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PubMed2003

Mechanical loading regulates the expression of tenascin-C in the myotendinous junction and tendon but does not induce de novo synthesis in the skeletal muscle.

Tenascin-C is a hexabrachion-shaped matricellular protein with a very restricted expression in normal musculoskeletal tissues, but it is expressed abundantly during regenerative processes of these tissues and embryogenesis. To examine the importance of mechanical stress for the regulation of tenascin-C expression in the muscle-tendon unit, the effects of various states of mechanical loading (inactivity by cast-immobilization and three-varying intensities of subsequent re-activity by treadmill running) on the expression of tenascin-C were studied using immunohistochemistry and mRNA in situ hybridization at the different locations of the muscle-tendon unit of the rat gastrocnemius muscle, the Achilles tendon complex. This muscle-tendon unit was selected as the study site, because the contracting activity of the gastrocnemius-soleus muscle complex, and thus the mechanical loading-induced stimulation, is easy to block by cast immobilization. Tenascin-C was expressed abundantly in the normal myotendinous and myofascial junctions, as well as around the cells and the collagen fibers of the Achilles tendon. Tenascin-C expression was not found in the normal skeletal muscle, although it was found in blood vessels within the muscle tissue. Following the removal of the mechanical loading-induced stimulation on the muscle-tendon unit by cast immobilization for 3 weeks, the immonoreactivity of tenascin-C substantially decreased or was completely absent in the regions expressing tenascin-C normally. Restitution of the mechanical loading by removing the cast and allowing free cage activity for 8 weeks resulted in an increase in tenascin-C expression, but it could not restore the expression of tenascin-C to the normal level (in healthy contralateral leg). In response to the application of a more strenuous mechanical loading stimulus after the removal of the cast (after 8 weeks of low- and high-intensity treadmill running), the expression of tenascin-C was markedly increased and reached the level seen in the healthy contralateral limb. Tenascin-C was abundantly expressed in myotendinous and myofascial junctions and in the Achilles tendon, but even the most strenuous mechanical loading (high-intensity treadmill running) could not induce the expression of tenascin-C in the skeletal muscle. This was in spite of the marked immobilization-induced atrophy of the previously immobilized skeletal muscle, which had been subjected to intensive stress during remobilization. mRNA in situ hybridization analysis confirmed the immunohistochemical results for the expression of tenascin-C in the study groups. In summary, this study shows that mechanical loading regulates the expression of tenascin-C in an apparently dose-dependent fashion at sites of the muscle-tendon unit normally expressing tenascin-C but can not induce de novo synthesis of tenascin-C in the skeletal muscle without accompanying injury to the tissue. Our results suggest that tenascin-C provides elasticity in mesenchymal tissues subjected to heavy tensile loading.

Animals↗
PubMed1994

Tenascin is induced at implantation sites in the mouse uterus and interferes with epithelial cell adhesion.

Expression of tenascin, an extracellular matrix protein associated with morphogenetic events and altered states of cellular adhesion, was examined in mouse uterus during the peri-implantation period. A uniform low level expression of tenascin was detected in stromal extracellular matrix during the estrous cycle and days 1 through 4 of early pregnancy. During the period of blastocyst attachment (day 4.5), an intense deposition of tenascin fibrils was located in the extracellular matrix of stroma immediately subjacent to the uterine epithelium surrounding the attaching blastocyst. This localized intensity of tenascin expression was both spatially and temporally restricted. By day 5.5, differentiation of stroma in the immediate area around the embryo to form the primary decidual zone was accompanied by a reduced amount of tenascin expression in the form of fragmented fibrils. Tenascin also could be induced by an artificial stimulus in uterine stroma of mice that had been hormonally prepared for implantation. The ability of artificial stimuli to induce tenascin expression suggested that the tenascin-inducing signals were derived from uterine cells, presumably lumenal epithelium, rather than embryonic cells. Consistent with this, conditioned medium from primary cultures of uterine epithelium was found to induce tenascin expression (2- to 4-fold) in isolated uterine stroma. Artificial stimuli generated a temporal pattern of tenascin expression similar to that observed during early pregnancy; however, in the artificially induced model, tenascin was induced in stroma immediately subjacent to lumenal epithelium along the entire length of the uterus. Purified tenascin and a recombinant tenascin fragment consisting of alternatively spliced fibronectin type III repeats, interfered with maintenance of uterine epithelial cell adhesion to Matrigel. In contrast, other recombinant tenascin fragments or fibronectin had no effect in this regard. Tenascin had no effect on adhesion of uterine stroma. Collectively, these results suggest that stimulation of TN expression in stromal extracellular matrix in vivo occurs via hormonally regulated, epithelial-mesenchymal interactions and serves as an early marker for uterine receptivity and the attachment phase of implantation. Furthermore, tenascin may facilitate embryo penetration by disrupting uterine epithelial cell adhesion to underlying basal lamina.

