Overexpression of Hyaluronan Synthase-2 Reduces the Tumorigenic Potential of Glioma Cells Lacking Hyaluronidase Activity

Enegd, Bouchra; King, James; Stylli, S S; Paradiso, Lucy; Kaye, Andrew H.; Novak, Ulrike

doi:10.1227/00006123-200206000-00023

Cited by 13 publications

(14 citation statements)

References 26 publications

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“…This conclusion may help us state generally that the physiological significance of changes in HA concentration with tumor grade or stage, because HA accumulation in clinical samples varies and occasionally shows little statistically change with tumor grade. A recent study using glioma cells has shown that overexpression of HAS2 inhibited tumor formation and suggested the importance of a balance between the HA synthesis and the degradation by hyaluronidase (29). Considering that the degradation of HA may be involved in controlling the HA accumulation (49), excess HA may also have suppressed tumor growth in glioma cells.…”

Section: Discussionmentioning

confidence: 99%

“…It is therefore plausible that the HAS isoforms are involved in different stages of malignant tumor progression. Molecular cloning of the HAS genes enabled us to control HA biosynthesis and investigate HA functions in malignant transformation (23)(24)(25)(26)(27)(28)(29)(30). Overexpression of HAS2 enhanced both the anchorage-independent growth and tumorigenicity of a human fibrosarcoma cell line (24).…”

Section: Ha Is a Linear Polysaccharide Composed Of The Repeating Disamentioning

confidence: 99%

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Selective Expression and Functional Characteristics of Three Mammalian Hyaluronan Synthases in Oncogenic Malignant Transformation

Itano

Sawai

Atsumi

et al. 2004

Journal of Biological Chemistry

133

102

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Malignant transformation of fibroblasts and epithelial cells is often accompanied by increased hyaluronan production and accumulation. Despite recent progress in the study of hyaluronan biosynthesis, the mechanisms underlying the transformation-induced overproduction of hyaluronan have not been elucidated. Here we report that activity and transcriptional levels of hyaluronan synthase (HAS) significantly increased after oncogenic malignant transformation of a rat 3Y1 fibroblast cell line. Of three HAS isoforms (HAS1, HAS2, and HAS3), only HAS2 gene expression was increased in the v-Ha-ras transformed 3Y1 cells, which show less malignancy. In contrast, both HAS1 and HAS2 expressions were elevated in the highly malignant cells transformed with v-src and/or v-fos. To assess the contribution of HAS expression to the oncogenic malignant transformation, we established stable cell transfectants expressing sense and antisense HAS genes. Antisense suppression of the HAS2 expression significantly decreased hyaluronan production in the cells transformed by the oncogenic v-Ha-ras and eventually led to a reduction in tumorigenicity in the rat peritoneum. The introduction of the HAS1 and HAS2 genes promoted the growth of subcutaneous tumors in a manner dependent on the levels of hyaluronan synthesis. Significant growth promotion was observed within a wide range of HAS1 expression. In contrast, the growth stimulation was only seen within a narrow range of HAS2 expression, and high levels of HAS2 expression even inhibited tumor growth. These results suggest that proper regulation of the expression of each HAS isoform is required for optimal malignant transformation and tumor growth.

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Section: Discussionmentioning

confidence: 99%

Section: Ha Is a Linear Polysaccharide Composed Of The Repeating Disamentioning

confidence: 99%

Selective Expression and Functional Characteristics of Three Mammalian Hyaluronan Synthases in Oncogenic Malignant Transformation

Itano

Sawai

Atsumi

et al. 2004

Journal of Biological Chemistry

133

102

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“…Accordingly, CD44-mediated HA binding at the cell surface of gliomas is thought to involve multivalent binding events affected by the size of the HA ligand, the quantity and density of cell surface CD44, and the activation state of CD44 (40). Moreover, high grade gliomas in the brain become more aggressive when they co-express HA synthase and hyaluronidases, further emphasizing the crucial implication of HA cell surface recognition and subsequent metabolism in the growing tumor (41).…”

Section: Discussionmentioning

confidence: 99%

Hyaluronan Cell Surface Binding Is Induced by Type I Collagen and Regulated by Caveolae in Glioma Cells

