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Markku Tammi - One of the best experts on this subject based on the ideXlab platform.
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plasma Hyaluronan and hemorheology in patients with septic shock a clinical and experimental study
Clinical Hemorheology and Microcirculation, 2014Co-Authors: Marko Sallisalmi, Markku Tammi, Anne Kultti, Jyrki Tenhunen, Ville PettilaAbstract:BACKGROUND: Total plasma Hyaluronan concentration is increased in septic shock. High-molecular-weight Hyaluronan has a high intrinsic viscosity. Excessive release of high-molecular-weight Hyaluronan in sepsis may induce hyperviscosity. METHODS: Plasma viscosity and the molecular size of plasma Hyaluronan were determined in 20 patients with septic shock and in 20 healthy controls. Ex vivo, the effects of 0.4% and 0.047% high-molecular-weight Hyaluronan 1560 kDa, 0.9% saline, and 6% hydroxy-ethyl-starch 130 kDa were compared to plasma and whole blood viscosity and red blood cell aggregation at a systemic hematocrit of 0.4, and at a microcirculatory hematocrit of 0.2. RESULTS: Plasma viscosity and total plasma protein content were low in septic shock patients on days one and four of treatment. Hyaluronan concentration was 10-fold higher in sepsis on day 1. Molecular weight of Hyaluronan was relatively low, mostly 50-500 kDa, and did not change significantly in sepsis. Ex vivo, 0.4% high-molecular-weight Hyaluronan 1560 kDa increased blood viscosity but did not promote red blood cell aggregation. Dilutions of 6% hydroxyl-ethyl-starch 130 kDa and 0.047% high-molecular-weight Hyaluronan 1560 kDa had comparable effects on blood viscosity and red blood cell aggregation. CONCLUSIONS: Plasma viscosity of the septic patients remained low for four days despite markedly elevated concentration of relatively small-molecular-weight Hyaluronan.
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Low Dose Ultraviolet B Irradiation Increases Hyaluronan Synthesis in Epidermal Keratinocytes via Sequential Induction of Hyaluronan Synthases Has1–3 Mediated by p38 and Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII) Signaling
The Journal of biological chemistry, 2013Co-Authors: Leena Rauhala, Markku Tammi, Genevieve Bart, Lasse Hämäläinen, Pauliina Salonen, Sanna Pasonen-seppänen, Raija TammiAbstract:Hyaluronan, a major epidermal extracellular matrix component, responds strongly to different kinds of injuries. This also occurs by UV radiation, but the mechanisms involved are poorly understood. The effects of a single ultraviolet B (UVB) exposure on Hyaluronan content and molecular mass, and expression of genes involved in Hyaluronan metabolism were defined in monolayer and differentiated, organotypic three-dimensional cultures of rat epidermal keratinocytes. The signals regulating the response were characterized using specific inhibitors and Western blotting. In monolayer cultures, UVB increased Hyaluronan synthase Has1 mRNA already 4 h postexposure, with a return to control level by 24 h. In contrast, Has2 and Has3 were persistently elevated from 8 h onward. Silencing of Has2 and especially Has3 decreased the UVB-induced accumulation of Hyaluronan. p38 and Ca2+/calmodulin-dependent protein kinase II pathways were found to be involved in the UVB-induced up-regulation of Has2 and Has3 expression, respectively, and their inhibition reduced Hyaluronan deposition. However, the expressions of the Hyaluronan-degrading enzymes Hyal1 and Hyal2 and the Hyaluronan receptor Cd44 were also up-regulated by UVB. In organotypic cultures, UVB treatment also resulted in increased expression of both Has and Hyal genes and shifted Hyaluronan toward a smaller size range. Histochemical stainings indicated localized losses of Hyaluronan in the epidermis. The data show that exposure of keratinocytes to acute, low dose UVB increases Hyaluronan synthesis via up-regulation of Has2 and Has3. The simultaneously enhanced catabolism of Hyaluronan demonstrates the complexity of the UVB-induced changes. Nevertheless, enhanced Hyaluronan metabolism is an important part of the adaptation of keratinocytes to radiation injury.
