The Regulation of Tenascin Expression by Tissue Microenvironments

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Biochimica et Biophysica Acta 1793 (2009) 888–892

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Review The regulation of tenascin expression by tissue microenvironments

Richard P. Tucker a,⁎, Ruth Chiquet-Ehrismann b

a Department of Cell Biology and Human Anatomy, University of California at Davis, Davis, California 95616, USA b Friedrich Miescher Institute for Biomedical Research, Novartis Research Foundation, Maulbeerstrasse 66, CH-4058 Basel, Switzerland

article info abstract

Article history: Tenascins are a family of four extracellular matrix proteins: tenascin-C, X, R and W. The four members of the Received 20 December 2007 family have strikingly diverse patterns of expression during development and in the adult organism Received in revised form 4 December 2008 indicating independent mechanisms of regulation. In this review we illustrate that there are two types of Accepted 19 December 2008 tenascins, those that are significantly regulated by the tissue microenvironment (tenascin-C and tenascin- Available online 31 December 2008 W), and those that have stabile, restricted expression patterns (tenascin-R and tenascin-X). We summarize what is known about the regulation of tenascin expression by transforming growth factor betas, fibroblast Keywords: fl Extracellular matrix growth factors, platelet derived growth factors, as well as pro- and anti-in ammatory cytokines or hormones Growth factor that either induce or inhibit expression of tenascins. Transforming growth factor beta © 2009 Elsevier B.V. All rights reserved. Development Tumor stroma Fibroblast growth factor

1. Introduction become more rounded or for growth cones to collapse (e.g., for tenascin-C see [11]; for tenascin-R see [12]; for tenascin-X see [13]). Tenascins are a family of four multimeric extracellular matrix This is often, but not always, accompanied by an increase in rates of (ECM) glycoproteins: tenascin-C, X, R and W [1]. The best described motility, invasive behavior and proliferation (for reviews see [4,14]). member of the family is tenascin-C, which is found in the embryo near Tenascin-W seems to have similar properties. For example, tenascin- migrating cells, at sites of epithelial–mesenchymal interactions and W added to the medium of primary cultures of osteoblasts on branching morphogenesis, and in developing connective tissue fibronectin leads to cell rounding [15] and the migration of a including bone, cartilage and tendons. Tenascin-C persists in some mammary tumor-derived cell line across a filter in a Boyden chamber connective tissue in the adult, and also appears in the stroma of many assay is stimulated by tenascin-W [8]. An attractive model to explain tumors and at sites of tissue repair and regeneration (for reviews see some of these observations, at least for tenascin-C, comes from studies [2–4]). Tenascin-X is primarily expressed in loose connective tissue of tenascin-C/fibronectin interactions. When cells are cultured on a such as dermis, epimysium and blood vessels both during develop- combination of tenascin-C and fibronectin, as opposed to fibronectin ment and in the adult; mutations in tenascin-X can lead to a type of alone, there is a reduction in the expression or activity of FAK, RhoA Ehlers–Danlos Syndrome (for review see [5]). In contrast, the patterns and tropomyosin I [16–18]. This appears to be mediated by tenascin-C of tenascin-R and tenascin-W expression in normal developing and inhibiting interactions between syndecan-4 and fibronectin [19,20], adult tissues are considerably more restricted. Tenascin-R is concen- which in turn inhibits the recruitment of syndecan-4 to the focal trated in the central and peripheral nervous system (e.g. [6]), and adhesion complex. This limits the size of the focal adhesion and alters tenascin-W is found primarily in bone (e.g. [7]). Like tenascin-C, integrin signaling. Associated with this is an increase in the expression tenascin-W is also a prominent component of the stroma of certain of endothelin receptor A, which is correlated with an inhibition of tumors [8–10]. The primary sites of tenascin expression are summar- focal adhesion kinase and a loss of function of RhoA, all of which can ized in Table 1. contribute to tumorigenesis [21]. Diverse functional roles have been assigned to tenascins during Since it was first observed in tumor stroma over two decades ago development and disease. When used as a substratum in tissue [22] considerable research has been directed toward understanding culture, some tenascins inhibit the spreading of cells and the the role of tenascin-C in cancer (for review see [23]). More recently, it formation of large focal adhesions. Similarly, tenascins added to the was observed that tenascin-W is also found in the stroma of murine medium of cells cultured on adhesive ECM can cause the cells to [8] and human [9,10] breast cancers. Given the effects of tenascin-C and tenascin-W on cells in vitro cited above, it is likely that these proteins can contribute directly to the growth and metastasis of at ⁎ Corresponding author. Tel.: +1 530 752 0238. least some tumors. However, care must be taken not to generalize E-mail address: [email protected] (R.P. Tucker). roles for all tenascins in cancer. For example, tenascin-R is expressed

