Expression of cell adhesion molecules in normal nerves, chronic axonal neuropathies and Schwann cell tumors

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Abstract

Cell adhesion molecules (CAMs) play a role in the normal development and regeneration of tissues as well as in the biological behaviour of tumors. We studied the immunohistochemical expression of various CAMs, such as neural cell adhesion molecule (NCAM), its polysialylated isoform (PSA-NCAM), epithelial (E-) cadherin, and β1 integrins (α2β1, α5β1, α6β1) in a series of frozen specimens of 10 normal nerves, 5 axonal neuropathies, 26 benign Schwannomas and 2 malignant peripheral nerve sheath tumors (MNST). NCAM was expressed by non-myelinating Schwann cells from normal nerves and overexpressed by Schwann cells from patients with chronic axonal neuropathies and Schwannomas. The expression was lower in MNST. Expression of PSA-NCAM was heterogeneously displayed by Schwann cells from the various tissues studied. Anti E-cadherin immunoreactivity was present in myelin sheath in normal nerves and axonopathies. It was expressed in some Schwannomas especially in vestibular Schwannomas. Integrins VLAα2 and VLAα6 were widely expressed by Schwann cells from normal nerves, axonal neuropathies and Schwannomas but their expression was low in MNST. VLAα5 was not expressed by Schwann cells from normal nerve and Schwannomas but present in chronic axonal neuropathies and MNST. In addition VLAα6 was strongly expressed by perineurial cells. These data show that CAMs have a characteristic pattern of expression in normal nerve. Also, some CAMs are always expressed by Schwann cells but the expression of others differs in normal nerves versus axonopathies or tumors, suggesting a role of the microcellular environment in the regulation of CAM expression. Schwannomas have different pattern of expression than MNST.

Introduction

Cell adhesion molecules (CAMs) are membranous proteins with tissue-specific behaviour. They selectively regulate intercellular and cell-extracellular matrix contacts. They play a role in embryological development and morphogenesis as well as in pathological events such as inflammation and tumoral processes. Four major classes of adhesion molecules have been defined according their primary amino-acid sequence: the members of the immunoglobulin superfamily, the cadherins, the integrins and the selectins. Here we focused on five different CAMs:

(a) The neural cell adhesion molecule (NCAM), a member of the immunoglobulin superfamily of adhesion molecules, is expressed by both neuroectodermal and mesenchymal cells and their tumors (Figarella-Branger et al., 1990, Mechtersheimer et al., 1991). In the central nervous system, NCAM molecules exist in three major isoforms with molecular masses of 180, 140 and 120 kDa, all generated by alternative splicing and posttranslational modifications affecting a single gene (Goridis and Brunet, 1992). NCAM mediates calcium-independent homophilic cell adhesion. Besides its role in cell migration and organogenesis during embryonic development, NCAM is also involved in preserving the differentiated state of some cells and tissues. The embryonic form of NCAM, PSA-NCAM, contains high levels of polysialic chains. These PSA chains on NCAM molecules decrease the homophilic interactions of the protein (Sadoul et al., 1983), which might be involved in the metastatic potential of some neuroectodermal tumors (Rougon et al., 1992). In peripheral nerve, NCAM is expressed by small unmyelimated fibers and non-myelinating Schwann cells (Le Forestier et al., 1993).

(b) Epithelial cadherin (E-Cadherin) is a cell surface membrane glycoprotein involved in homophilic calcium-dependent cell-cell adhesion. It plays a critical role in morphogenesis (Takeichi, 1988; Takeichi, 1991) and is expressed by almost all the epithelial tissues and their tumors in adults (Gumbiner et al., 1988). Loss of cadherin expression and function play a role in the invasive behaviour of epithelial cells (Albeda, 1993, Frixen et al., 1991, Takeichi, 1993). Recently, E-Cadherin expression has been reported in rat peripheral nervous system Schwann cells. It was concentrated at the paranodes, Schmidt-Lanterman incisures and at the inner and outer loops (Fannon et al., 1995).

(c) Integrins are αβ heterodimeric transmembrane glycoproteins integrating the extracellular matrix with the cytoskeleton (Hynes, 1992, Ruoslahti, 1991). The β1 integrin family, also called the VLA (very late activation) integrin family, includes receptors for extracellular matrix components such as collagen, fibronectin, laminin or tenascin. The ligand specificity is determined by the particular combination of subunits, but, many integrins can recognize the same ligand and many matrix components can be recognized by the same integrin. β1 integrins are involved in cell morphology and repair, motility, proliferation and differentiation (Chan et al., 1992, Hynes, 1992). Abnormal expression of integrins in many tumors has been correlated with aggressive and invasive behavior (Juliano and Varner, 1993, Ruoslahti, 1991). We have focused here on three VLA integrins, VLAα2, VLAα5, VLAα6, receptors for collagen, fibronectin and laminin, respectively, which are heterogeneously expressed in the normal peripheral nervous system of adults (Hsiao et al., 1991).

The aim of this study was 1) to establish the pattern of expression of these CAM in human normal nerves with peculiar attention to Schwann cells, 2) to observe whether changes in CAM expression in Schwann cells were related to various pathological conditions such as chronic axonal neuropathies, benign Schwannomas and MNST in order to search for diagnostic and prognostic markers and to understand better the biological role of CAMs in human Schwann cells in vivo.

Section snippets

Normal nerve and chronic axonal neuropathies

Ten normal nerve specimens were studied. Five of them belonged to peripheral nerve trunks and were obtained surgically. The last 5 samples consisted of cranial nerve roots obtained from fresh cadavers less than six h after death. Five cases of chronic axonal neuropathies showing regeneration were also studied.

Tumors

Twenty-six surgical samples were obtained from patients with Schwannomas. The tissue samples were cut into two pieces. One of them was snap-frozen in liquid nitrogen and stored at −80°C

Normal nerve (Fig. 1) and chronic axonal neuropathies

NCAM was expressed by small unmyelinated fibers and non-myelinating Schwann cells in all the specimens (Fig. 1A), as previously reported by Le Forestier et al., 1993). The isoform PSA-NCAM was expressed by some of the NCAM positive cells (Fig. 1B). E-Cadherin expression was not observed in Schwann cells, whereas the myelin sheath of the thicker fibers expressed E-Cadherin (Fig. 1F). VLAα2 subunit was expressed by the unmyelinated Schwann cells (cells expressing VLAα2 also expressed S100 antigen

Discussion

In this study, we investigated the pattern of expression of various CAMs in normal, regenerative, and tumoral human Schwann cells using immunohistochemical procedures with specific monoclonal antibodies. We observed that some of the CAM investigated, namely NCAM, VLAα2 and VLAα6, were strongly expressed by Schwann cells in the various tissues studied, whereas the expression of others such as polysialylated isoform of NCAM, VLAα5 and E-Cadherin may differ between normal and pathological

Acknowledgements

We are grateful to Profs. N. Graziani, F. Grisoli, J.C. Peragut for providing clinical data on some patients, and to B. Devictor for statistical analysis. This research was supported by credits de recherche ministeriels (PHRC CA 2426) and by the Association de la Recherche Contre le Cancer.

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