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Role of CD44 in the organization of keratinocyte pericellular Hyaluronan
Histochemistry and Cell Biology, 2012Co-Authors: Sanna Pasonen-seppänen, Markku Tammi, Kirsi Rilla, Juha M. T. Hyttinen, Tiina Jokela, Paul W. Noble, Raija TammiAbstract:CD44 is a ubiquitous cell surface glycoprotein, involved in important cellular functions including cell adhesion, migration, and modulation of signals from cell surface receptors. While most of these CD44 functions are supposed to involve Hyaluronan, relatively little is known about the contribution of CD44 to Hyaluronan maintenance and organization on cell surface, and the role of CD44 in Hyaluronan synthesis and catabolism. Blocking Hyaluronan binding either by CD44 antibodies, CD44-siRNA or Hyaluronan decasaccharides (but not hexasaccharides) removed most of the Hyaluronan from the surfaces of both human (HaCaT) and mouse keratinocytes, resembling results on cells from CD44−/− animals. In vitro, compromising CD44 function led to reduced and increased amounts, respectively, of intracellular and culture medium Hyaluronan, and specific accumulation below the cells. In vivo, CD44-deficiency caused no marked differences in Hyaluronan staining intensity or localization in the fetal skin or in adult ear skin, while tail epidermis showed a slight reduction in epidermal Hyaluronan staining intensity. However, CD44-deficient tail skin challenged with retinoic acid or tape stripping revealed diffuse accumulation of Hyaluronan in the superficial epidermal layers, normally negative for Hyaluronan. Our data indicate that CD44 retains Hyaluronan in the keratinocyte pericellular matrix, a fact that has not been shown unambiguously before, and that Hyaluronan abundance in the absence of CD44 can result in Hyaluronan trapping in abnormal locations possibly interfering there with normal differentiation and epidermal barrier function.
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transcriptional and post translational regulation of Hyaluronan synthesis
FEBS Journal, 2011Co-Authors: Raija Tammi, Kirsi Rilla, Davide Vigetti, Alberto Passi, Evgenia Karousou, Katri M Makkonen, Markku TammiAbstract:Hyaluronan, a ubiquitous high-molecular-mass glycinoglycan on cell surfaces and in extracellular matrices, has a number of specific signaling functions in cell–cell communication. Changes in its content, molecular mass and turnover rate are crucial for cell proliferation, migration and apoptosis, processes that control tissue remodeling during embryonic development, inflammation, injury and cancer. To maintain tissue homeostasis, the synthesis of Hyaluronan must therefore be tightly controlled. In this review, we highlight some recent data on the transcriptional regulation of Hyaluronan synthase (Has1–3) expression and on the post-transcriptional control of Hyaluronan synthase activity, which, in close association with the supply of the UDP-sugar substrates of Hyaluronan synthase, adjust the rate of Hyaluronan synthesis.
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Hyaluronan in human malignancies.
Experimental cell research, 2010Co-Authors: Reijo Sironen, Raija Tammi, Markku Tammi, Päivi Auvinen, Maarit Anttila, Veli-matti KosmaAbstract:Hyaluronan, a major macropolysaccharide in the extracellular matrix of connective tissues, is intimately involved in the biology of cancer. Hyaluronan accumulates into the stroma of various human tumors and modulates intracellular signaling pathways, cell proliferation, motility and invasive properties of malignant cells. Experimental and clinicopathological evidence highlights the importance of Hyaluronan in tumor growth and metastasis. A high stromal Hyaluronan content is associated with poorly differentiated tumors and aggressive clinical behavior in human adenocarcinomas. Instead, the squamous cell carcinomas and malignant melanomas tend to have a reduced Hyaluronan content. In addition to the stroma-cancer cell interaction, Hyaluronan can influence stromal cell recruitment, tumor angiogenesis and epithelial-mesenchymal transition. Hyaluronan receptors, Hyaluronan synthases and Hyaluronan degrading enzymes, hyaluronidases, are involved in the modulation of cancer progression, depending on the tumor type. Furthermore, intracellular signaling and angiogenesis are affected by the degradation products of Hyaluronan. Hyaluronan has also therapeutic implications since it is involved in multidrug resistance.
Raija Tammi - One of the best experts on this subject based on the ideXlab platform.
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Low Dose Ultraviolet B Irradiation Increases Hyaluronan Synthesis in Epidermal Keratinocytes via Sequential Induction of Hyaluronan Synthases Has1–3 Mediated by p38 and Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII) Signaling
The Journal of biological chemistry, 2013Co-Authors: Leena Rauhala, Markku Tammi, Genevieve Bart, Lasse Hämäläinen, Pauliina Salonen, Sanna Pasonen-seppänen, Raija TammiAbstract:Hyaluronan, a major epidermal extracellular matrix component, responds strongly to different kinds of injuries. This also occurs by UV radiation, but the mechanisms involved are poorly understood. The effects of a single ultraviolet B (UVB) exposure on Hyaluronan content and molecular mass, and expression of genes involved in Hyaluronan metabolism were defined in monolayer and differentiated, organotypic three-dimensional cultures of rat epidermal keratinocytes. The signals regulating the response were characterized using specific inhibitors and Western blotting. In monolayer cultures, UVB increased Hyaluronan synthase Has1 mRNA already 4 h postexposure, with a return to control level by 24 h. In contrast, Has2 and Has3 were persistently elevated from 8 h onward. Silencing of Has2 and especially Has3 decreased the UVB-induced accumulation of Hyaluronan. p38 and Ca2+/calmodulin-dependent protein kinase II pathways were found to be involved in the UVB-induced up-regulation of Has2 and Has3 expression, respectively, and their inhibition reduced Hyaluronan deposition. However, the expressions of the Hyaluronan-degrading enzymes Hyal1 and Hyal2 and the Hyaluronan receptor Cd44 were also up-regulated by UVB. In organotypic cultures, UVB treatment also resulted in increased expression of both Has and Hyal genes and shifted Hyaluronan toward a smaller size range. Histochemical stainings indicated localized losses of Hyaluronan in the epidermis. The data show that exposure of keratinocytes to acute, low dose UVB increases Hyaluronan synthesis via up-regulation of Has2 and Has3. The simultaneously enhanced catabolism of Hyaluronan demonstrates the complexity of the UVB-induced changes. Nevertheless, enhanced Hyaluronan metabolism is an important part of the adaptation of keratinocytes to radiation injury.