Table 1 Summary of tenascin expression and regulation

Examples of prominent expressiona Examples of regulationb [Ref.] Tenascin-C Organogenesis TGFβ1 [27–31,33,34] Dense connective tissue FGF1 [49] Smooth muscle FGF2 [28,46–50] Inﬂammation FGF4 [49] Cancer stroma PDGF [55] TNFα [59–61] Notch [77] Downregulation by miRNAs [78] Mechanical strain [76,83] Tenascin-W Bone BMP2 [7,8] Cancer stroma TNFα [8] Tenascin-X Loose connective tissue BDNF [70] Endothelial cells No effect seen with EGF, bFGF, TGFβ1, PDGF, and TNFα [69] Tenascin-R Central and peripheral nervous system NGFc [68]

a See text for references to reviews of expression patterns. b Upregulation unless otherwise noted. c May be related to the differentiation of a cell line. at lower levels in medulloblastomas than in control cerebellum tissue pattern of TGFβ1 in the developing heart [38] and in inflamed joints [24], and melanoma cells are more invasive in the ECM of tenascin-X [39] closely matches that of tenascin-C, tenascin-C is abundant around knockout mice than in controls [25]. TGFβ1-expressing megakaryocytes in bone marrow [40], and levels of Clearly tenascin gene expression is tightly regulated and is tenascin-C and levels of TGFβ1 expression are correlated in breast dependent on the tissue microenvironment, especially on the growth carcinomas [41] and ovarian tumors [42]. Care must be taken before factor milieux. This is apparent from the distinctive and often making generalizations based on the latter observations, as others complementary patterns of tenascin gene expression in the embryo have shown no correlation between the level of tenascin-C expression and from the presence or absence of tenascins in the stroma of certain and TGFβ1 expression in gliomas [43], though both are present. This tumors. In this review we will summarize the research on the effects may be explained, in part, by differences in the timing of the first of growth factors on the expression of tenascins in vitro and the appearance of tenascin-C and TGFβ1. signaling pathways used to stimulate tenascin expression. Studies with function-blocking antibodies also link TGFβ1 with the regulation of tenascin-C expression. For example, pre- and post- 2. Regulation of tenascin-C expression by transforming growth operative treatment of rats with anti-TGFβ1 inhibits the induction of factor betas tenascin-C expression in radiation-induced wounds [44]. Others have taken advantage of cells derived from knockout mice. Kalembeyi et al. Transforming growth factor betas (TGFβ) are a superfamily of [45] showed that a matrix metalloprotease, MMP-9, is induced by cytokines that play important roles in regulating cell differentiation TGFβ1 in a tenascin-C knockout-derived tumor cell line, but that this and proliferation, both during development and in pathologies (for induction is increased in the presence of exogenous tenascin-C. Thus, review see [26]). In one of the earliest studies of any tenascin, Pearson tenascin-C and TGFβ1 may act synergistically to increase the levels of et al. [27] showed that tenascin-C expression by chick embryo proteases in tumor stroma that can contribute to metastasis. fibroblasts is upregulated four-fold by the addition of 6–20 ng/ml of TGFβ1 to low-serum medium (see Table 1 for a summary of the 3. Tenascin-C expression and fibroblast growth factors regulation of tenascin expression). Similar induction of tenascin-C expression by low levels of TGFβ1 was reported in Swiss 3T3 cells [28] Fibroblast growth factor 2 (FGF2), also known as basic fibroblast and in various human carcinoma-derived cell lines [29] and growth factor, was first characterized as a potent promoter of transformed mouse mammary epithelial cells [30]. Interestingly, angiogenesis (for a review of the history of its discovery see [46]). It when melanoma cells are transfected with TGFβ1 and seeded into is one of the founding members of a large family of growth factors that collagen gels together with fibroblasts, tenascin-C expression can regulate cell motility, proliferation, differentiation and survival. increases in the fibroblasts [31], suggesting that some of the Like TGFβ1, the pattern of expression of FGF2 is also often correlated tenascin-C found in tumor stroma may be deposited by the stromal with the expression of tenascin-C, especially in the central nervous cells under the influence of the tumor-derived microenvironment. system (e.g. [28]). Accordingly, FGF2 can induce the expression of Tenascin-C and TGFβ1 are both found in developing connective tissue tenascin-C in astrocytes [47,48] and neuroectoderm-derived tumors (e.g., see [32]), so it is not surprising that explants of mouse limb bud [49]. In the latter study FGF1 (aFGF) and FGF4 (K-FGF) also induced mesenchyme also express