Animals↗
PubMed1995

Tenascin-C induction by the diffusible factor epidermal growth factor in stromal-epithelial interactions.

Tenascin-C, a six-armed extracellular matrix glycoprotein, is expressed in a temporally and spatially restricted pattern during carcinogenesis and invasion or metastasis of carcinoma cells in association with stromal-epithelial interactions. The human epidermoid carcinoma-derived cell lines, A431 and HEp-2, which do not express tenascin-C by themselves in vitro, do express tenascin-C after transplantation into nude mice, and transforming growth factor beta 1 (TGF-beta 1) induces them to express tenascin-C in vitro. Epidermal growth factor (EGF) induced tenascin-C in these cells more effectively (about 3.5-fold greater) than did TGF-beta 1. Hepatocyte growth factor (HGF) and platelet-derived growth factor (PDGF) had little effect on the induction of tenascin-C. EGF also induced other extracellular matrix components, fibronectin and laminin. Tenascin-C was also induced when the carcinoma cells were co-cultured with embryonic fibroblasts from mice which were homozygous for a null mutation in the tenascin-C gene, or when the conditioned medium from these cells was added. The induction of tenascin-C in the co-culture was reduced by treating the cells with antibodies against EGF or its receptor. The addition of EGF caused both cell types to disrupt their cytoskeleton and focal contacts as evidenced by the loss of stress fibers and vinculin plaques. EGF did neither induce tenascin-C nor affect the morphology in tenascin-C-nonproducing A549 carcinoma cells, which did not produce tenascin-C after transplantation. Thus, EGF induces tenascin-C in tenascin-C-nonproducing human carcinoma cells through EGF receptors. Furthermore, in stromalepithelial interactions, the diffusible factor EGF participates in the induction of human tenascin-C in these cells through EGF receptors.

Animals↗
PubMed1999

Coordinate upregulation of tenascin C expression with degree of photodamage in human skin.

Tenascin C is a large extracellular matrix glycoprotein involved in morphogenesis and wound healing. The distribution and expression levels of tenascin were examined in photodamaged skin to investigate the hypothesis that photoaged skin displays characteristics of wound repair. In situ hybridization and semiquantitative immunohistochemistry were performed on paired skin biopsies from patients with varying levels of photodamage, using monoclonal antibodies and cRNA probes for tenascin and its large isoform. In sun-protected skin, tenascin protein was distributed adjacent to the dermoepidermal junction, usually sparsely and discontinuously; tenascin mRNA was detected in dermal fibroblasts and some keratinocytes. In photodamaged skin, tenascin protein was increased in proportion to the clinical level of photodamage (analysis of variance: P < 0.0001, n = 29). With increased photodamage, tenascin protein expression became continuous along the dermoepidermal junction, extending deeper into and sometimes throughout the papillary dermis; tenascin mRNA was detected throughout the epidermis. Large tenascin isoform protein and mRNA distribution mirrored that of pantenascin, suggesting that it may be the predominant species in photodamaged skin. There was no correlation between tenascin expression levels and age or sex, and no seasonal variation was noted. The results indicate that photodamaged skin demonstrates tenascin increases consistent with an early wound healing response. However, tenascin increases in photodamage appear to be permanent and may therefore interfere with effective repair of ultraviolet-induced damage. In conclusion, this study has shown that dermal tenascin expression increases in proportion to the degree of photodamage. In normal skin, the temporal and spatial patterns of tenascin expression during morphogenesis and tissue remodelling are crucial to their correct progression. In photoageing, the 'normal' control of tenascin expression seems to be abrogated.

Adult↗
PubMed2001

A recessive form of the Ehlers-Danlos syndrome caused by tenascin-X deficiency.