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Role of CD44 in the organization of keratinocyte pericellular Hyaluronan
Histochemistry and Cell Biology, 2012Co-Authors: Sanna Pasonen-seppänen, Markku Tammi, Kirsi Rilla, Juha M. T. Hyttinen, Tiina Jokela, Paul W. Noble, Raija TammiAbstract:CD44 is a ubiquitous cell surface glycoprotein, involved in important cellular functions including cell adhesion, migration, and modulation of signals from cell surface receptors. While most of these CD44 functions are supposed to involve Hyaluronan, relatively little is known about the contribution of CD44 to Hyaluronan maintenance and organization on cell surface, and the role of CD44 in Hyaluronan synthesis and catabolism. Blocking Hyaluronan binding either by CD44 antibodies, CD44-siRNA or Hyaluronan decasaccharides (but not hexasaccharides) removed most of the Hyaluronan from the surfaces of both human (HaCaT) and mouse keratinocytes, resembling results on cells from CD44−/− animals. In vitro, compromising CD44 function led to reduced and increased amounts, respectively, of intracellular and culture medium Hyaluronan, and specific accumulation below the cells. In vivo, CD44-deficiency caused no marked differences in Hyaluronan staining intensity or localization in the fetal skin or in adult ear skin, while tail epidermis showed a slight reduction in epidermal Hyaluronan staining intensity. However, CD44-deficient tail skin challenged with retinoic acid or tape stripping revealed diffuse accumulation of Hyaluronan in the superficial epidermal layers, normally negative for Hyaluronan. Our data indicate that CD44 retains Hyaluronan in the keratinocyte pericellular matrix, a fact that has not been shown unambiguously before, and that Hyaluronan abundance in the absence of CD44 can result in Hyaluronan trapping in abnormal locations possibly interfering there with normal differentiation and epidermal barrier function.
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transcriptional and post translational regulation of Hyaluronan synthesis
FEBS Journal, 2011Co-Authors: Raija Tammi, Kirsi Rilla, Davide Vigetti, Alberto Passi, Evgenia Karousou, Katri M Makkonen, Markku TammiAbstract:Hyaluronan, a ubiquitous high-molecular-mass glycinoglycan on cell surfaces and in extracellular matrices, has a number of specific signaling functions in cell–cell communication. Changes in its content, molecular mass and turnover rate are crucial for cell proliferation, migration and apoptosis, processes that control tissue remodeling during embryonic development, inflammation, injury and cancer. To maintain tissue homeostasis, the synthesis of Hyaluronan must therefore be tightly controlled. In this review, we highlight some recent data on the transcriptional regulation of Hyaluronan synthase (Has1–3) expression and on the post-transcriptional control of Hyaluronan synthase activity, which, in close association with the supply of the UDP-sugar substrates of Hyaluronan synthase, adjust the rate of Hyaluronan synthesis.
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Hyaluronan in human malignancies.
Experimental cell research, 2010Co-Authors: Reijo Sironen, Raija Tammi, Markku Tammi, Päivi Auvinen, Maarit Anttila, Veli-matti KosmaAbstract:Hyaluronan, a major macropolysaccharide in the extracellular matrix of connective tissues, is intimately involved in the biology of cancer. Hyaluronan accumulates into the stroma of various human tumors and modulates intracellular signaling pathways, cell proliferation, motility and invasive properties of malignant cells. Experimental and clinicopathological evidence highlights the importance of Hyaluronan in tumor growth and metastasis. A high stromal Hyaluronan content is associated with poorly differentiated tumors and aggressive clinical behavior in human adenocarcinomas. Instead, the squamous cell carcinomas and malignant melanomas tend to have a reduced Hyaluronan content. In addition to the stroma-cancer cell interaction, Hyaluronan can influence stromal cell recruitment, tumor angiogenesis and epithelial-mesenchymal transition. Hyaluronan receptors, Hyaluronan synthases and Hyaluronan degrading enzymes, hyaluronidases, are involved in the modulation of cancer progression, depending on the tumor type. Furthermore, intracellular signaling and angiogenesis are affected by the degradation products of Hyaluronan. Hyaluronan has also therapeutic implications since it is involved in multidrug resistance.