tenascin-C in response to TGFβs [33]. the expression of tenascin-C. Interestingly, introduction of FGF1 into Though the most robust inductive response was seen with TGFβ1, the lateral ventricles of the rat leads to the specific induction of the significant induction was also reported with TGFβ2 and TGFβ3. large splice variants of tenascin-C [50], and FGF2 induces the Interestingly, TGFβ1 tends to induce most strongly the expression of a expression of large splice variants of tenascin-C in Swiss 3T3 cells low molecular weight alternatively spliced variant of tenascin-C that [28]. Large splice variants of tenascin-C are often associated with lacks the so-called ‘variable domain’. This has been reported in Swiss motile cells and with malignancy and poor outcome (e.g. [51–54]). 3T3 cells [28] and endometrial adenocarcinoma cell lines [34]. The functional significance of this is unclear, but different splice variants 4. Platelet derived growth factors and tenascin-C expression have been shown to be differentially expressed during development (e.g. [35,36]) and in tumors (e.g. [37]) and to have different effects on Platelet derived growth factors (PDGF) are dimers of A, B, C and D cell adhesion in vitro (e.g. [36]). subunits. Best known are PDGF-AA, PDGF-AB and PDGF-BB, which Correlative evidence suggests that TGFβ1 is likely to be a regulator play important rules in influencing cell proliferation and motility in a of tenascin-C expression in vivo as well as in vitro: the expression variety of tissues. Tenascin-C and PDGFs are found together in some 890 R.P. Tucker, R. Chiquet-Ehrismann / Biochimica et Biophysica Acta 1793 (2009) 888–892 blood vessel walls and PDGF-BB has a potent inductive effect on arterial hypertension (see review by [73]), which is characterized in tenascin-C expression in smooth muscle cells derived from the aorta part by the extensive deposition of tenascin-C in the arterial wall (e.g. [55]. As described above for FGF2, PDGF-BB induces primarily large [74]). The receptor mutation leads to a reduction in BMP-induced splice variants of tenascin-C; this variant may play a role in the Smad signaling and an increase in MAPK signaling pathways, which invasion of smooth muscles cells into the vessel wall and the leads to the induction of tenascin-C expression by vascular smooth development of atherosclerotic plaque. Both PDGF receptor alpha muscle cells [75]. The tenascin-C can contribute to the pathobiology of and tenascin-C are expressed in the developing central nervous the disease by increasing vascular smooth muscle cell proliferation system by early oligodendroglia and their precursors (e.g. [56,57]). and survival. Regulation of tenascin-C expression can also depend on PDGF has a potent mitogenic effect on oligodendrocyte precursor the Rho/Rock pathway and actin dynamics ([76]; see accompanying cells; interestingly, this effect requires tenascin-C in the ECM [58], article by M. Chiquet on “Mechanotransduction in Fibroblasts”). implying that synergistic effects between growth factors and Recently, two novel mechanisms regulating tenascin-C expression tenascin-C may account in part for the mitogenic effects of exogenous have been described. On the one hand Notch signaling was shown to tenascin-C. induce tenascin-C expression representing a new oncogenic pathway active in glioblastoma [77]. On the other hand micro RNA (miRNA)- 5. Other growth factors and other tenascins 335 was shown to downregulate tenascin-C expression and the loss of this miRNA in metastatic breast tumors led to increased tenascin-C The induction of tenascin-C in tumor stroma and at other sites of expression. Restoration of miRNA-126 inhibited metastatic cell disease progression is likely to be related to its induction by invasion which depended on the down-regulation of tenascin-C [78]. cytokines associated with inflammation. For example, TNFα expression is linked to tenascin-C expression in bronchial fibroblasts [59] 7. Tenascin promoters and transcription factors and cultured chondrocytes [60], and TNFα and interferon gamma induce tenascin-C expression in bronchial epithelial cells ([61]; see The distinctive differences in the expression and regulation of the also reviews [3,23]). Anti-inflammatories like dexamethasone inhibit tenascins are reflected in features found in their promoters. For the expression of tenascin-C in cultured human macrophages (e.g. example, the promoters of tenascin-X and tenascin-R lack TATA boxes [62]), in the granulation tissue of healing skin wounds [63], and in and in both cases transcription is initiated at multiple sites, whereas the stroma of experimentally induced murine tumors [64]. Gluco- tenascin-C is regulated by a typical TATA-box containing promoter. corticoids can reduce the