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PubMed2001

Versican accumulation in human prostatic fibroblast cultures is enhanced by prostate cancer cell-derived transforming growth factor beta1.

We have previously demonstrated that peritumoral stromal matrix derived from prostate cancer patients who relapse after radical surgery contains elevated levels of versican. The purpose of this study was to determine whether prostate cancer cells control stromal cell secretion of versican. Serum-free conditioned medium from three prostate adenocarcinoma cell lines, LNCaP, PC3, and DU145, was added to cultures of fibroblasts established from prostatic tissue of patients with benign prostatic hyperplasia, and the medium was harvested at 24, 48, and 72 h. Immunoblotting with an antiversican core protein antibody revealed that prostatic fibroblast medium harvested at 72 h contained increased levels of versican after treatment with either LNCaP-, PC3- or DU145-conditioned medium (2.5-, 4.5-, and 5-fold, respectively) compared with control cultures. This increase in versican in the culture medium was not observed after coincubation with transforming growth factor beta1-neutralizing antisera. The results of this study suggest that prostate tumor cells induce host stromal cells to secrete increased versican levels via a paracrine mechanism mediated by transforming growth factor beta1.

Adenocarcinoma↗
PubMedDate not supplied

Synthesis and expression of mRNA encoding for different versican splice variants is related to the aggregation of human epithelial mesothelioma cells.

Malignant mesothelioma often has a biphasic growth pattern of epithelial and/or sarcomatous morphology. In culture, epithelial cells form aggregates, whereas fibroblast-like cells do not. Two human mesothelioma cell sub-lines, one with epithelial differentiation and the other with fibroblast-like phenotype were studied. We have previously shown (Dobra et al, 2000) that distinct types of the cell-associated syndecans are involved in the regulation of mesothelioma cell differentiation, whereas the role of matrix proteoglycans (PGs) remains unknown. This study was undertaken to examine whether cell aggregation of the epithelial mesothelioma cells correlates to the differential expression of the matrix PGs versican and perlecan at different degrees of confluence. PGs were isolated from the culture medium using ion-exchange chromatography and identified by high-performance liquid chromatography, capillary electrophoresis and Western blotting. Fibroblast-like cells express substantially more versican than epithelial cells. RT-PCR showed that both cell lines express mRNA coding for versican splice variants V0 and V1, but not for V2. The dominating splice variant in both cell lines is the V0. Screening of versican splice variants in various degrees of culture confluence showed that the expression of mRNA conding for the versican splice variants V0 and V1 is different only in confluent cultures. No significant differences in the expression of perlecan between the two cell lines were recorded. These results suggest that the aggregation of epithelial cells is related to a significant decrease (p < or = 0.001) of the splice variant V1. This variant seems to be a biologically active constituent that affects tumor biology.

Alternative Splicing↗
PubMed2003

Modulation of prostate cancer cell attachment to matrix by versican.

In this study, we examined whether versican, a recognized anti-cell adhesive molecule for various mesenchymal and nerve cell types, influences prostate cancer cell adhesion to extracellular matrix components. Prostate cancer cell adhesion to fibronectin, a major component of the stromal extracellular matrix was inhibited by versican-rich conditioned medium (CM) from cultured human prostatic fibroblasts. In contrast, cancer cell attachment to laminin, a component of basement membranes, was not affected by the same CM. Consistent with versican being the active inhibitory factor in the CM, the integrity of chondroitin sulfate side chains and an ability to bind the RGD (Arg-Gly-Asp) peptide sequence of fibronectin were essential for the inhibition of prostate cancer cell attachment to fibronectin. Subsequent studies with versican purified from human prostate fibroblast CM confirmed its anti-adhesive activity. We conclude that versican is an important modulator of tumor cell attachment to the interstitial stromal matrix of the prostate, the latter being an essential step in cancer cell motility and local invasion of the prostatic stroma.

Cell Adhesion↗
PubMed2005

Versican splice variants in human trabecular meshwork and ciliary muscle.