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Hyaluronan synthases (HAS1-3) and hyaluronidases (HYAL1-2) in the accumulation of Hyaluronan in endometrioid endometrial carcinoma.
BMC cancer, 2010Co-Authors: Timo K. Nykopp, Raija Tammi, Markku Tammi, Kirsi Rilla, Reijo Sironen, Veli-matti Kosma, Kirsi Hämäläinen, Seppo Heinonen, Maarit AnttilaAbstract:Background Hyaluronan accumulation correlates with the degree of malignancy in many solid tumor types, including malignant endometrial carcinomas. To elucidate the mechanism of Hyaluronan accumulation, we examined the expression levels of the Hyaluronan synthases (HAS1, HAS2 and HAS3) and hyaluronidases (HYAL1 and HYAL2), and correlated them with Hyaluronan content and HAS1-3 immunoreactivity.
Paul W. Noble - One of the best experts on this subject based on the ideXlab platform.
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Hyaluronan as a therapeutic target in human diseases.
Advanced drug delivery reviews, 2015Co-Authors: Jiurong Liang, Dianhua Jiang, Paul W. NobleAbstract:Accumulation and turnover of extracellular matrix is a hallmark of tissue injury, repair and remodeling in human diseases. Hyaluronan is a major component of the extracellular matrix and plays an important role in regulating tissue injury and repair, and controlling disease outcomes. The function of Hyaluronan depends on its size, location, and interactions with binding partners. While fragmented Hyaluronan stimulates the expression of an array of genes by a variety of cell types regulating inflammatory responses and tissue repair, cell surface Hyaluronan provides protection against tissue damage from the environment and promotes regeneration and repair. The interactions of Hyaluronan and its binding proteins participate in the pathogenesis of many human diseases. Thus, targeting Hyaluronan and its interactions with cells and proteins may provide new approaches to developing therapeutics for inflammatory and fibrosing diseases. This review focuses on the role of Hyaluronan in biological and pathological processes, and as a potential therapeutic target in human diseases.
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Role of CD44 in the organization of keratinocyte pericellular Hyaluronan
Histochemistry and Cell Biology, 2012Co-Authors: Sanna Pasonen-seppänen, Markku Tammi, Kirsi Rilla, Juha M. T. Hyttinen, Tiina Jokela, Paul W. Noble, Raija TammiAbstract:CD44 is a ubiquitous cell surface glycoprotein, involved in important cellular functions including cell adhesion, migration, and modulation of signals from cell surface receptors. While most of these CD44 functions are supposed to involve Hyaluronan, relatively little is known about the contribution of CD44 to Hyaluronan maintenance and organization on cell surface, and the role of CD44 in Hyaluronan synthesis and catabolism. Blocking Hyaluronan binding either by CD44 antibodies, CD44-siRNA or Hyaluronan decasaccharides (but not hexasaccharides) removed most of the Hyaluronan from the surfaces of both human (HaCaT) and mouse keratinocytes, resembling results on cells from CD44−/− animals. In vitro, compromising CD44 function led to reduced and increased amounts, respectively, of intracellular and culture medium Hyaluronan, and specific accumulation below the cells. In vivo, CD44-deficiency caused no marked differences in Hyaluronan staining intensity or localization in the fetal skin or in adult ear skin, while tail epidermis showed a slight reduction in epidermal Hyaluronan staining intensity. However, CD44-deficient tail skin challenged with retinoic acid or tape stripping revealed diffuse accumulation of Hyaluronan in the superficial epidermal layers, normally negative for Hyaluronan. Our data indicate that CD44 retains Hyaluronan in the keratinocyte pericellular matrix, a fact that has not been shown unambiguously before, and that Hyaluronan abundance in the absence of CD44 can result in Hyaluronan trapping in abnormal locations possibly interfering there with normal differentiation and epidermal barrier function.
