1,721,006 research outputs found
Endothelial Glycocalyx as a Regulator of Fibrotic Processes
Full text linkThe endothelial glycocalyx, the gel layer covering the endothelium, is composed of glycosaminoglycans, proteoglycans, and adsorbed plasma proteins. This structure modulates vessels' mechanotransduction, vascular permeability, and leukocyte adhesion. Thus, it regulates several physiological and pathological events. In the present review, we described the mechanisms that disturb glycocalyx stability such as reactive oxygen species, matrix metalloproteinases, and heparanase. We then focused our attention on the role of glycocalyx degradation in the induction of profibrotic events and on the possible pharmacological strategies to preserve this delicate structure
Heparanase as active player in endothelial glycocalyx remodeling
Full text linkThe surface of all animal cells is coated with a layer of carbohydrates linked in various ways to the outer side of the plasma membrane. These carbohydrates are mainly bound to proteins in the form of glycoproteins and proteoglycans and together with the glycolipids constitute the so-called glycocalyx. In particular, the endothelial glycocalyx that covers the luminal layer of the endothelium is composed of glycosaminoglycans (heparan sulphate -HS and hyaluronic acid -HA), proteoglycans (syndecans and glypicans) and adsorbed plasma proteins. Thanks to its ability to absorb water, this structure contributes to making the surface of the vessels slippery but at the same time acts by modulating the mechano-transduction of the vessels, the vascular permeability and the adhesion of leukocytes in thus regulating several physiological and pathological events. Among the various enzymes involved in the degradation of the glycocalyx, heparanase (HPSE) has been shown to be particularly involved. This enzyme is responsible for the cutting of heparan sulfate (HS) chains at the level of the proteoglycans of the endothelial glycocalyx whose dysfunction appears to have a role in organ fibrosis, sepsis and viral infection. In this mini-review, we describe the mechanisms by which HPSE contributes to glycocalyx remodeling and then examine the role of glycocalyx degradation in the development of pathological conditions and pharmacological strategies to preserve glycocalyx during disease pathogenesis
LGI1 Affects survival of neuroblastoma cells by inhibiting signalling through phosphoinositide 3-Kinase
No full textOverexpression of the leucine-rich, glioma-inactivated 1 (LGI1) gene in neuroblastoma cells inhibited proliferation and efficiently induced apoptosis. Cell clones stably transfected with LGI1 cDNA showed greater mortality during a period of serum starvation in comparison with control cells stably transfected with empty vector. This observation suggested hindrance of the PI3K/Akt pathway, a central transducer of survival stimuli elicited by serum growth factors. Treatment with inhibitors of PI3K significantly increased the death of control cells but substantially failed to influence LGI1 cell death, which was greatest independently of the presence of inhibitors. Blockage of the PI3K/Akt pathway in LGI1 cells was confirmed by the lack of serum-induced Akt phosphorylation, in contrast with the strong response of control cells. Instead, serum-induced phosphorylation of ERK1/2 was not impaired by the expression of LGI1. This study showed that overexpression of LGI1 caused neuroblastoma cell death by blocking activation of the PI3K/Akt pathway. Thus, the possibility of upregulating LGI1 expression may be a novel strategy in suppressing oncogenesis and metastasis sustained by excessive activation of the PI3K/Akt pathway
Expression of LGI1 Impairs Proliferation and Survival of HeLa Cells
Full text linkThe LGI1 gene was suggested to function as tumor suppressor for its ability to reduce malignant features of glioblastoma cells. In support to this proposal were the findings that overexpression of LGI1 in neuroblastoma cells inhibited proliferation and induced apoptosis. In this study we performed stable LGI1 expression in HeLa cells to examine whether the noxious effect of LGI1 might be extended to cancer cells of diverse origin. HeLa cell clones stably expressing LGI1 exhibited a significant impairment of proliferation and a consistent increase of cell death when compared with control cells lacking expression of LGI1. Expression of LGI1 increased the activity of apoptosis effectors caspase-3/7; furthermore it downregulated the antiapoptotic BCL2 gene and upregulated the proapoptotic BAX gene expression, suggesting that the cause of HeLa cells death might be an increased susceptibility to apoptosis induced by LGI1. The results suggested that LGI1 is capable to restrain growth and survival of adenocarcinoma cells such as HeLa
Biological effects of xylocore, a glucose sparing pd solution, on mesothelial cells: Focus on mesothelial-mesenchymal transition, inflammation and angiogenesis
Full text linkGlucose-based solutions remain the most used osmotic agents in peritoneal dialysis (PD), but unavoidably they contribute to the loss of peritoneal filtration capacity. Here, we evaluated at a molecular level the effects of XyloCore, a new PD solution with a low glucose content, in mesothelial and endothelial cells. Cell viability, integrity of mesothelial and endothelial cell membrane, activation of mesothelial and endothelial to mesenchymal transition programs, inflammation, and angiogenesis were evaluated by several techniques. Results showed that XyloCore preserves mesothelial and endothelial cell viability and membrane integrity. Moreover XyloCore, unlike glucose-based solutions, does not exert pro-fibrotic,-inflammatory, and angiogenic effects. Overall, the in vitro evidence suggests that XyloCore could represent a potential biocompatible solution promising better outcomes in clinical practice