expression of tenascin-C in bone marrow Nothing is known yet about the tenascin-W promoter, which is [65] and in the respiratory mucosa of patients suffering from pollen- waiting to be identified and characterized. In the case of tenascin-R induced asthma [66]. the information for cell-type specific expression in cells of neuronal Tenascin-W, the most recently discovered member of the tenascin origin is contained within 167 bp of the first exon and contains family [67], is also expressed in tumor stroma and its expression can binding sites for a variety of transcription factors such as p53/p73, NF1 also be upregulated by TNFα in vitro [8]. Nevertheless, tenascin-C and and glucocorticoid receptors [79]. However, it is not known which tenascin-W are clearly regulated independently, since there are factors are relevant for the expression of tenascin-R in the central tumors that express one of these two tenascins but not the other nervous system. In the case of tenascin-X it is thought that several [9,10]. During development, tenascin-W is most abundantly expressed regions harboring binding sites for Sp1 and Sp3 are involved in its in developing bone [7,15]. Accordingly, tenascin-W expression is regulation [80]. In line with the many signaling pathways able to increased in C2C12 cells [7] and HC11 cells [8] by bone morphogenetic induce tenascin-C expression (see above and Table 1) binding sites for protein-2 (BMP-2), but not by TGFβ1. the transcription factors activated by these pathways have been Relatively little is known about the regulation of tenascin-R and identified and are functional in the promoter of tenascin-C. These tenascin-X expression by the tissue microenvironment. Nerve growth include binding sites for paired-related homeobox1 Prx1 shown to be factor (NGF) can stimulate the expression of tenascin-R by PC12 cells activated by focal adhesion kinase signaling [81], Ets factor binding in vitro [68], but NGF stimulates the differentiation of these cells into sites [82] and AP1 elements [83,84] responding to the ERK/MAPK neuron-like cells and the induction may be indirect. The expression of pathway, and Smad2/3 binding sites involved in TGFβ signaling [85]. tenascin-X by fibroblasts in vitro is not upregulated by a host of Interestingly, many of these transcription factors can also collaborate growth factors, including TGFβ1, bFGF or PDGF, but like tenascin-C its in the regulation of tenascin-C expression, since it was shown that expression can be downregulated by glucocorticoids [69]. However, mutations of either the Smad, Ets or SP1/3 binding sites abrogated there is one report that BDNF is able to upregulate tenascin-X tenascin-C promoter induction by TGFβ [85]. Recently, a transcrip- expression by cultured endothelial cells [70]. tional repressor for tenascin-C was found. Overexpression of GATA6 reduced tenascin-C expression and inhibited IL-4 and TGFβ-induced 6. Signaling pathways used to induce tenascin expression tenascin-C promoter activity [86]. This ubiquitously expressed transcriptional inhibitor could be one of the factors keeping TGFβ1 and BMP-2, which are both members of the TGFβ super- tenascin-C expression low under normal conditions in the absence family, induce the expression of tenascin-C and tenascin-W, respec- of microenvironmental stimuli leading to tenascin-C upregulation. tively (see above and especially [8]). Both growth factors signal through ligand-specific transmembrane receptor serine-threonine 8. Conclusions and future directions kinases. Growth factor binding leads to conformational changes, receptor phosphorylation, and the activation of the Smad complex of This review illustrates that there are two types of tenascins: 1) transcription factors (reviewed by [71]). In contrast, osteoblast gene those that are significantly regulated by the tissue microenviron- expression is regulated by BMP-2 via non-canonical MAPK signaling ment (tenascin-C and tenascin-W), and 2) those that have stabile, pathways (e.g. [72]). Scherberich et al. [8] have shown that this latter restricted expression patterns (tenascin-R and tenascin-X). Accord- pathway is important in the induction of tenascin-W: inhibitors of p38 ingly, it is the former group that is frequently encountered in the and JNK reduce the endogenous expression of tenascin-W by mouse ECM at sites of disease or trauma, especially in the tumor stroma. embryo fibroblasts, and p38 inhibitors block the induction of tenascin- Tenascin-C and tenascin-W are also the types of tenascin with the W expression by BMP-2 [8]. In another system, these pathways can best documented effects on cell proliferation, differentiation and lead to the expression not of tenascin-W, but of tenascin-C. 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