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Role of Hyaluronan and Hyaluronan-binding proteins in human asthma
The Journal of allergy and clinical immunology, 2011Co-Authors: Jiurong Liang, Dianhua Jiang, Yoosun Jung, Ting Xie, Jennifer L. Ingram, Tony D. Church, Simone Degan, Maura Leonard, Monica Kraft, Paul W. NobleAbstract:Background The characteristics of human asthma are chronic inflammation and airway remodeling. Hyaluronan, a major extracellular matrix component, accumulates during inflammatory lung diseases, including asthma. Hyaluronan fragments stimulate macrophages to produce inflammatory cytokines. We hypothesized that Hyaluronan and its receptors would play a role in human asthma. Objective To investigate the role of Hyaluronan and Hyaluronan-binding proteins in human asthma. Methods Twenty-one subjects with asthma and 25 healthy control subjects underwent bronchoscopy with endobronchial biopsy and bronchoalveolar lavage. Fibroblasts were cultured, and Hyaluronan and Hyaluronan synthase expression was determined at baseline and after exposure to several mediators relevant to asthma pathobiology. The expression of Hyaluronan-binding proteins CD44, TLR (Toll-like receptor)–2, and TLR4 on bronchoalveolar lavage macrophages was determined by flow cytometry. IL-8 production by macrophages in response to Hyaluronan fragment stimulation was compared. Results Airway fibroblasts from patients with asthma produced significantly increased concentrations of lower-molecular-weight Hyaluronan compared with those of normal fibroblasts. Hyaluronan synthase 2 mRNA was markedly increased in asthmatic fibroblasts. Asthmatic macrophages showed a decrease in cell surface CD44 expression and an increase in TLR2 and TLR4 expression. Macrophages from subjects with asthma showed an increase in responsiveness to low-molecular-weight Hyaluronan stimulation, as demonstrated by increased IL-8 production. Conclusion Hyaluronan homeostasis is deranged in asthma, with increased production by fibroblasts and decreased CD44 expression on alveolar macrophages. Upregulation of TLR2 and TLR4 on macrophages with increased sensitivity to Hyaluronan fragments suggests a novel proinflammatory mechanism by which persistence of Hyaluronan fragments could contribute to chronic inflammation and airway remodeling in asthma.
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Hyaluronan as an Immune Regulator in Human Diseases
Physiological reviews, 2011Co-Authors: Dianhua Jiang, Jiurong Liang, Paul W. NobleAbstract:Accumulation and turnover of extracellular matrix components are the hallmarks of tissue injury. Fragmented Hyaluronan stimulates the expression of inflammatory genes by a variety of immune cells at the injury site. Hyaluronan binds to a number of cell surface proteins on various cell types. Hyaluronan fragments signal through both Toll-like receptor (TLR) 4 and TLR2 as well as CD44 to stimulate inflammatory genes in inflammatory cells. Hyaluronan is also present on the cell surface of epithelial cells and provides protection against tissue damage from the environment by interacting with TLR2 and TLR4. Hyaluronan and Hyaluronan-binding proteins regulate inflammation, tissue injury, and repair through regulating inflammatory cell recruitment, release of inflammatory cytokines, and cell migration. This review focuses on the role of Hyaluronan as an immune regulator in human diseases.
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Hyaluronan mediates ozone induced airway hyperresponsiveness in mice
Journal of Biological Chemistry, 2009Co-Authors: Stavros Garantziotis, Paul W. Noble, Erin N Potts, Koji Kimata, Lisheng Zhuo, Daniel L Morgan, Rashmin C Savani, Michael W Foster, David A Schwartz, John W HollingsworthAbstract:Abstract Ozone is a common urban environmental air pollutant and significantly contributes to hospitalizations for respiratory illness. The mechanisms, which regulate ozone-induced bronchoconstriction, remain poorly understood. Hyaluronan was recently shown to play a central role in the response to noninfectious lung injury. Therefore, we hypothesized that Hyaluronan contributes to airway hyperreactivity (AHR) after exposure to ambient ozone. Using an established model of ozone-induced airways disease, we characterized the role of Hyaluronan in airway hyperresponsiveness. The role of Hyaluronan in response to ozone was determined by using therapeutic blockade, genetically modified animals, and direct challenge to Hyaluronan. Ozone-exposed mice demonstrate enhanced AHR associated with elevated Hyaluronan levels in the lavage fluid. Mice deficient in either CD44 (the major receptor for Hyaluronan) or inter-α-trypsin inhibitor (molecule that facilitates Hyaluronan binding) show similar elevations in Hyaluronan but are protected from ozone-induced AHR. Mice pretreated with Hyaluronan-binding peptide are protected from the development of ozone-induced AHR. Overexpression of Hyaluronan enhances the airway response to ozone. Intratracheal instillation of endotoxin-free low molecular weight Hyaluronan induces AHR dependent on CD44, whereas instillation of high molecular weight Hyaluronan protects against ozone-induced AHR. In conclusion, we demonstrate that Hyaluronan mediates ozone-induced AHR, which is dependent on the fragment size and both CD44 and inter-α-trypsin inhibitor. These data support the conclusion that pulmonary matrix can contribute to the development of airway hyperresponsiveness.
Kirsi Rilla - One of the best experts on this subject based on the ideXlab platform.