BACKGROUND: The Ehlers-Danlos syndrome is a heritable connective-tissue disorder caused by defects in fibrillar-collagen metabolism. Mutations in the type V collagen genes account for up to 50 percent of cases of classic Ehlers-Danlos syndrome, but many other cases are unexplained. We investigated whether the deficiency of the tenascins, extracellular-matrix proteins that are highly expressed in connective tissues, was associated with the Ehlers-Danlos syndrome. METHODS: We screened serum samples from 151 patients with the classic, hypermobility, or vascular types of the Ehlers-Danlos syndrome; 75 patients with psoriasis; 93 patients with rheumatoid arthritis; and 21 healthy persons for the presence of tenascin-X and tenascin-C by enzyme-linked immunosorbent assay. We examined the expression of tenascins and type V collagen in skin by immunohistochemical methods and sequenced the tenascin-X gene. RESULTS: Tenascin-X was present in serum from all normal subjects, all patients with psoriasis, all patients with rheumatoid arthritis, and 146 of 151 patients with the Ehlers-Danlos syndrome. Tenascin-X was absent from the serum of the 5 remaining patients with Ehlers-Danlos syndrome, who were unrelated. Tenascin-X deficiency was confirmed in these patients by analysis of skin fibroblasts and by immunostaining of skin. The expression of tenascin-C and type V collagen was normal in these patients. All five of these patients had hypermobile joints, hyperelastic skin, and easy bruising, without atrophic scarring. Tenascin-X mutations were identified in all tenascin-X-deficient patients; one patient had a homozygous tenascin-X gene deletion, one was heterozygous for the deletion, and three others had homozygous truncating point mutations, confirming a causative role for tenascin-X and a recessive pattern of inheritance. CONCLUSIONS: Tenascin-X deficiency causes a clinically distinct, recessive form of the Ehlers-Danlos syndrome. This finding indicates that factors other than the collagens or collagen-processing enzymes can cause the syndrome and suggests a central role for tenascin-X in maintaining the integrity of collagenous matrix.

Arthritis, Rheumatoid↗
PubMed1993

Endothelial cell attachment and spreading on human tenascin is mediated by alpha 2 beta 1 and alpha v beta 3 integrins.

Human umbilical vein endothelial cells were found to attach and partially spread on human tenascin. The attachment of endothelial cells to tenascin results in elongated cells with interconnecting processes and is distinct from the flattened appearance of endothelial cells on fibronectin, collagen, vitronectin or laminin substrata, suggesting a role for tenascin in modulating cell adhesion and motility. Endothelial attachment to tenascin was partially inhibitable by the SRRGDMS peptide derived from human tenascin and completely inhibitable by anti-integrin antibodies to alpha 2 beta 1 and alpha v beta 3. Endothelial cell attachment to tenascin could be inhibited up to 80% with anti-alpha 2 and anti-beta 1 monoclonal antibodies P1E6 and P4C10, respectively, and this was associated with a complete loss in cell spreading. In contrast, pretreatment of endothelial cells with the anti-alpha v beta 3 monoclonal antibody LM609, resulted in a 35% inhibition in cell attachment but did not alter cell spreading. In combination the anti-alpha 2 and anti-alpha v beta 3 antibodies, could completely abrogate cell spreading and attachment to tenascin-coated surfaces. Affinity purification of 125I-labeled endothelial cell extract on a tenascin matrix column followed by immunoprecipitation with monoclonal antibodies to different integrin alpha and beta subunits resulted in the identification of alpha 2 beta 1 and alpha v beta 3 integrins, respectively, as tenascin binding receptors. Collagen affinity-purified alpha 2 beta 1 receptor from endothelial cells bound not only to collagen and laminin but also to tenascin in a radio receptor binding assay. The results demonstrate that alpha 2 beta 1 and alpha v beta 3 mediate distinct endothelial cell interactions with tenascin; cell spreading and cell binding, respectively. Binding by alpha v beta 3 is mediated by the SRRGDMS site on tenascin, whereas the alpha 2 beta 1 binding site remains undefined. The interaction of alpha 2 beta 1 and alpha v beta 3 with tenascin may be regulated in a cell type-specific manner as evidenced by the binding of endothelial cell alpha 2 beta 1 and alpha v beta 3 to tenascin, and the lack of binding by the same receptors on osteosarcoma MG63 to tenascin.

Amino Acid Sequence↗
PubMed1996

Tenascin-X expression in tumor cells and fibroblasts: glucocorticoids as negative regulators in fibroblasts.

