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

Abstract

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.

Extracellular Matrix of Glioblastoma Inhibits Polarization and Transmigration of T Cells: The Role of Tenascin-C in Immune Suppression

“…6). Glioma cells were stained positive with tenascin-C. An accumulation of tenascin-C around blood vessels in all glioblastoma tissues has been reported (29), and, in support of this, we found that many CD3-positive cells accumulated in the blood vessels stained strongly with tenascin-C. Few CD3-positive cells transmigrated into brain tumor tissue. In addition, tenascin-C inhibited the LPS-induced in vivo migration of leukocytes into the mouse air pouch model (Supplemental Fig.…”

“…Blocking of a5b1 integrins reverses the inhibitory effect of tenascin-C on chemotaxis of human monocytes and neutrophils (28); however, the real receptor for effective tenascin-C binding is yet to be confirmed. Although Ab (BC-24) recognized an epitope located within the N-terminal EGF-like sequence of the human tenascin-C molecule and reduced the migration and proliferation of glioma cells (29), it reduced cell adhesion (32) but did not affect the transmigration rate of T cells through glioma cell monolayers (this study). It is thus possible that cell adhesion requires the EGFL domain but migration is blocked by other parts of tenascin-C.…”

“…Notably, only glioblastoma cells expressed collagen IV and tenascin-C. Tenascin-C is highly expressed during embryogenesis but is downregulated in most adult tissues except for wound-healing regions and tumors (33). Recently, tenascin-C was identified as a prognostic marker for tumor recurrence and shown to play a role in glioblastoma growth and invasion (29). Tenascin-C inhibits b1-integrin-dependent T lymphocyte adhesion to fibronectin (34) and thus potentially inhibits the transmigration processes of Jurkat cells across glioblastoma cells.…”

Identification of molecular subtypes of glioblastoma by gene expression profiling

“…Hierarchical clustering of these tumors based on these 157 genes continued to support the presence of three primary GBM subtypes ( Figure 5). In addition to the previously mentioned genes, the EGFR+ tumors had increased expression of extracellular matrix proteins including tenascin C and fibronectin, which play a role in GBM cell invasion (Ohnishi et al, 1998;Herold-Mende et al, 2002), while the 12q13-15+ group had very high transcript levels of autotaxin, a secreted motility factor that promotes tumor cell invasion and metastasis (Stracke et al, 1992;Nam et al, 2000). These results suggest that these GBM subtypes may differ in their invasion patterns, and suggest additional potential biological, and perhaps clinical differences.…”

Targeted radiotherapy of brain tumours

“…The expression of tenascin increases with advancing tumour grade, with more than 90% of glioblastoma multiforme biopsies exhibiting very high levels of tenascin expression. Tenascin-C expression occurs primarily around tumour-supplying blood vessels, with this staining pattern becoming more pronounced with increasing tumour grade (Herold-Mende et al, 2002). Furthermore, in WHO II and III gliomas, there appears to be a correlation between perivascular staining and earlier tumour recurrence.…”