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Role of CD44 in the organization of keratinocyte pericellular Hyaluronan
Histochemistry and Cell Biology, 2012Co-Authors: Sanna Pasonen-seppänen, Markku Tammi, Kirsi Rilla, Juha M. T. Hyttinen, Tiina Jokela, Paul W. Noble, Raija TammiAbstract:CD44 is a ubiquitous cell surface glycoprotein, involved in important cellular functions including cell adhesion, migration, and modulation of signals from cell surface receptors. While most of these CD44 functions are supposed to involve Hyaluronan, relatively little is known about the contribution of CD44 to Hyaluronan maintenance and organization on cell surface, and the role of CD44 in Hyaluronan synthesis and catabolism. Blocking Hyaluronan binding either by CD44 antibodies, CD44-siRNA or Hyaluronan decasaccharides (but not hexasaccharides) removed most of the Hyaluronan from the surfaces of both human (HaCaT) and mouse keratinocytes, resembling results on cells from CD44−/− animals. In vitro, compromising CD44 function led to reduced and increased amounts, respectively, of intracellular and culture medium Hyaluronan, and specific accumulation below the cells. In vivo, CD44-deficiency caused no marked differences in Hyaluronan staining intensity or localization in the fetal skin or in adult ear skin, while tail epidermis showed a slight reduction in epidermal Hyaluronan staining intensity. However, CD44-deficient tail skin challenged with retinoic acid or tape stripping revealed diffuse accumulation of Hyaluronan in the superficial epidermal layers, normally negative for Hyaluronan. Our data indicate that CD44 retains Hyaluronan in the keratinocyte pericellular matrix, a fact that has not been shown unambiguously before, and that Hyaluronan abundance in the absence of CD44 can result in Hyaluronan trapping in abnormal locations possibly interfering there with normal differentiation and epidermal barrier function.
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transcriptional and post translational regulation of Hyaluronan synthesis
FEBS Journal, 2011Co-Authors: Raija Tammi, Kirsi Rilla, Davide Vigetti, Alberto Passi, Evgenia Karousou, Katri M Makkonen, Markku TammiAbstract:Hyaluronan, a ubiquitous high-molecular-mass glycinoglycan on cell surfaces and in extracellular matrices, has a number of specific signaling functions in cell–cell communication. Changes in its content, molecular mass and turnover rate are crucial for cell proliferation, migration and apoptosis, processes that control tissue remodeling during embryonic development, inflammation, injury and cancer. To maintain tissue homeostasis, the synthesis of Hyaluronan must therefore be tightly controlled. In this review, we highlight some recent data on the transcriptional regulation of Hyaluronan synthase (Has1–3) expression and on the post-transcriptional control of Hyaluronan synthase activity, which, in close association with the supply of the UDP-sugar substrates of Hyaluronan synthase, adjust the rate of Hyaluronan synthesis.
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Hyaluronan synthases (HAS1-3) and hyaluronidases (HYAL1-2) in the accumulation of Hyaluronan in endometrioid endometrial carcinoma.
BMC cancer, 2010Co-Authors: Timo K. Nykopp, Raija Tammi, Markku Tammi, Kirsi Rilla, Reijo Sironen, Veli-matti Kosma, Kirsi Hämäläinen, Seppo Heinonen, Maarit AnttilaAbstract:Background Hyaluronan accumulation correlates with the degree of malignancy in many solid tumor types, including malignant endometrial carcinomas. To elucidate the mechanism of Hyaluronan accumulation, we examined the expression levels of the Hyaluronan synthases (HAS1, HAS2 and HAS3) and hyaluronidases (HYAL1 and HYAL2), and correlated them with Hyaluronan content and HAS1-3 immunoreactivity.
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4 methylumbelliferone inhibits Hyaluronan synthesis by depletion of cellular udp glucuronic acid and downregulation of Hyaluronan synthase 2 and 3
Experimental Cell Research, 2009Co-Authors: Anne Kultti, Raija Tammi, Sanna Pasonenseppanen, Kirsi Rilla, Riikka Kärnä, Marjo Jauhiainen, Emma Pyoria, Markku TammiAbstract:Hyaluronan accumulation on cancer cells and their surrounding stroma predicts an unfavourable disease outcome, suggesting that Hyaluronan enhances tumor growth and spreading. 4-Methylumbelliferone (4-MU) inhibits Hyaluronan synthesis and retards cancer spreading in experimental animals through mechanisms not fully understood. These mechanisms were studied in A2058 melanoma cells, MCF-7 and MDA-MB-361 breast, SKOV-3 ovarian and UT-SCC118 squamous carcinoma cells by analysing Hyaluronan synthesis, UDP-glucuronic acid (UDP-GlcUA) content, and Hyaluronan synthase (HAS) mRNA levels. The maximal inhibition in Hyaluronan synthesis ranged 22-80% in the cell lines tested. Active glucuronidation of 4-MU produced large quantities of 4-MU-glucuronide, depleting the cellular UDP-GlcUA pool. The maximal reduction varied between 38 and 95%. 4-MU also downregulated HAS mRNA levels: HAS3 was 84-60% lower in MDA-MB-361, A2058 and SKOV-3 cells. HAS2 was the major isoenzyme in MCF-7 cells and lowered by 81%, similar to 88% in A2058 cells. These data indicate that both HAS substrate and HAS2 and/or HAS3 mRNA are targeted by 4-MU. Despite different target point sensitivities, the reduction of Hyaluronan caused by 4-MU was associated with a significant inhibition of cell migration, proliferation and invasion, supporting the importance of Hyaluronan synthesis in cancer, and the therapeutic potential of Hyaluronan synthesis inhibition.