Tenascin-X has recently been shown to be a novel member of the tenascin family and its distribution is often reciprocal to that of tenascin-C in the developing mouse embryo. We have investigated the expression of tenascin-X in fibroblasts and carcinoma cells in culture. Tenascin-X protein was secreted in vitro in the conditioned media at an apparent molecular mass of approximately 450 kDa. In addition fibroblasts contained a major tenascin-X isoform of 220 kDa. On northern blots, a single major transcript with a size of approximately 13 kb was detected. No overexpression of tenascin-X protein was found in primary fibroblasts of the tenascin-C-gene knockout mice. Steroid hormone glucocorticoids, were found to downregulate tenascin-X mRNA levels and protein synthesis in fibroblasts but not carcinoma cells at physiological concentrations. None of the growth factors or cytokines examined affected the expression level of tenascin-X. As in vivo study, carcinoma cells were transplanted into nude mice. In contrast to the ubiquitous presence of tenascin-X in adult skin, expression of tenascin-X protein during tumorigenesis was found to be down-regulated considerably not only in tumor cells themselves but also in tumor stroma. These findings provide evidence that the expression of tenascin-X can be influenced by stromal-epithelial interactions. We have identified glucocorticoids as physiological inhibitors of tenascin-X and suggest that glucocorticoids may in part participate in the downregulation of tenascin-X in fibroblasts in vivo.

Animals↗
PubMed1999

Induction of vascular smooth muscle cell tenascin-C gene expression by denatured type I collagen is dependent upon a beta3 integrin-mediated mitogen-activated protein kinase pathway and a 122-base pair promoter element.

Tenascin-C is an extracellular matrix glycoprotein, the expression of which is upregulated in remodeling arteries. In previous studies we showed that the presence of tenascin-C alters vascular smooth muscle cell shape and amplifies their proliferative response by promoting growth factor receptor clustering and phosphorylation. Moreover, we demonstrated that denatured type I collagen induces smooth muscle cell tenascin-C protein production via beta3 integrins. In the present study, we examine the pathway by which beta3 integrins stimulate expression of tenascin-C, and define a promoter sequence that is critical for its induction. On native collagen, A10 smooth muscle cells adopt a stellate morphology and produce low levels of tenascin-C mRNA and protein, whereas on denatured collagen they spread extensively and produce high levels of tenascin-C mRNA and protein, which is incorporated into an elaborate extracellular matrix. Increased tenascin-C synthesis on denatured collagen is associated with elevated protein tyrosine phosphorylation, including activation of extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2). beta3 integrin function-blocking antibodies attenuate ERK1/2 activation and tenascin-C protein synthesis. Consistent with these findings, treatment with the specific MEK inhibitor, PD 98059, results in suppression of tenascin-C protein synthesis. To investigate whether beta3 integrin-dependent activation of ERK1/2 regulates the tenascin-C promoter, we transfected A10 cells with a full-length (approx. 4 kb) mouse tenascin-C gene promoter-chloramphenicol acetyltransferse reporter construct and showed that, relative to native collagen, its activity is increased on denatured collagen. Next, to identify regions of the promoter involved, we examined a series of tenascin-C promoter constructs with 5' deletions and showed that denatured collagen-dependent promoter activity was retained by a 122-base pair element, located -43 to -165 bp upstream of the RNA start site. Activation of this element was suppressed either by blocking beta3 integrins, or by preventing ERK1/2 activation. These observations demonstrate that smooth muscle cell binding to beta3 integrins activates the mitogen activated protein kinase pathway, which is required for the induction of tenascin-C gene expression via a potential extracellular matrix response element in the tenascin-C gene promoter. Our data suggest a mechanism by which remodeling of type I collagen modulates tenascin-C gene expression via a beta3 integrin-mediated signaling pathway, and as such represents a paradigm for vascular development and disease whereby smooth muscle cells respond to perturbations in extracellular matrix composition by altering their phenotype and patterns of gene expression.

Animals↗
PubMed1996

Tenascin-C is associated with early stages of chondrogenesis by chick mandibular ectomesenchymal cells in vivo and in vitro.