Annabi

Thibeault

Moumdjian

et al. 2004

Journal of Biological Chemistry

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Hyaluronan (HA) is a component of the brain extracellular matrix environment that is synthesized and secreted by glioma cells. The primary cell surface receptor for HA is CD44, a membrane glycoprotein that is functionally regulated by a membrane type 1 matrix metalloproteinase (MT1-MMP). Both CD44 and MT1-MMP are partially located in Triton X-100-insoluble domains, but no functional link has yet been established between them. In the present study, we studied the regulation of HA cell surface binding in U-87 glioma cells. We show that an MMP-dependent mechanism regulates the intrinsic cell surface binding of HA as ilomastat, a broad MMP inhibitor, increased HA binding to glioma cells. HA binding was also rapidly and specifically up-regulated by 3-fold by type I collagen in U-87 cells, which also induced a significant morphological reorganization associated with the activation of a latent form of MMP-2 through a MT1-MMP-mediated mechanism. Interestingly, caveolae depletion with a cell surface cholesteroldepleting agent ␤-cyclodextrin triggered an additional increase (9-fold) in the binding of HA, in synergy with type I collagen. On the other hand, HA cell surface binding was diminished by the MEK inhibitor PD98059 and by the overexpression of a recombinant, wild type MT1-MMP, whereas its cytoplasmic-deleted form had no effect. Taken together, our results suggest that MT1-MMP regulates, through its cytoplasmic domain, the cell surface functions of CD44 in a collagen-rich pericellular environment. Additionally, we describe a new molecular mechanism regulating the invasive potential of glioma cells involving a MT1-MMP/CD44/caveolin interaction, which could represent a potential target for anti-cancer therapies.The principal molecules that have been identified in the normal brain extracellular matrix (ECM) 1 are hyaluronan (HA; also known as hyaluronic acid, hyaluronate) and chondroitin sulfate (1, 2). HA is an important glycosaminoglycan constituent believed to be implicated in angiogenesis, the formation of new blood vessels from preexisting vasculature. Although the serum level of HA is already used as an indicator of progressive malignant disease (3), its effects on in vivo angiogenesis and endothelial cell (EC) function are complex and have been reported to depend on HA concentration and molecular size (4, 5). Accordingly, whereas high molecular weight HA was shown to inhibit EC functions (6), low molecular weight HA stimulated EC proliferation, tubulogenesis (6, 7), and neovascularization (8). Moreover, small HA polymers efficiently regulated CD44 cell surface functional expression and promoted tumor cell migration (9). Astrocytic tumors of the central nervous system express CD44 among other cell adhesion receptors of the integrin or immunoglobulin superfamily. Although HA is the principal ligand of CD44, other CD44 ligands include the ECM components collagen, fibronectin, laminin, and chondroitin sulfate, whereas mucosal addressin, serglycin, osteopontin, and the class II invariant chain represent ECM-unrelat...

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“…1). Increased hyaluronan deposition has been implicated in glioma progression [101,102], although an increased production of hyaluronan alone does not seem to be sufficient, unless it is associated with concomitant hyaluronidase expression [103]. Increased expression of hyaluronan is likely to change the ratio between the number of hyaluronan-binding proteoglycans and link proteins on the one hand, and the number of potential docking places for these proteins along the hyaluronan molecules on the other.…”

Section: Hyaluronan Hyaluronidase and Hyaluronan-binding Moleculesmentioning

confidence: 99%

Extracellular matrix components associated with remodeling processes in brain

Rauch

2004

CMLS, Cell. Mol. Life Sci.

183

146

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In the central nervous system, various extracellular matrix components have been identified which are strongly expressed during development and in most areas of the brain down-regulated during maturation. Examples are tenascin-C, neurocan and hyaluronan. While tenascin-C is well known to be associated with morphogenic events and the active contribution of hyaluronan to various physiological processes is increasingly acknowledged, neurocan belongs to a class of molecules thought to be generally more associated with barrier functions: chondroitin sulfate CMLS Cellular and Molecular Life Sciencesproteoglycans. Consideration of these and related molecules and their processing in the context of the general organization of the brain extracellular matrix, their changes during brain maturation and their implication in different types of remodeling processes in adult brain, like normal and pathological synaptic plasticity, inflammatory and dementia-associated diseases and gliomas, may indicate that components of the extracellular matrix could provide valuable early information about the pathological state of the brain.

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Overexpression of Hyaluronan Synthase-2 Reduces the Tumorigenic Potential of Glioma Cells Lacking Hyaluronidase Activity

Cited by 13 publications

References 26 publications

Selective Expression and Functional Characteristics of Three Mammalian Hyaluronan Synthases in Oncogenic Malignant Transformation

Selective Expression and Functional Characteristics of Three Mammalian Hyaluronan Synthases in Oncogenic Malignant Transformation

Hyaluronan Cell Surface Binding Is Induced by Type I Collagen and Regulated by Caveolae in Glioma Cells

Extracellular matrix components associated with remodeling processes in brain

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