Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Tenascin-W (Tnn, TNN)

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101623

Synonyms

Historical Background

Tenascins are glycoproteins found in the extracellular matrix of chordates (Chiquet-Ehrismann and Tucker 2011). Near their N-terminus tenascins have heptad repeats that support trimerization, and two trimers can be bound by disulfide bridges spanning N-terminal domains to form a hexabrachion. The N-terminal region is followed by one or more epidermal growth factor (EGF)-like domains that have a distinctive arrangement of cysteine residues (****C***C*****C****C*C********C). These are followed by a string of fibronectin type III (FNIII) domains and a C-terminal fibrinogen-related domain.

The original tenascin is tenascin-C (the “C” stands for cytotactin, a name given to this tenascin by one of its codiscoverers). Tenascin-C is the best studied of the tenascins and is prominently expressed in the embryo at sites of cell migration, epithelial-mesenchymal interactions, and in developing connective tissue. In the adult, tenascin-C is found at the edges of healing wounds, in many stem cell niches, at sites of inflammation, and in the stroma of solid tumors. Since it does not contribute to the structural integrity of the extracellular matrix and instead is involved in cell signaling via modifying other glycoproteins, anchoring growth factors, or acting as an integrin ligand, tenascin-C is often referred to as a matricellular protein. Tenascin-W is another member of the tenascin family that is likely to be a matricellular protein.

Tenascin-W was first identified in the zebrafish by Philipp Weber and colleagues (Weber et al. 1998), and the “W” designation is based on the first letter of the discoverer’s last name. Zebrafish tenascin-W has the characteristic tenascin architecture, including 3.5 EGF-like domains and 5 or 6 FNIII domains (Fig. 1a). Like tenascin-C, tenascin-W can form a hexabrachion (Fig. 1b). The next description of this glycoprotein was in the mouse (Neidhardt et al. 2003), but these authors failed to realize that they were studying the murine homolog of tenascin-W. Instead, they named the protein tenascin-N (after the first author) and gave their discovery the gene designation Tnn. Their confusion was likely the result of the fact that murine tenascin-W has twice as many FNIII domains as zebrafish tenascin-W (Fig. 1a). Later sequence alignment studies as well as the observation that both zebrafish tenascin-W and mouse tenascin-N are found adjacent to tenascin-R in their respective genomes (Tucker et al. 2006) led to the acceptance of the original designation, tenascin-W, as the proper name for this tenascin. The difference in the number of FNIII domains between tenascin-W from the zebrafish and mouse is due to multiple duplications of the single exon encoding the third FNIII domain.
Tenascin-W (Tnn, TNN), Fig. 1

The domain architecture of tenascin-W from zebrafish and mouse (a). While there are twice as many FNIII domains in the murine homolog of tenascin-W, this is the result of duplications of the third FNIII domain. Tenascin-W is a six-armed hexabrachion (b) (Image reproduced with permission from Scherberich et al. (2004)) Scale bar = 50 nm

Patterns of Expression

The expression of tenascin-W has been studied by immunoblotting and immunohistochemistry in the developing and adult chicken (Meloty-Kapella et al. 2006). In the embryo the primary site of expression is in developing bone. There is also expression in the fibrous skeleton of the heart, the central core of large tendons, and in gut smooth muscle. In many of these regions, tenascin-W is found in a subset of the extracellular matrix where tenascin-C is located. Tenascin-W expression in mouse is similar (Scherberich et al. 2004). It is first expressed in developing maxillary processes at E11.5, and it is relatively abundant in bone both during development and in the adult. As in the chicken, tenascin-W is transiently expressed in smooth muscle in the developing mouse gut. In the adult mouse, tenascin-W is expressed at the base of the aortic and pulmonary valves, in the corneal limbus, and in the kidney. Scherberich and colleagues (Scherberich et al. 2004) did not detect tenascin-W in the developing or adult mouse central nervous system. Interestingly, others (Neidhardt et al. 2003) found tenascin-W throughout the adult mouse brain; there is no clear explanation for these contradictory results. More recently, tenascin-W has been observed in the trabecular region of adult mouse whisker follicles (Fig. 2a) and in a ring around hair follicles adjacent to the bulge (Tucker et al. 2013). These patterns of expression suggest possible roles for tenascin-W in stem cell niches (Chiquet-Ehrismann et al. 2014).
Tenascin-W (Tnn, TNN), Fig. 2

Tenascin-W is found in the adult mouse whisker follicle in the trabecular region (tr), where various stem cell populations have been identified (a). b bulge, f fibrous capsule, Rw ring wulst, ws whisker shaft. Tenascin-W is an adhesion modulatory protein (b, c). C2C12 cells, which can be converted into osteoblasts in culture, spread on fibronectin, but on a combination of fibronectin and tenascin-W the cells fail to spread and form focal adhesions. Tenascin-W promotes the expression of alkaline phosphatase in vitro (d, e). When cultured on tissue culture plastic primary cultures of calvareal osteoblasts do not form alkaline phosphatase-positive nodules, but they do in the presence of tenascin-W (Images reproduced with permission from Meloty-Kapella et al. (2008) and Brellier et al. (2012a))