PURPOSE: Versican, chondroitin sulfate glycoprotein 2, is thought to play a role in regulating aqueous humor outflow and intraocular pressure via the human trabecular meshwork (HTM) of the eye. This protein was upregulated in HTM cells when they were treated with TGF-beta. There are four splice variant forms of versican (V0-V3) with different numbers of glycoaminoglycan (GAG) attachment domains. In this study, we investigated the various isoforms of versican from ocular tissues and cultured cells. METHODS: HTM and human ciliary muscle (HCM) tissues were dissected from three pairs of donors eyes with no histories of eye disease. Cultures of HTM and HCM cells were established from five donor eyes, and HTM cells were treated for 72 h with 1 ng/ml of either with hrTGF-beta1 or hrTGF-beta2. Total RNA was isolated from cells and tissues from each of the samples. Relative quantitation of gene expression of each variant was detected by real-time PCR with SYBR Green dye. RESULTS: All four variants of versican existed in each sample. In cultured HTM cells, the two variants with the largest number of GAG domains predominate. The V1 form is about 20% greater than the V0 form. There is an upregulation, particularly in the V0 form, when the cells are cultured. In tissue, the V1 form is about five fold greater than the other three. In the ocular ciliary muscle, the V1 form is the most prominent, but with this tissue, the relative amount of the V0 form did not change when cells were cultured. There was an upregulation of all splice variants in HTM cells when they were cultured with either TGF-beta1 or TGF-beta2. The increase in expression in the HTM with TGF-beta treatments were greatest with the V0 and V2 forms. CONCLUSIONS: This is the first report about the presence of various forms of versican in the anterior segment of the eye and the alterations in the mRNA patterns of these forms when cells are placed in culture. The results indicate the variants with the largest numbers of GAG attachment domains are the most prominent in the HTM and HCM. The increases in these forms that have the most GAG domains would be consistent with the increases in chondroitin sulfate reported in glaucoma.

Cell Culture Techniques↗
PubMed1996

Biglycan, decorin, and versican protein expression patterns in coronary arteriopathy of human cardiac allograft: distinctness as compared to native atherosclerosis.

BACKGROUND: Histochemical staining has demonstrated previously dramatic deposits of glycosaminoglycans associated with prominent lipid accumulations in thickened vessel walls of allograft coronary arteries. In this study, we characterized the amount, distribution, and types of proteoglycan in the walls of coronary arteries from human cardiac allografts and from native atherosclerotic (NA) controls as part of a strategy to understand the pathogenesis of transplant arteriopathy (TA). METHOD: We used polyclonal rabbit antibodies against human biglycan, decorin, and versican localize the proteoglycan molecules in standardized transverse sections of the proximal left anterior descending and right coronary arteries. Slides were scored in a blinded fashion for intensity of proteoglycan staining (0 to 6+) and for localization in the vessel walls. RESULTS: Unique patterns of proteoglycan distribution were present in TA and NA. Biglycan was particularly prominent in intima and evolving atheromata in severely diseased TA coronary arteries, but not in NA. Decorin was present mainly in adventitia of all vessels and in the intima of NA. Prominent versican accumulation occurred in intima and media of TA coronaries, associated with smooth muscle cells and foam cells. There was a reciprocal pattern of biglycan and decorin staining. Versican colocalized with biglycan. Intimal biglycan and versican deposits were positively correlated to the extent of luminal narrowing in TA. CONCLUSION: The distinctive staining patterns for biglycan, decorin and versican in both native and allograft disease indicate that the synthesis and distribution of these proteoglycans are regulated by different local mechanisms in different atheromatous diseases.

Biglycan↗
PubMed1999

Distinct spatial and temporal distributions of aggrecan and versican in the embryonic chick heart.