Tenascin-C is an extracellular matrix protein thought to be involved in skeletogenesis. We have examined the distribution of tenascin-C in the developing chick mandibular arch between stages 18-36, and during in vitro chondrogenesis of mandibular ectomesenchymal cells in micromass cultures using a probe and antibody that correspond to the portion of the tenascin-C transcript conserved in all of the three known chick splice variants. In situ hybridization and immunohistochemical analyses demonstrate that tenascin-C is predominantly expressed in the condensing mesenchyme of developing cartilage, and in the perichondrium of differentiated cartilage. Tenascin-C expression, although detected in differentiating chondroblasts, was not detected in differentiated cartilage. Tenascin-C was also expressed in the developing membranous bones. In addition, the expression of tenascin-C transcripts during in vitro chondrogenesis of mandibular ectomesenchymal cells in micromass cultures was compared to the patterns of expression of aggrecan core protein and alpha 1(I) collagen transcripts. Our in situ hybridization analyses of micromass cultures demonstrate the expression of tenascin-C and aggrecan core protein mRNAs by pre-chondrogenic aggregates in the 1-day cultures and by chondroblasts in differentiating cartilage nodules in 2-day cultures. In 4- and 9-day cultures, the pattern of expression of tenascin-C mRNA was different from the patterns of expression of aggrecan core protein mRNA, and appeared to be more closely related to the expression of alpha 1(I) collagen mRNA. Aggrecan core protein mRNA was expressed by chondrocytes in cartilage nodules in 4- and 9-day cultures. On the other hand, tenascin-C and alpha 1(I) collagen mRNAs, in addition to being expressed in the loose connective tissues in the inter-nodular spaces, were predominantly expressed by the elongated, flattened, and fibroblast-like cells around the cartilage nodules. These results indicate that during the in vitro chondrogenesis of mandibular ectomesenchymal cells, expression of tenascin-C mRNA identifies chondrocytes in their early stages of differentiation. The patterns of expression of tenascin-C mRNA in 4- and 9-day cultures further suggest that tenascin-C is expressed in the perichondrium-like structures that form around the cartilage nodules in micromass cultures. Therefore, our in vitro studies, in agreement with our in vivo studies, suggest an association of tenascin-C with the initial or early stages of chondrogenesis in the chicken mandibular arch.

Aggrecans↗
PubMed1996

Tenascin-C lines the migratory pathways of avian primordial germ cells and hematopoietic progenitor cells.

Tenascin-C is a large hexameric extracellular matrix glycoprotein associated with epithelial-mesenchymal interactions, connective tissue development, and the formation of the central nervous system. Tenascin-C also lines the pathways followed by migrating avian neural crest cells, although its role in neural crest morphogenesis remains unclear. In vitro, tenascin-C interferes with cell-fibronectin interactions, and promotes the motility of many cell types including the neural crest. To determine if tenascin-C is a consistent component of matrices through which invasive embryonic cells migrate, we have investigated if tenascin-C is associated with 2 additional populations of motile, embryonic cells: primordial germ cells and hematopoietic progenitor cells. We have found that HNK-1, a monoclonal antibody used as a marker of neural crest, also stains avian primordial germ cells. Double-label immunohistochemistry reveals that tenascin-C is found in the mesenchyme adjacent to the ventral half of the dorsal aorta where the primordial germ cells penetrate the vessel wall, and both tenascin-C and fibronectin are present in the extracellular matrix through which the primordial germ cells migrate to reach the genital ridges. Unlike fibronectin, which is found throughout the splanchnic mesoderm, tenascin-C is concentrated in the proximal part of the splanchnic region where the primordial germ cells are concentrated. In embryos where the gonadal anlagen are surgically removed before the primordial germ cells leave the bloodstream, ectopic primordial germ cells were found exclusively in head and trunk mesenchyme containing tenascin-C. Like primordial germ cells, a subset of hematopoietic progenitor cells migrate through the mesenchyme ventral to the dorsal aorta where they form hematopoietic clusters. Others bud directly into the lumen of the aorta. Anti-tenascin-C stains the mesenchyme surrounding the migrating cells as well as the basal surfaces of the cells that appear to be budding into the lumen. In situ hybridization with a tenascin-C-specific cDNA probe shows that the major sources of the tenascin-C mRNA in this region are the hematopoietic progenitor cells themselves as well as the cells in the wall of the ventral aorta. mRNAs encoding 3 major splice variants of tenascin-C were identified by reverse transcriptase polymerase chain reaction (PCR) in the embryonic aorta and adjacent mesenchyme dissected from both the region of primordial germ cell and hematopoietic precursor cell migration. These experiments indicate that tenascin-C is a component of the migratory environment for many motile cells in the early embryo, where it has the potential to mediate cell-fibronectin interactions.

Animals↗
PubMed1995

Molecular basis of interactions between regenerating adult rat thalamic axons and Schwann cells in peripheral nerve grafts. II. Tenascin-C.