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Hyaluronan synthesis induces microvillus-like cell surface protrusions
The Journal of biological chemistry, 2006Co-Authors: Anne Kultti, Raija Tammi, Kirsi Rilla, Riikka Tiihonen, Andrew P. Spicer, Markku TammiAbstract:Hyaluronan synthases (HASs) are plasma membrane enzymes that simultaneously elongate, bind, and extrude the growing Hyaluronan chain directly into extracellular space. In cells transfected with green fluorescent protein (GFP)-tagged Has3, the dorsal surface was decorated by up to 150 slender, 3-20-microm-long microvillus-type plasma membrane protrusions, which also contained filamentous actin, the Hyaluronan receptor CD44, and lipid raft microdomains. Enzymatic activity of HAS was required for the growth of the microvilli, which were not present in cells transfected with other GFP proteins or inactive GFP-Has3 mutants or in cells incubated with exogenous soluble Hyaluronan. The microvilli induced by HAS3 were gradually withered by introduction of an inhibitor of Hyaluronan synthesis and rapidly retracted by hyaluronidase digestion, whereas they were not affected by competition with Hyaluronan oligosaccharides and disruption of the CD44 gene, suggesting independence of Hyaluronan receptors. The data bring out the novel concept that the glycocalyx created by dense arrays of Hyaluronan chains, tethered to HAS during biosynthesis, can induce and maintain prominent microvilli.
Veli-matti Kosma - One of the best experts on this subject based on the ideXlab platform.
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Hyaluronan in human malignancies.
Experimental cell research, 2010Co-Authors: Reijo Sironen, Raija Tammi, Markku Tammi, Päivi Auvinen, Maarit Anttila, Veli-matti KosmaAbstract:Hyaluronan, a major macropolysaccharide in the extracellular matrix of connective tissues, is intimately involved in the biology of cancer. Hyaluronan accumulates into the stroma of various human tumors and modulates intracellular signaling pathways, cell proliferation, motility and invasive properties of malignant cells. Experimental and clinicopathological evidence highlights the importance of Hyaluronan in tumor growth and metastasis. A high stromal Hyaluronan content is associated with poorly differentiated tumors and aggressive clinical behavior in human adenocarcinomas. Instead, the squamous cell carcinomas and malignant melanomas tend to have a reduced Hyaluronan content. In addition to the stroma-cancer cell interaction, Hyaluronan can influence stromal cell recruitment, tumor angiogenesis and epithelial-mesenchymal transition. Hyaluronan receptors, Hyaluronan synthases and Hyaluronan degrading enzymes, hyaluronidases, are involved in the modulation of cancer progression, depending on the tumor type. Furthermore, intracellular signaling and angiogenesis are affected by the degradation products of Hyaluronan. Hyaluronan has also therapeutic implications since it is involved in multidrug resistance.
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Hyaluronan synthases (HAS1-3) and hyaluronidases (HYAL1-2) in the accumulation of Hyaluronan in endometrioid endometrial carcinoma.
BMC cancer, 2010Co-Authors: Timo K. Nykopp, Raija Tammi, Markku Tammi, Kirsi Rilla, Reijo Sironen, Veli-matti Kosma, Kirsi Hämäläinen, Seppo Heinonen, Maarit AnttilaAbstract:Background Hyaluronan accumulation correlates with the degree of malignancy in many solid tumor types, including malignant endometrial carcinomas. To elucidate the mechanism of Hyaluronan accumulation, we examined the expression levels of the Hyaluronan synthases (HAS1, HAS2 and HAS3) and hyaluronidases (HYAL1 and HYAL2), and correlated them with Hyaluronan content and HAS1-3 immunoreactivity.