Cell Biology

Tenascin-C, the original tenascin, is perhaps the best known as an adhesion modulatory protein: tenascin-C inhibits cell spreading on fibronectin (Chiquet-Ehrismann et al. 1988; Lotz et al. 1989) and through this inhibition it potentially regulates not only cell migration but also proliferation (Murphy-Ullrich et al. 1991; Huang et al. 2001; Midwood et al. 2004). Like tenascin-C, tenascin-W also appears to act as an adhesion modulatory protein. C2C12 cells fail to spread on fibronectin-coated dishes if tenascin-W is added to the medium, and these cells fail to spread as well on mixtures of tenascin-W and fibronectin or form vinculin-positive focal adhesions as they do on fibronectin alone (Fig. 2b, c) (Brellier et al. 2012a). However, unlike cells cultured in the presence of tenascin-C, there is no evidence to date of an increase in cell proliferation as a consequence of culture on tenascin-W (Meloty-Kapella et al. 2008; Tucker et al. 2013). In fact, there may be a decrease in proliferation in the presence of tenascin-W under certain culture conditions (Kimura et al. 2007).

Murine tenascin-W may be an integrin ligand. More 3T3 cells attach to tenascin-W, and more will cross a tenascin-W-coated filter, if they are transiently transfected to express α8 integrin (Scherberich et al. 2005). Additionally, CHOB2 cells expressing αvβ1 or α4β1 integrins spread more on tenascin-W than on control substrata (Degen et al. 2007). Tenascin-C from chicken or human has an RGD motif that is exposed to integrin binding in its third FNIII domain (Tucker and Chiquet-Ehrismann 2015). Interestingly, there is a strong correlation between the presence of an RGD motif in the second FNIII domain of tenascin-W and the absence of an RGD motif in the third FNIII domain of tenascin-C (Adams et al. 2015). For example, tenascin-C from reptiles, birds, carnivores, and primates has an RGD motif in the third FNIII domain, but tenascin-C from cetaceans, even-toed ungulates, and most rodents does not. Tenascin-W from cetaceans, even-toed ungulates, and most rodents has an RGD motif in the second FNIII domain, but tenascin-W from reptiles, birds, carnivores, and primates does not.

Given its relatively high level of expression in developing and adult bone, much of the in vitro analysis of tenascin-W has been conducted with primary cultures of osteoblasts or osteogenic cell lines. For example, BMP2 can upregulate tenascin-W expression in osteogenic C2C12 cells (Scherberich et al. 2004) and in ATDC5 osteochondroprogenitors (Kimura et al. 2007), and primary cultures of chicken calvarial osteoblasts show increased alkaline phosphatase activity in the presence of recombinant tenascin-W (Fig. 2d, e) (Meloty-Kapella et al. 2008). Expression of tenascin-W is also upregulated in mouse embryo fibroblasts and HC11 cells by BMP2 (Scherberich et al. 2005). The upregulation by BMP2 is blocked by pharmacological inhibitors of p38MAPK and JNK, but not by inhibitors of ERK-1/ERK-2, which is consistent with the pathways used by BMP2 during osteogenesis. TNFα also upregulates tenascin-W in mouse embryo fibroblasts and this can be inhibited with indomethacin (Scherberich et al. 2005). Thus, inflammatory cytokines may also be able to upregulate tenascin-W.

Cancer Biology

A high level of expression of tenascin-C at the invasive front of tumors is usually associated with a poor prognosis (Lowy and Oskarsson 2015). Tenascin-W is also found in the stroma of solid tumors. It was first observed in murine breast tumors with a high likelihood of metastasis by Scherberich and colleagues (Scherberich et al. 2005). Initial studies in humans revealed prominent tenascin-W expression in the tumor stroma in a large majority of human breast tumors and complete absence in adjacent normal mammary tissue (Degen et al. 2007). In contrast to murine breast tumors, in which tenascin-W was associated with the metastatic potential, tenascin-W in human breast cancer was enriched in low-grade tumors (Degen et al. 2007). Tenascin-W overexpression has been identified in several other human solid tumors, including colorectal (Degen et al. 2008), brain (oligodenroglioma, astrocytoma, and glioblastoma) (Martina et al. 2010), pancreatic, prostate, ovarian, kidney, and lung cancers as well as in melanoma (Brellier et al. 2012b) (Fig. 3ad). In all of these tissues, tenascin-W was not detectable in the respective neighboring normal tissues. In the tumor stroma, tenascin-W is often associated with blood vessels and colocalizes with CD31 and von Willebrand factor, which are markers for blood vessels (Martina et al. 2010; Brellier et al. 2012b) (Fig. 3e, d).
Tenascin-W (Tnn, TNN), Fig. 3