Although chondroitin sulfate proteoglycans (CSPGs) are major components of the embryonic extracellular matrix, little attention has been paid to specific CSPGs in early heart development, in part because appropriate antibodies were not available. Therefore we prepared specific polyclonal antibodies against chicken aggrecan, versican, neurocan, and phosphacan. Western blotting and immunohistochemical studies revealed the presence of aggrecan and versican in stages 12-21 chicken embryo hearts in distinctive spatial and temporal patterns. Because this is the first demonstration of aggrecan in heart tissue, we further used RT-PCR to confirm that aggrecan is expressed in the heart and in situ hybridization to confirm the pattern of expression determined using antibodies. Versican is found in the myocardium and the myocardial basement membrane. In contrast, aggrecan is specifically colocalized with several groups of migrating cells including endocardial cushion tissue cells, epicardial cells, a mesenchymal cell population in the outflow tract that may be of neural crest origin, and a mesenchymal cell population in the inflow tract. The combined observations indicate that versican and aggrecan are expressed in unique patterns and suggest that they play very different roles in development.

Aggrecans↗
PubMed2005

V3 versican isoform expression alters the phenotype of melanoma cells and their tumorigenic potential.

Versican is a large chondroitin sulfate proteoglycan produced by several tumor cell types, including malignant melanoma. The expression of increased amounts of versican in the extracellular matrix may play a role in tumor cell growth, adhesion and migration. We have expressed the V3 isoform of versican in human and canine melanoma cell lines. Retroviral overexpression of V3 did not change the morphology of any of the cell lines but markedly reduces cell growth in the V3 versican expressing melanoma cells. The V3-overexpressing melanoma cells retain their diminished growth potential in vivo because primary tumors arising from these cell lines growth more slowly than their vector only counterparts. This effect was accompanied by increases in cell adhesion on hyaluronan and an enhanced ability to migrate on hyaluronan-coated transwell chambers. This enhanced migration is blocked when cells are preincubated with soluble hyaluronan, or anti-CD44 antibodies, suggesting that V3 acts by altering the hyaluronan-CD44 interaction. Hyaluronan content and CD44 expression are not altered in V3-overexpressing cells compared to vector-transduced cells. Our results show that V3 overproduction modulates the in vitro behavior of human and canine melanoma cell lines and reduces their tumorigenicity in vivo.

Animals↗
PubMed2001

Platelet-derived growth factor stimulates the formation of versican-hyaluronan aggregates and pericellular matrix expansion in arterial smooth muscle cells.

Hyaluronan and versican-rich pericellular matrices form around arterial smooth muscle cells (ASMC) preferentially during the detachment phase of proliferation and migration. PDGF is a potent mitogen and chemotactic agent for ASMC and also stimulates the production of extracellular matrix molecules which may regulate the proliferative and migratory capacity of the cells. We have examined the effect of PDGF on the formation of hyaluronan-dependent pericellular matrices, and on the synthesis and interaction of several major pericellular coat constituents. As demonstrated using a particle exclusion assay, PDGF stimulated the formation of pericellular matrices and was seen both in an increased proportion of cells with a coat and a greater coat size. This increase was accompanied by a transient increase in hyaluronan synthase 2 (HAS2) expression and an increase in hyaluronan synthesis and polymer length. PDGF also increased the synthesis of versican and link protein as measured at the mRNA and protein levels. The amount of native versican-hyaluronan aggregates and link-stabilized aggregate was also increased following PDGF treatment. Time lapse imaging showed that pericellular matrix formation occurred around trailing cell processes prior to their detachment. These data suggest that PDGF modulates the synthesis and organization of ASMC pericellular coat-forming molecules such as versican, hyaluronan, and link protein, which leads to extracellular matrix expansion and alterations in ASMC phenotype.

Aorta↗
PubMed1998

Differential regulation of expression of hyaluronan-binding proteoglycans in developing brain: aggrecan, versican, neurocan, and brevican.

