaluate minimum selling price of fucoidan extract product.•CAPEX estimates were 1.6 to 12.7% lower in the alternative project.•Main product minimum selling price reduced up to 55.3% in the alternative project.
This work assesses scale effects in designing a biorefinery from Sargassum muticum seaweed by applying a detailed process modeling methodology. Two process conversion units were simulated: one considering anaerobic digestion steps for producing biogas and generating electricity (base project), and the other with residual seaweed solids sold as fertilizer (alternative project). A comprehensive economic analysis was performed to estimate the minimum selling price of the process's main product (fucoidan extract). Results indicated that capital expenditures are up to 12.7% times higher in the base project. Minimum selling prices of the fucoidan extract product demonstrate the biorefinery’s economies of scale for both projects. Seaweed’s low methane potential reduces the economic attractiveness of electricity generation from biogas in the base project. Conversely, organic fertilizer price was more influential in the alternative project. Nonetheless, risk analyses show similar results for both scenarios, mainly due to fucoidan extract selling price and CAPEX estimates uncertainties.
Inflammation and cancer are related pathologies acting synergistically to promote tumor progression. In both, hematogenous metastasis and inflammation, P-selectin participates in interactions ...involving tumor cells, platelets, leukocytes and endothelium. Heparin has been shown to inhibit P-selectin and as a consequence it blunts metastasis and inflammation. Some heparin analogs obtained from marine invertebrates are P-selectin inhibitors and do not induce bleeding effects. The present work focuses on the P-selectin blocking activity of a unique heparan sulfate (HS) from the bivalve mollusk Nodipecten nodosus. Initially, we showed that the mollusk HS inhibited LS180 colon carcinoma cell adhesion to immobilized P-selectin in a dose-dependent manner. In addition, we demonstrated that this glycan attenuates leukocyte rolling on activated endothelium and inflammatory cell recruitment in thioglycollate-induced peritonitis in mice. Biochemical analysis indicated that the invertebrate glycan also inhibits heparanase, a key player in cell invasion and metastasis. Experimental metastasis of Lewis lung carcinoma cells was drastically attenuated by the mollusk HS through a mechanism involving inhibition of platelet-tumor-cell complex formation in blood vessels. These data suggest that the mollusk HS is a potential alternative to heparin for inhibiting P-selectin-mediated events such as metastasis and inflammatory cell recruitment.
Syndecan‐1 is a cell surface heparan sulfate proteoglycan with various biological functions relevant to tumor progression and inflammation, including cell–cell adhesion, cell–matrix interaction, and ...cytokine signaling driving cell proliferation and motility. Syndecan‐1 is a prognostic factor in breast cancer, and has a predicitive value for neodadjuvant chemotherapy. It is still poorly understood how syndecan‐1 integrates matrix‐dependent and cytokine‐dependent signaling processes in the tumor microenvironment. Here, we evaluated the potential role of syndecan‐1 in modulating matrix‐dependent breast cancer cell migration in the presence of interleukin‐6, and its potential involvement in resistance to irradiation in vitro. MDA‐MB‐231 breast cancer cells were transiently transfected with syndecan‐1 small interfering RNA or control reagents, and this was followed by stimulation with interleukin‐6 or irradiation. Cellular responses were monitored by adhesion, migration and colony formation assays, as well as analysis of cell signaling. Syndecan‐1 depletion increased cell adhesion to fibronectin. Increased migration on fibronectin was significantly suppressed by interleukin‐6, and GRGDSP peptides inhibited both adhesion and migration. Interleukin‐6‐induced activation of focal adhesion kinase and reduction of constitutive nuclear factor kappaB signaling were decreased in syndecan‐1‐deficient cells. Focal adhesion kinase hyperactivation in syndecan‐1‐depleted cells was associated with dramatically reduced radiation sensitivity. We conclude that loss of syndecan‐1 leads to enhanced activation of β1‐integrins and focal adhesion kinase, thus increasing breast cancer cell adhesion, migration, and resistance to irradiation. Syndecan‐1 deficiency also attenuates the modulatory effect of the inflammatory microenvironment constituent interleukin‐6 on cancer cell migration.
The cell surface heparan sulfate proteoglycan syndecan‐1 modulates breast cancer cell adhesion to fibronectin in an integrin‐dependent manner, while increased cell motility in syndecan‐1‐deficient cells depends on both integrins and IL‐6. Increased activation of FAK in the absence of Sdc‐1 is associated with increased resistance to irradiation. IL‐6‐dependent modulation of FAK and NF‐ кB are inhibited by syndecan‐1 depletion.
Heparin-like glycans with diverse disaccharide composition and high anticoagulant activity have been described in several families of marine mollusks. The present work focused on the structural ...characterization of a new heparan sulfate (HS)-like polymer isolated from the mollusk Nodipecten nodosus (Linnaeus, 1758) and on its anticoagulant and antithrombotic properties. Total glycans were extracted from the mollusk and fractionated by ethanol precipitation. The main component (>90%) was identified as HS-like glycosaminoglycan, representing ∼4.6 mg g−1 of dry tissue. The mollusk HS resists degradation with heparinase I but is cleaved by nitrous acid. Analysis of the mollusk glycan by one-dimensional 1H, two-dimensional correlated spectroscopy, and heteronuclear single quantum coherence nuclear magnetic resonance revealed characteristic signals of glucuronic acid and glucosamine residues. Signals corresponding to anomeric protons of nonsulfated, 3- or 2-sulfated glucuronic acid as well as N-sulfated and/or 6-sulfated glucosamine were also observed. The mollusk HS has an anticoagulant activity of 36 IU mg−1, 5-fold lower than porcine heparin (180 IU mg−1), as measured by the activated partial thromboplastin time assay. It also inhibits factor Xa (IC50 = 0.835 μg ml−1) and thrombin (IC50 = 9.3 μg ml−1) in the presence of antithrombin. In vivo assays demonstrated that at the dose of 1 mg kg−1, the mollusk HS inhibited thrombus growth in photochemically injured arteries. No bleeding effect, factor XIIa-mediated kallikrein activity, or toxic effect on fibroblast cells was induced by the invertebrate HS at the antithrombotic dose.
Acute and chronic dermatological injuries need rapid tissue repair due to the susceptibility to infections. To effectively promote cutaneous wound recovery, it is essential to develop safe, low-cost, ...and affordable regenerative tools. Therefore, we aimed to identify the biological mechanisms involved in the wound healing properties of the glycosaminoglycan dermatan sulfate (DS), obtained from ascidian Styela plicata, a marine invertebrate, which in preliminary work from our group showed no toxicity and promoted a remarkable fibroblast proliferation and migration. In this study, 2,4-DS (50 µg/mL)-treated and control groups had the relative gene expression of 84 genes participating in the healing pathway evaluated. The results showed that 57% of the genes were overexpressed during treatment, 16% were underexpressed, and 9.52% were not detected. In silico analysis of metabolic interactions exhibited overexpression of genes related to: extracellular matrix organization, hemostasis, secretion of inflammatory mediators, and regulation of insulin-like growth factor transport and uptake. Furthermore, in C57BL/6 mice subjected to experimental wounds treated with 0.25% 2,4-DS, the histological parameters demonstrated a great capacity for vascular recovery. Additionally, this study confirmed that DS is a potent inducer of wound-healing cellular pathways and a promoter of neovascularization, being a natural ally in the tissue regeneration strategy.
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