Correlation of N-cadherin expression in high grade gliomas with tissue invasion

Abstract

Cadherins are Ca2+-dependent cell adhesion molecules that play an important role in tissue construction and morphogenesis in multicellular organisms. Over the last few years, reports have emerged in the literature describing the involvement of cadherins in tumor invasion and metastasis. Cadherins typically demonstrate up and down-regulation according to the biological needs of the tissue. Additionally, up-regulation of N-cadherin is thought to be important for tumor formation in early stages of tumor development. We studied N-cadherin in surgical specimens of patients with primary glioblastoma by microarray analysis and found that N-cadherin mRNA expression is up-regulated compared to normal brain. To study the effects of N-cadherin expression on invasion and metastasis in vitro and in vivo, we overexpressed N-cadherin in the rat C6 glioma cell line which normally has low levels of N-cadherin. We found that up-regulation of N-cadherin resulted in a slight decreased adhesion to type IV collagen, fibronectin, and laminin, but statistically significant decreased adhesion to type I collagen. Furthermore, increased expression of N-cadherin correlated with a dramatic decrease in invasive behavior in extracellular matrix invasion assays. We then proceeded to study these cell lines in vivo in a rat intracranial glioma model, and found that N-cadherin expression inversely correlated with invasion into surrounding tissues, irregular margins, and extracranial invasion. In summary, these data collectively demonstrate that N-cadherin levels are important in the malignant behavior of gliomas, and may serve as a prognostic indicator for patients with high-grade gliomas.

N-cadherin expression level modulates integrin-mediated polarity and strongly impacts on the speed and directionality of glial cell migration

“…Changes in N-cadherin expression are still controversial mainly owing to the observation of an inverse correlation between N-cadherin mRNA and protein levels (Asano et al, 2004;Shinoura et al, 1995), which we also observed (data not shown). This discrepancy most probably reflects defects in protein synthesis or stability.…”

“…Although sometimes contradictory, evidence showing changes in N-cadherin levels in gliomas is accumulating (Asano et al, 2004;Asano et al, 1997;Utsuki et al, 2002). We analyzed N-cadherin levels in normal and glioma samples by western blots.…”

“…In gliomas, no obvious scenario has emerged on the basis of N-cadherin protein levels, and the role of N-cadherin in glioma cell migration is still unknown (Asano et al, 2004;Asano et al, 2000;Foty and Steinberg, 2004;Hegedus et al, 2006;Shinoura et al, 1995;Utsuki et al, 2002). We have recently shown that N-cadherin is a key regulator in the polarity of non-migrating astrocytes (Dupin et al, 2009).…”

Role of aquaporin-4 in the regulation of migration and invasion of human glioma cells

“…cell-cell adhesion ability was detected by an aggregation assay, which was carried out as described previously (15). cells were washed three times with rPMi-1640 (serum-free medium) and were subsequently trypsinized with 4.0 mM eDta with calcium to protect cadherin subtypes on the cell surface from cleavage.…”

Molecular Mechanisms of Glioma Cell Motility

“…In contrast to its role in carcinoma, N-cadherin is frequently downregulated in GBM compared to the healthy brain (177,178). N-cadherin overexpression has been shown to decrease glioma invasion in vitro and in vivo (179). Interestingly, the role of N-cadherin in glioma is postulated not only to be determined by its expression level but also by its distribution in the cell membrane (180).…”