Tenascin-C is a developmentally regulated extracellular matrix component. There is evidence that it may be involved in axon growth and regeneration in peripheral nerves. We have used in situ hybridization and immunocytochemistry to investigate the association of tenascin-C with central nervous system axons regenerating through a peripheral nerve autograft inserted into the thalamus of adult rats. Between 3 days and 4 weeks after implantation, tenascin-C immunoreactivity was increased in the grafts, first at the graft/brain interface, then in the endoneurium of the graft, and finally within the Schwann cell columns of the graft. By electron microscopy, reaction product was present around collagen fibrils and basal laminae in the endoneurium, but the heaviest deposits were found at the surface of regenerating thalamic axons within Schwann cell columns. Schwann cell surfaces were not associated with tenascin-C reaction product except where they faced the tenascin-rich basal lamina or were immediately opposite axons surrounded by tenascin-C. By 8 weeks after graft implantation tenascin-C in the endoneurium and around axons of the graft was decreased. In the brain parenchyma around the proximal part of the graft, axonal sprouts associated with tenascin-C could not be identified earlier than 2 weeks after grafting and were sparse at this stage. Larger numbers of such axons were present at 8-13 weeks after grafting and were located predominantly where the glia limitans between brain and graft appeared to be incomplete, suggesting that the tenascin-C may have penetrated the brain parenchyma from the graft. By in situ hybridization, cells expressing tenascin-C mRNA (probably Schwann cells) appeared first at the brain/graft interface 3 days after grafting and thereafter were mainly located within the grafts. Lightly labelled cells containing tenascin-C mRNA (probably glial cells) were scattered in the thalamic parenchyma both ipsilateral and contralateral to the graft and a few heavily labelled cells were located very close to the tip of the graft. These results show that regenerating adult thalamic axons, unlike regenerating peripheral axons, become intimately associated with peripheral nerve graft-derived tenascin-C, suggesting that they express a tenascin-C receptor, as many neurons do during development, and that tenascin-C derived from Schwann cells may play a role in the regenerative growth of such axons through the grafts.

Animals↗
PubMed2006

Avian tenascin-W: expression in smooth muscle and bone, and effects on calvarial cell spreading and adhesion in vitro.

Tenascins are glycoproteins found primarily in the embryonic extracellular matrix. Here we have characterized the fourth and final member of the tenascin family in birds: tenascin-W. Avian tenascin-W has 3.5 epidermal growth factor-like repeats, 6 fibronectin type III domains, and a C-terminal fibrinogen-related domain. Immunohistochemistry reveals that avian tenascin-W is expressed transiently in developing smooth muscle, tendons, and ligaments, but the primary site of tenascin-W expression during development is in the extracellular matrix of bone and the cellular periosteum. In bony matrix, tenascin-W-coated fibrils partly overlap with fibrils that contain tenascin-C. The anti-tenascin-W also labels fibrils in cultures of osteogenic embryonic chicken calvarial cells. Primary calvarial cells cultured on purified tenascin-W become rounded, and fewer of these cells spread on fibronectin when tenascin-W is added to the medium when compared with calvarial cells cultured on fibronectin alone. Moreover, tenascin-W reduces the adhesion of calvarial cells to collagen type I in a shear force assay. We conclude that tenascin-W is likely to play a phylogenetically conserved role in developing bone and that it shares some of the basic anti-adhesive and matrix modulatory properties as tenascin-C.

Amino Acid Sequence↗
PubMed2002

Clinical impact and functional aspects of tenascin-C expression during glioma progression.

The extracellular matrix protein tenascin-C is expressed in processes like embryogenesis and wound healing and in neoplasia. Tenascin-C expression in gliomas has been described previously; however, the relation to clinical data remains inconsistent. Generally, analysis of tenascin-C function is difficult due to different alternatively spliced isoforms. Our studies focus on changes in tenascin-C expression in human gliomas, correlating these changes with tumor progression and elucidating the functional role of the glioma cell-specific tenascin-C isoform pool. Eighty-six glioma tissues of different World Health Organization (WHO) grades were analyzed immunohistochemically for tenascin-C expression. The influence of the specific tenascin-C isoforms produced by glioblastoma cells on proliferation and migration was examined in vitro using blocking antibodies recognizing all isoforms. In general, tenascin-C expression increased with tumor malignancy. Perivascular staining of tenascin-C around tumor-supplying blood vessels was observed in all glioblastoma tissues, whereas in WHO II and III gliomas, perivascular tenascin-C staining appeared less frequently. The appearance of perivascular tenascin-C correlated significantly with a shorter disease-free time. Analysis of proliferation and migration in the presence of blocking antibodies revealed an inhibition of proliferation by around 30% in all 3 glioblastoma cell cultures, as well as a decrease in migration of 30.6-46.7%. Thus we conclude that the endogenous pool of tenascin-C isoforms in gliomas supports both tumor cell proliferation and tumor cell migration. In addition, our data on the perivascular staining of tenascin-C in WHO II and III gliomas and its correlation with a shorter disease-free time suggest that tenascin-C may be a new and potent prognostic marker for an earlier tumor recurrence.