We have used a slot-blot radioimmunoassay to quantitate the levels of hyaluronan-binding chondroitin sulfate proteoglycans in developing rat brain from embryonic day 14 (E 14) to eight months postnatal. Recombinant nonhomologous regions of the core proteins were used for immunization to obtain polyclonal antibodies specific for aggrecan, the alpha and beta domains of versican mRNA splice variants, and N- and C-terminal portions of neurocan, while brevican was quantitated using a specific monoclonal antibody. The concentration of aggrecan increased steadily during brain development up to 5 months of age, when it reached a level that was 18-fold higher than at E14. Alternatively spliced versican isoforms containing the alpha domain of the glycosaminoglycan attachment region were present at a relatively low level during the late embryonic and early postnatal period, decreased by approximately 50% between 1 and 2 weeks postnatal, and then increased steadily in concentration to reach a maximum at 100 days that was 7-fold that present at 10 days postnatal. In contrast to these results, versican isoforms containing the beta domain more than doubled in concentration between E14 and birth, after which they decreased by greater than 90% to reach a low "mature" level that remained unchanged between 2 and 8 months. The N- and C-terminal portions of neurocan (produced by a developmentally-regulated proteolytic cleavage in the middle of its chondroitin sulfate attachment region) both increased in embryonic brain during development, reached a peak in the early postnatal period, and then declined thereafter. As in the case of aggrecan, only traces of brevican were detected in embryonic brain and its concentration increased steadily after birth to reach an adult level that was approximately 14-fold higher than that present in neonatal brain. These striking and distinctive changes in the concentrations of the different members of this family of structurally related proteoglycans in developing brain, including changes in opposite directions for versican mRNA splice variants, indicate that the individual proteoglycans and their isoforms probably serve unique functions during nervous tissue histogenesis.

Aggrecans↗
PubMed2001

Versican modulates embryonic chondrocyte morphology via the epidermal growth factor-like motifs in G3.

This investigation was designed to characterize the effect of the extracellular matrix molecule versican on chondrocyte morphology, using the well-studied chondrocyte cell culture system. When cultured chondrocytes reverted or "dedifferentiated" to a fibroblast-like morphology, we found that versican expression was significantly enhanced. Transfection of chondrocytes, isolated from embryonic chicken sterna, with a chicken miniversican construct accelerated the reversion process, while expression of an antisense construct inhibited it. A mutant miniversican lacking two epidermal growth factor-like motifs (versicanDeltaEGF) promoted differentiation, as shown by morphological changes and changes in the expression of other extracellular matrix molecules. A truncated versican mutant, the G3DeltaEGF, a G3 domain lacking its two epidermal growth factor-like motifs, also enhanced differentiation. This effect is related to G3DeltaEGF-induced change in cytoskeleton, since transfected cells exhibited misassembly of actin filaments. This article thus provides the first evidence that versican modulates chondrocyte morphology via changes in cytoskeletal structure, and may imply that extracellular matrix molecules play an important role in cell differentiation.

Actins↗
PubMed1992

Isolation and characterization of bovine gingival proteoglycans versican and decorin.

1. We have isolated, chemically and immunologically characterized versican and decorin from bovine gingiva. 2. Versican was of large molecular weight and the molecular size of the core protein was estimated to be greater than 200 kDa. 3. The glycosaminoglycan chains were susceptible to chondroitinase ABC and N-linked oligosaccharides were present on the protein core of the molecule. 4. Immunological studies provided evidence that a hyaluronic acid binding region was present in the core protein of versican. 5. The overall structure was similar to that of versican isolated from bovine sclera. 6. Decorin had a molecular weight of 102 kDa and its glycosaminoglycan chain was completely digested by specific glycosidases. 7. The partially deglycosylated core protein had a molecular weight of 55 kDa and N-linked oligosaccharides were present on the molecule.

Amino Acids↗
PubMed2005

Limb chondrogenesis is compromised in the versican deficient hdf mouse.