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Hyaluronan in Human Tumors: Importance of Stromal and Cancer Cell-Associated Hyaluronan
Hyaluronan in Cancer Biology, 2009Co-Authors: Raija H. Tammi, Anne Kultti, Päivi Auvinen, Veli-matti Kosma, Risto Pirinen, Markku TammiAbstract:Publisher Summary Hyaluronan has turned out to be an active regulator of cell behavior rather than solely an inert extracellular matrix component. The high concentration of Hyaluronan in many embryonic tissues correlates with their rates of cell migration and proliferation. Recent reports suggest that Hyaluronan is not only a prognostic indicator, but also an active participant in the disease and a novel target of therapy. There is a large body of evidence from experimental animals and in vitro models suggesting that the production of Hyaluronan by tumor cells is important for their malignant behavior. The assays on tumor biopsies do not give information about the dynamic processes that control the synthesis and catabolism of Hyaluronan. Analyses of clinical patient materials show that alterations in the Hyaluronan content, whether on the actual malignant cells or their surrounding stroma, are tightly associated with patient prognosis. Tumor progression is highly likely when Hyaluronan is abundant on the surface or within tumor cells of gastric or colon carcinoma. There are number of ways Hyaluronan can be involved in the regulation of cancer growth and spreading, as suggested by experiments on animals, and studies in vitro. However, understanding the relative importance of the various aspects of Hyaluronan functions and metabolism in human cancers in vivo is still lacking and warrants more research on clinical materials.
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Hyaluronan in human tumors: pathobiological and prognostic messages from cell-associated and stromal Hyaluronan.
Seminars in cancer biology, 2008Co-Authors: Raija Tammi, Anne Kultti, Päivi Auvinen, Veli-matti Kosma, Risto Pirinen, Markku TammiAbstract:Cancers are supported by a distinct type of connective tissue stroma, crucial for tumor survival and advancement. Hyaluronan is a major matrix molecule in the stroma of many common tumors, and involved in their growth and spreading. Here we focus in recent data on stromal Hyaluronan in human tumors, and that on the surface of the malignant cells. Hyaluronan accumulation is most conspicuous in malignancies that develop in cells and tissues normally devoid of Hyaluronan, such as single layered epithelia and their Hyaluronan-poor connective tissue stroma. The magnitude of the Hyaluronan accumulation in the malignant epithelium itself (e.g. colon and gastric cancers) or tumor stroma (breast, ovarian, prostate cancers) strongly correlates with an unfavorable prognosis of the patient, i.e. advancement of the malignancy. A completely different pattern arises from stratified epithelia that normally produce Hyaluronan and are surrounded by a Hyaluronan-rich stroma. The cell surface of the latter group of tumors (e.g. squamous cell carcinomas of skin, mouth, larynx and esophagus, and skin melanoma) show abundant Hyaluronan which tends to get reduced and patchy in the most advanced stages of the tumors, suggesting enhanced turnover. While the assays of human tumors represent snapshots of currently unknown processes and kinetics of Hyaluronan metabolism, it is obvious that Hyaluronan accumulation at some stage is an inherent feature in most of the common epithelial malignant tumors. The possible contributions of inflammatory cells, stem cells, mutated stromal cells, or otherwise deranged growth factor exchange between stromal and cancer cells are discussed as possible explanations to Hyaluronan abundance in the tumors. The importance of Hyaluronan in human tumor progression will be further clarified when drugs become available to modify Hyaluronan metabolism.
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high levels of stromal Hyaluronan predict poor disease outcome in epithelial ovarian cancer
Cancer Research, 2000Co-Authors: Maarit Anttila, Raija Tammi, Markku Tammi, Kari Syrjanen, Seppo Saarikoski, Veli-matti KosmaAbstract:Several malignant tumors accumulate Hyaluronan, a matrix component suggested to promote cancer cell migration and growth. To explore the potential clinical importance of this concept, we assessed the Hyaluronan levels in epithelial ovarian cancer. A biotinylated affinity probe specific for Hyaluronan was prepared and applied to histological sections of 309 epithelial ovarian cancers and 45 matched metastatic lesions. The staining was scored according to the percentage area of strong Hyaluronan signal of total peri- and intratumoral stroma as low ( 75%). Low, moderate, and high levels of stromal Hyaluronan were observed in 95, 116, and 98 carcinomas, respectively. The high stromal Hyaluronan level was significantly associated with poor differentiation, serous histological type, advanced stage, and large primary residual tumor, whereas it was not correlated with high CD44 expression on cancer cells. The 5-year outlook of the disease deteriorated with increasing stromal Hyaluronan levels for both overall (45% versus 39% versus 26%; P = 0.002) and recurrence-free (66% versus 56% versus 40%; P = 0.008) survival. High levels of stromal Hyaluronan were more frequent in metastatic lesions than in primary tumors ( z = −3.9; P = 0.0001). In Cox’s multivariate analyses, high level of stromal Hyaluronan was an independent prognostic factor in all patients, as well as in stage-specific subgroups. These results suggest that stromal Hyaluronan accumulation may be a powerful enhancer of tumor progression and, as such, provides a novel, independent prognostic marker and a potential target of therapy.