Antibodies, Monoclonal↗
PubMed2004

CD44 and tenascin play critical roles in growth and vascular development of the chick chorioallantoic membrane and are targets of cigarette smoke.

Chorioallantoic membranes (CAMs) were used to determine which extracellular matrix molecules play essential roles in growth and vascular development in vivo and whether expression of critical molecules is affected by cigarette smoke exposure. Treatment of CAMs on day 5 of development with antibodies to CD44 or tenascin, but not to other matrix molecules, inhibited CAM growth and affected various aspects of blood vessel development including normal growth and branching of vessels, migration of vessels, and formation and differentiation of the capillary plexus. DNA synthesis was inhibited by antibodies to both C44 and tenascin which probably accounted for many of the phenotypic changes observed in treated CAMs. CD44 was located on all cells in day 5 CAMs, and tenascin, while present throughout the CAM, was especially abundant around large, non-migratory mesodermal blood vessels and endodermal cells that were positioned away from the direction of blood vessel migration. These data suggest that while tenascin is required for normal blood vessel migration, high levels of tenascin inhibit migration. The different distributions of CD44 and tenascin in CAMs and the observation that antibodies to either CD44 or tenascin produced similar phenotypes indicate that CD44 and tenascin were not functionally redundant. Mainstream smoke solutions, which produce a phenotype similar to that seen with anti-tenascin and anti-CD44, inhibited expression of CD44 mRNA and increased tenascin mRNA expression. 3-Ethylpyridine, a chemical in cigarette smoke that produced changes in CAM development similar to anti-CD44 and anti-tenascin treatment, also increased tenascin mRNA expression, but did not affect CD44. Together these data show that tenascin and CD44 play critical roles in early growth and vascular development of the CAM and support the idea that 3-ethylpyridine in mainstream smoke impairs CAM growth and vascular development by targeting expression of tenascin. 3-Ethylpyridine is generally regarded as safe and is used in many consumer products including food and tobacco.

Animals↗
PubMed1992

Altered content and distribution of tenascin in colitis, colon adenoma, and colorectal carcinoma.

Tenascin is a fibroblast product and extracellular matrix protein probably excerting a fibronectin-antagonizing role. Tenascin is broadly distributed interstitially during embryogenesis but restricted to a small range of structures in normal adult tissues. Using tenascin antibodies and an indirect immunoperoxidase method, normal colon, colitis, colon adenomas, and colorectal carcinomas were examined for tissue distribution of tenascin. Normal mucosa displayed a sparce meshwork of microfibrillar tenascin in the lamina propria. The basement membrane was tenascin negative at the bottom of the crypt and developed into a positive band steadily broadening towards the mucosal surface. In colitis, this polarity was effaced; the basement membrane was a broad tenascin-positive band nearly throughout while interstitial tenascin was moderately increased. Loss of polarity in tenascin content of the basement membrane was a constant feature of adenomas, inconsistently paralleled by structural alterations in surface qualities and continuity of tenascin pattern of the basement membrane. These were most pronounced in carcinomas, where this interface was often discontinuous and had a rough surface; in addition, interstitial tenascin was considerably increased. In carcinomas, the rough surface aspect of the tenascin pattern of the basement membrane was correlated with presence of lymph node metastases (P = 0.04). It is concluded that alterations in tenascin pattern and content reflect complex disturbances in the interaction of inflamed/neoplastic colon epithelium and underlying matrix, leading to an organoid induction of tenascin in the inflammatory context and to induction together with structural abnormalities in neoplasia.

Adenoma↗
PubMed1994

Stromal expression of tenascin is inversely correlated to epithelial differentiation of hormone dependent tissues.

We were previously investigating the expression of the extracellular matrix glycoprotein tenascin in normal and malignant endometrial tissues of humans and rodents. These studies suggested that the expression of tenascin was induced by proliferating epithelia (normal and particularly malignant) and was downregulated with their differentiation. The aim of this study was to investigate the hormone dependency of tenascin expression in (a) the transplantable EnDA endometrial tumor model with or without estrogen deprivation (ovariectomy) of the animals, (b) DMBA-induced rat mammary tumors with or without a hormonal treatment of the animals [ovariectomy, antiestrogen (tamoxifen) or antiprogestin (ZK 98299) treatment] and (c) in the rat prostate of untreated or androgen deprived animals (orchiectomy, flutamide-, casodex- or cyproterone acetate (CPA)-treatment). 1. Estrogen withdrawal by ovariectomy did not affect tenascin expression in transplantable EnDA endometrial adenocarcinoma, meaning the entire extracellular space of the stromal mesenchyme was decorated by tenascin immunoreactivity. 2. In untreated DMBA-induced rat mammary tumors almost the entire extracellular space of the stroma was stained by tenascin immunoreactivity. Ovariectomy and antiestrogen treatment did not affect tenascin expression. In contrast, antiprogestin treatment induced terminal differentiation of mammary tumor cells and in parallel downregulated tenascin expression. 3. In the normal rat prostate no tenascin was detectable by immunocytochemistry. However, following androgen deprivation we found tenascin expression in the stroma of the prostate. The most prominent expression was observable after CPA-treatment, possibly due to its progestagenic potency. In conclusion, the hormones and antihormones tested show no direct effect on the stromal expression of tenascin. However, proliferative activity and a low degree of differentiation of the epithelium induces tenascin expression, whereas epithelial differentiation apparently shuts down tenascin expression. Preliminary in vitro studies suggest that paracrine acting growth factors trigger the hormonal regulation of tenascin expression.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1999