It has been suggested that the matrix proteoglycan, versican, may perform a functional role during early events of limb skeletogenesis largely by virtue of its spatiotemporal expression pattern in precartilage mesenchymal aggregations. The versican-deficient hdf transgenic mouse has provided the first model to explore the implications of a null mature versican on limb chondrogenesis. Due to lethality of hdf homozygous embryos prior to limb cartilage differentiation, high-density micromass cultures were employed to compare the chondrogenic capacity of hdf mutant limb mesenchyme to that of wild-type. In homozygous hdf mesenchyme, aggregation was severely compromised and neither cartilage-characteristic Type II collagen nor alcian blue positive foci were detected during a 6-day period of culture. Three-dimensional culture of hdf mutant mesenchyme, however, showed that in a permissive environment mutant cells also expressed Type II collagen. Results strongly suggest that mature versican proteoglycan is essential for precartilage aggregation and subsequent cartilage differentiation.

Animals↗
PubMed2004

Retrovirally mediated overexpression of versican v3 reverses impaired elastogenesis and heightened proliferation exhibited by fibroblasts from Costello syndrome and Hurler disease patients.

The phenotypic resemblance of patients with Costello syndrome and Hurler disease has been linked to impaired formation of elastic fibers that coincides with elevated cellular proliferation. Impaired elastogenesis in these diseases associates with respective abnormal accumulation of chondroitin sulfate and dermatan sulfate proteoglycans that induce cell surface shedding of elastin-binding protein (EBP) normally required for intracellular chaperoning of tropoelastin and its assembly into elastic fibers. A variant of the chondroitin sulfate proteoglycan versican, V3, which lacks chondroitin sulfate, has recently been shown to stimulate elastic fiber assembly and decrease proliferation when expressed by retroviral transduction in arterial smooth muscle cells. However, the mechanism(s) by which V3 influences this phenotype is not known. We now demonstrate that transduction of skin fibroblasts from Costello syndrome and Hurler disease patients with cDNA to versican V3 completely reverses impaired elastogenesis and restores normal proliferation of these cells. This phenotypic reversal is accompanied by loss of chondroitin sulfate from the cell surface and increased levels of EBP. Versican V3 transduction of skin fibroblasts from GM(1)-gangliosidosis patients, which lack EBP, failed to restore impaired elastogenesis. These results suggest that induction of elastic fiber production by gene transfer of versican V3 in skin fibroblasts is mediated by rescue of the tropoelastin chaperone, EBP.

Animals↗
PubMed2003

Differential expression of versican isoforms is a component of the human melanoma cell differentiation process.

Versican is a large chondroitin sulfate proteoglycan produced by human melanoma cell lines and malignant melanocytic lesions. In the present work, we have analyzed the expression of versican spliced variants V0, V1, V2 and V3 in human melanoma cell lines at several differentiation degrees. The isoform expression pattern depends on the degree of cell differentiation. Differentiated cell lines do not produce any of the versican isoforms as analyzed by Western blot, Northern blot and RT-PCR. All cell lines with an early or intermediate degree of differentiation (AX3, SK-mel-37, Rider, SK-mel-1.36-1-5 and SK-mel-3.44) expressed V0 and V1 transcripts, whereas V2 and V3 expression was shown only by the undifferentiated cell lines SK-mel-1.36-1-5 and Rider. Furthermore, we have analyzed the expression of versican isoforms in SK-mel-3.44 and SK-mel-1.36-1-5 cells induced to differentiate by TPA treatment. The expression of the large V0, V1 and V2 isoforms practically disappears in differentiated cells, whereas V3 remains detectable by RT-PCR analysis.

Biomarkers, Tumor↗
PubMed2002

Occurrence and structural characterization of versican-like proteoglycan in human vitreous.

Human vitreous gel is a special type of extracellular matrix, in which interpenetrating networks of collagen fibrils and hyaluronan are found. In this study, we report that apart from significant amounts of collagen, hyaluronan and sialylated glycoproteins, it was found that the human vitreous gel also contained low amounts of versican-like proteoglycan. The concentration of versican-like proteoglycan in the whole vitreous is 0.06 mg protein/ml of vitreous gel and represents a small percentage (about 5%) of the total protein content. The versican-like proteoglycan has a molecular mass of 380 kDa, as estimated by gel chromatography. Its core protein is substituted by chondroitin sulphate side chains (average molecular weight 37 kDa), in which 6-sulphated disaccharides predominated. According to the physicochemical data, the number of chondroitin sulphate chains is likely to be 5-7 per molecule. These proteoglycan monomers form large aggregates with endogenous hyaluronan. Versican, which is able to bind lectins via its C-terminal region, may bridge or interconnect various constituents of the extracellular matrix via its terminal domains in order to stabilize large supramolecular complexes at the vitreous, contributing towards the integrity and specific properties of the tissue.

