Contactin is expressed in human astrocytic gliomas and mediates repulsive effects

Abstract

Contactin is a cell surface adhesion molecule that is normally expressed by neurons and oligodendrocytes. Particularly high levels of contactin are present during brain development. Using subtractive cloning, we identified contactin transcripts as overexpressed in glioblastomas compared with normal brain. We confirmed contactin overexpression in glioblastomas at the protein level, and localized contactin to the surface of glial fibrillary acidic protein (GFAP)-expressing glioblastoma cells. In contrast, normal astrocytes did not express contactin. Analyzing different types of astrocytic tumors, we detected an association between increasing malignancy grade and contactin expression. Functionally, contactin had repellent effects on glioma cells in vitro, as demonstrated by adhesion and migration assays. Overexpression of contactin by transfection into glioblastoma cells did not alter the proliferation rate or adhesion to various extracellular matrix proteins as well as adhesion to cells expressing the specific contactin ligand the protein tyrosine phosphatase zeta (PTPzeta). Our findings suggest that contactin has repellent effects on glioma cells to which it is presented as a ligand, but it does not alter the proliferative or adhesive capacities of cells that overexpress the molecule. The repulsive properties of contactin may be a key factor in glioma disaggregation, and may contribute to the diffuse infiltration pattern characteristic of glioma cells in human brain.

The mouse F3/contactin glycoprotein

“…56 Such an expression, however, may represent a consequence of astrocyte dedifferentiation as normal astrocytes do not express the molecule. On these cells, F3/Contactin bears the properties of a repellent molecule demonstrated by adhesion and migration assays.…”

“…Indeed, although brain-specific, F3/Contactin cannot be strictly considered as a neuron-specific glycoprotein as it is also expressed on cells of glial derivation. Indeed, some expression has been also found on an astrocytic glioma, 56 although the main non-neuronal cells expressing the molecules are rather oligodendrocytes, on which the protein has been found by both in vitro and in vivo approaches. 126 Expression on oligodendrocytes may be in keeping with the hypothesis of the F3/Contactin involvement in early stages of myelination besides than in the abovementioned organization of the nodal/paranodal regions.…”

“…Coordinated regulation of axonal glycoprotein expression may therefore represent a prerequisite for their involvement in morphogenetic events typical of distinct developmental steps. In this respect, while the primary role of such molecules was supposed to be the control of neurite elongation and pathfinding, several reports indicate that in fact some of them may mediate earlier events, related to neuronal commitment/early differentiation [53][54][55] or later ones as development of glia, 56 regeneration, 57,58 myelination [59][60][61] and synaptogenesis. [4][5][6]62 The arising corollary is therefore that the articulated role of these molecules may be closely dependent upon the specific times and sites of activation of the underlying genes.…”

Receptor protein tyrosine phosphatases and cancer

“…Consistent with this notion, CNTN1 is expressed in astrocytic tumors with increasing malignancies correlating with increasing CNTN1 expression. 113 In particular, it was demonstrated that PTPRZ-expressing cells adhered less strongly to CNTN1-expressing cells than control cells and that this decreased adhesion was due to the presence of PTPRZ. The sum of these experiments suggested that interactions between CNTN1 and PTPRZ could have a repulsive effect 113 and thus would promote the migration of the PTPRZ-expressing glioma cells.…”

“…113 In particular, it was demonstrated that PTPRZ-expressing cells adhered less strongly to CNTN1-expressing cells than control cells and that this decreased adhesion was due to the presence of PTPRZ. The sum of these experiments suggested that interactions between CNTN1 and PTPRZ could have a repulsive effect 113 and thus would promote the migration of the PTPRZ-expressing glioma cells. Keeping in mind the notion that interactions between PTN and PTPRZ result in loss of adhesiveness in part because of enhanced tyrosine phosphorylation of β-catenin and subsequent loss of cadherinmediated adhesion, one is tempted to speculate that formation of CNTN1/PTPRZ complexes may also inactivate PTPRZ, leading to enhanced phosphorylation of PTPRZ substrates such as β-catenin and ultimately promote cell migration.…”