The expression of tenascin-X in developing and adult rat and human eye.

Tenascin-X has been studied in developing and adult rat eye and in foetal and adult human eyes, using immunohistochemistry and frozen sections. The data were compared with the distribution of tenascin-C. The immunoreactivity for tenascin-X was seen in a basement membrane-like feature in different structures of embryonic (E) day 16-17 rat eyes. Postnatal (P) day 2 and older rat eyes showed immunoreactivity for tenascin-X in different connective tissues. In the epithelial basement membrane zone of the cornea, immunostaining was positive in P5 eyes, negative in P10 and P15 eyes and again positive in P30 and adult eyes. In the 20-week-old human foetus, immunoreactivity for the tenascin was seen in the posterior parts of the conjunctival stroma adjacent to the sclera and in a basement membrane-like fashion in anterior conjunctiva. In the adult human eye, immunoreactivity for tenascin-X was seen in the anterior one-third stroma of cornea as thin fibrils, in the stroma of the limbus and conjunctiva, and in blood vessels. Immunostaining for tenascin-C was seen in the posterior aspect of the further cornea, and in mesenchyme adjacent to cornea in E1617 rat eyes. Corneal keratocytes and Descemet's membrane showed immunoreactivity for tenascin-C in P2-P15 rat eyes. Sclera and the junction of the cornea, and sclera expressed tenascin-C in P2 and older rat eyes. In human foetal eyes, immunostaining for tenascin-C was seen in the anterior parts of the corneal stroma, in the basement membrane zone and Bowman's membrane of the corneal epithelium, in the posterior one-fifth of the corneal stroma and the sclera starting from the junction of the cornea and sclera. In normal human adult eyes, immunostaining for tenascin-X was seen in the anterior one-third stroma of cornea, in the stroma of limbus and conjunctiva, and in blood vessels. The association of tenascin-X and basement membranes in early development evokes a question of its potential function in the development of the basement membrane. The results also suggest the association of tenascin-X with connective tissue development as well as the association of tenascin-C with the migration of keratocytes during the development of the corneal stroma.

Adult↗
PubMed2005

Tenascin-W is found in malignant mammary tumors, promotes alpha8 integrin-dependent motility and requires p38MAPK activity for BMP-2 and TNF-alpha induced expression in vitro.

Tenascins represent a family of extracellular matrix glycoproteins with distinctive expression patterns. Here we have analyzed the most recently described member, tenascin-W, in breast cancer. Mammary tumors isolated from transgenic mice expressing hormone-induced oncogenes reveal tenascin-W in the stroma around lesions with a high likelihood of metastasis. The presence of tenascin-W was correlated with the expression of its putative receptor, alpha8 integrin. HC11 cells derived from normal mammary epithelium do not express alpha8 integrin and fail to cross tenascin-W-coated filters. However, 4T1 mammary carcinoma cells do express alpha8 integrin and their migration is stimulated by tenascin-W. The expression of tenascin-W is induced by BMP-2 but not by TGF-beta1, though the latter is a potent inducer of tenascin-C. The expression of tenascin-W is dependent on p38MAPK and JNK signaling pathways. Since preinflammatory cytokines also act through p38MAPK and JNK signaling pathways, the possible role of TNF-alpha in tenascin-W expression was also examined. TNF-alpha induced the expression of both tenascin-W and tenascin-C, and this induction was p38MAPK- and cyclooxygenase-dependent. Our results show that tenascin-W may be a useful diagnostic marker for breast malignancies, and that the induction of tenascin-W in the tumor stroma may contribute to the invasive behavior of tumor cells.

Bone Morphogenetic Protein 2↗