Tenascin-W is found in the stroma of solid tumors and is also associated with tumor microvasculature. Antibodies to tenascin-W do not immunostain normal lung (a), but they do label the stroma of a lung tumor (b). Similarly, antitenascin-W does not label normal adult skin (c), but it does label the stroma of a melanoma (d). In glioblastoma tenascin-W is expressed in the tumor vasculature (e). Coimmunofluorescence of tenascin-W (red) and CD31 (green) in a kidney tumor shows tenascin-W expression around CD31-positive blood vessels (f) (Images reproduced with permission from Brellier et al. (2012b) and Martina et al. (2010))

The cellular source of tenascin-W in tumors still remains to be elucidated. However, there is evidence that tenascin-W expression is restricted to stromal cells, but this might also depend on the tumor type. Using the MDA-MB231–1833 xenograft model of breast cancer metastasis to the bone, it was found that the metastasizing tumor cells induced tenascin-W in bone marrow-derived stromal cells in a TGFβ1-dependent manner. Similar to tenascin-C, which is a component of the lung-metastatic niche for breast cancer cells (Oskarsson et al. 2011), tenascin-W is part of a congenial metastatic niche in breast cancer cells disseminating to the bone (Chiovaro et al. 2015). So far, there are no data indicating that tenascin-W is also produced and secreted by cancer cells themselves. This is in contrast to tenascin-C, which is known to be expressed by some cancer cells (e.g., brain cancer cells) as well as stromal cells.

Functionally, tenascin-W seems to influence the behavior of cancer cells as well as stromal cells in the tumor microenvironment. Tenascin-W modulates cellular adhesion (see section above), and it also stimulates tumor cell migration. Both mouse and human breast cancer cells displayed increased migration in the presence of tenascin-W in transfilter migration assays (Scherberich et al. 2005; Degen et al. 2007). Similarly, endothelial cells show an increased speed of movement when cultured on a substratum composed of tenascin-W/collagen I compared to collagen I alone (Martina et al. 2010). Furthermore, using a well-established angiogenesis assay, the authors presented evidence that tenascin-W is able to induce sprouting of HUVEC spheroids embedded in collagen gels (Martina et al. 2010) suggesting a role for tenascin-W in tumor angiogenesis.

Expression of tenascin-C and tenascin-W is highly upregulated in the stroma of various solid human tumors. Often the two tenascins are coexpressed, but there are also many tumor patients who selectively express tenascin-C and not tenascin-W, and vice versa. This suggests independent regulatory mechanisms responsible for tenascin-W and tenascin-C expression. A striking difference in the expression of tenascin-C and tenascin-W is their detection in normal healthy tissue. While tenascin-C is readily expressed in certain healthy tissues, tenascin-W shows no detectable expression in normal tissues adjacent to the tumor. Moreover, it is well established that tenascin-C expression can be induced under pathological conditions other than cancers, such as inflammation, healing wounds, and asthma (Orend and Chiquet-Ehrismann 2006). However, there is no in situ evidence so far that tenascin-W can be induced under conditions other than tumorigenesis. Therefore, the prominent and highly tumor-specific expression of tenascin-W makes the molecule an attractive candidate for a potential diagnostic and/or prognostic tumor marker. In that regard, it is noteworthy that tenascin-W can also be detected in human serum. Elevated levels of tenascin-W in sera of breast and colon cancer patients compared to controls have been described using a sensitive tenascin-W-specific sandwich ELISA (Degen et al. 2008). The possibility to measure tenascin-W in body fluids further increases its potential as a tumor biomarker. Whether tenascin-W levels in tissues and/or body fluids can be used as a prognostic marker has not yet been analyzed in detail.

Summary

Tenascin-W is a matricellular protein that is particularly abundant in developing and adult bone. It is upregulated in vitro by BMP2, and it promotes alkaline phosphatase expression by primary cultures of osteoblasts. There is some evidence that tenascin-W can support cell attachment and migration by acting as an integrin ligand and, like tenascin-C, tenascin-W can modulate cell spreading on fibronectin. Tenascin-W is found in the serum of patients with certain tumors, and it is upregulated in the stroma of many solid tumors. Since it is not found in adjacent normal tissues, tenascin-W may prove to be a better tumor marker than tenascin-C. The highly tumor-specific expression of tenascin-W as well as its presence around the tumor vasculature makes tenascin-W a very attractive potential antigen for antibody-drug-conjugates (ADC). ADCs are complex molecules consisting of an antibody targeting a tumor-specific antigen linked to a cytotoxic payload. This approach allows sensitive discrimination between healthy and diseased tissue. Similar approaches are being tested for the treatment of refractory Hodgkin’s lymphoma patients using a labeled antibody fragment targeting a tumor-specific tenascin-C isoform (Aloj et al. 2014). Unlike tenascin-C, relatively little is known about how tenascin-W participates in cell signaling. This is still and active area of research.

See Also

References

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Orthodontics and Dentofacial OrthopedicsSchool of Dental Medicine, University of BernBernSwitzerland
  2. 2.Department of Cell Biology and Human AnatomyUniversity of CaliforniaDavisUSA