Adult↗
PubMed1992

Mapping of the versican proteoglycan gene (CSPG2) to the long arm of human chromosome 5 (5q12-5q14).

Versican is a major chondroitin sulfate proteoglycan of vascularized connective tissues whose eponym reflects its functional versatility in macromolecular affinity and interactions. In this report we have localized the versican gene (CSPG2) to the long arm of human chromosome 5 by utilizing a combination of somatic cell hybrids, Southern blotting, polymerase chain reaction, and chromosomal in situ hybridization. The proteoglycan gene segregated concordantly with hybrid cell lines containing the long arm of chromosome 5, comprising the 5q12-q14 band regions. To refine this locus further, we screened a chromosome 5-specific library and isolated several genomic clones encoding a portion of the 5' end of versican. One of these genomic clones was used as a probe for in situ hybridization of human chromosome metaphases. The results corroborated the data obtained using somatic cell hybrids and further refined the assignment of the versican gene to the narrow band region of 5q12-5q14, with the primary site likely to be 5q13.2. The availability of novel genomic clones and the mapping data presented here will make possible the identification of any defect genetically linked to this proteoglycan gene.

Amino Acid Sequence↗
PubMed2002

Versican: a versatile extracellular matrix proteoglycan in cell biology.

Versican is a large extracellular matrix proteoglycan that is present in a variety of tissues. Successful cloning of the gene in man, mouse, cow and chicken has revealed the existence of at least four splice variants of versican, which differ in the size of the core protein and the number of glycosaminoglycan chains. The highly interactive nature of versican provides a basis for its importance as a structural molecule, creating loose and hydrated matrices during key events in development and disease; and by interacting either directly with cells or indirectly with molecules that associate with cells to, in part, regulate cell adhesion and survival, cell proliferation, cell migration and extracellular matrix assembly. Several studies within the past two years have confirmed a significant role for versican in regulating cell phenotype.

Animals↗
PubMed2002

Distribution pattern of versican, link protein and hyaluronic acid in the rat periodontal ligament during experimental tooth movement.

The ability of the periodontal ligament (PDL) to rapidly remodel is the basis of orthodontic tooth movement. During the tooth movement, matrix proteoglycans (PGs) may play important roles in spatial, mechanical and biological aspects for the maintenance and repair of the PDL. The aim of this study was to characterize the distribution of a large hyaluronic acid (HA)-binding proteoglycan, versican, link protein (LP) and HA in the rat molar PDL during experimental tooth movement by histochemical and immunohistochemical methods. Experimental tooth movement was performed according to Waldo's method. Histologically, regressive changes, such as decrease of fibroblasts and collagen fibers and exudative change of edema were observed in the compressive side and progressive changes, such as proliferation of fibroblasts and collagen fibers, in the strain side one day after treatment. By 3 days after tooth movement, regressive or progressive changes were not observed in either side. Using monoclonal antibodies specific to versican core protein or LP, the positive immunoreactivity for both molecules was constantly observed throughout the PDL. After the experimental force was applied to the tooth, however, the immunostainings of versican and LP became significantly intense only in the compressive side but decreased in the strain side. The intensity in the compressive side was strongest one day after the force was applied and gradually diminished thereafter. HA of both sides did not change during experimental tooth movement. Since HA is present in the PDL, large amounts of versican and LP expressed in the compressive side may create large hydrated aggregates via their association with HA that dissipates the compressive force applied to this tissue.

Animals↗