Long filopodia and tunneling nanotubes define new phenotypes of breast cancer cells in 3D cultures
No full textCancer cell invasion into the surrounding extracellular matrix (ECM) takes place when cell-cell junctions are disrupted upon epithelial-to-mesenchymal transition (EMT). Both cancer cell-stroma and cell-cell crosstalk are essential to support the continuous tumor invasion. Cancer cells release microvesicles and exosomes containing bioactive molecules and signal peptides, which are recruited by neighboring cells or carried to distant sites, thus supporting intercellular communication and cargo transfer. Besides this indirect communication mode, cancer cells can develop cytoplasmic intercellular protrusions or tunneling nanotubes (TNTs), which allow the direct communication and molecular exchange between connected distinct cells. Using scanning electron microscopy (SEM) we show for the first time that MDA-MB-231 (high metastatic potential) and shERβ MDA-MB-231 (low metastatic potential) breast cancer cells cultured on fibronectin and collagen type I or 17β-estradiol (E2) develop TNTs and very long flexible filopodia. Interestingly, the less aggressive shERβ MDA-MB-231 cells treated with E2 in 3D collagen matrix showed the highest development of TNTs and filopodia. TNTs were often associated to adhering exosomes and microvesicles surfing from one cell to another, but no filopodia exhibited vesicle-like cytoplasmic structures on their surface. Moreover, E2 affected the expression of matrix macromolecules and cell effectors mostly in the presence of ERβ. Our novel data highlights the significance of matrix substrates and the presence of E2 and ERβ in the formation of cellular protrusion and the production of surface structures, defining novel phenotypes that unravel nodal reports for breast cancer progression
Heparanase: A Paramount Enzyme for Cancer Initiation, Progression, and Metastasis.
No full textConsolidated data indicate that tumor bulk is not only made up of a heterogeneous set of neoplastic cells but also of a variety of resident and infiltrating host cells, soluble factors, and components of the extracellular matrix which as a whole is defined as the tumor microenvironment. In this context, the extracellular matrix plays a fundamental role in tumor progression as it acts as a repository for various biomolecules such as growth factors, cytokines, enzymes, and inhibitors which are mainly linked to heparan sulfate proteoglycans (HSPG) and whose release can regulate the response or not of cancer cells. Among the various enzymes involved in the degradation of the ECM, heparanase (HPSE) has been shown to be particularly involved in tumor progression and metastatic invasion. This enzyme, capable of cutting heparan sulfate (HS) chains, is overexpressed in practically all solid tumors, clearly demonstrating that it has pro-invasive and pro-angiogenic characteristics for neoplastic cells. Furthermore, considering that heparanase is released not only by tumor cells but also by platelets, endothelial cells, and immune cells, we can admit that its enzymatic activity has a strong impact on the tumor microenvironment. Here, we discuss the recent development in the study of heparanase in cancer progression as well as on novel mechanisms by which heparanase regulates the nature of the tumor microenvironment
Heparanase regulates EMT and cancer stem cell properties in prostate tumors
No full textProstate cancer displays a certain phenotypic plasticity that allows for the transition of cells from the epithelial to the mesenchymal state. This process, known as epithelial-mesenchymal transition (EMT), is one of the factors that give the tumor cells greater invasive and migratory capacity with subsequent formation of metastases. In addition, many cancers, including prostate cancer, are derived from a cell population that shows the properties of stem cells. These cells, called cancer stem cells (CSCs) or tumor-initiating cells, not only initiate the tumor process and growth but are also able to mediate metastasis and drug resistance. However, the impact of EMT and CSCs in prostate cancer progression and patient survival is still far from fully understood. Heparanase (HPSE), the sole mammalian endoglycosidase capable of degrading heparan sulfate (HS), is also involved in prostate cancer progression. We had previously proved that HPSE regulates EMT in non-cancerous pathologies. Two prostate cancer cell lines (DU145 and PC3) were silenced and overexpressed for HPSE. Expression of EMT and stemness markers was evaluated. Results showed that the expression of several EMT markers are modified by HPSE expression in both the prostate cancer cell lines analyzed. In the same way, the stemness markers and features are also modulated by HPSE expression. Taken together, the present findings seem to prove a new mechanism of action of HPSE in sustaining prostate cancer growth and diffusion. As for other tumors, these results highlight the importance of HPSE as a potential pharmacological target in prostate cancer treatment
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