Malignant gliomas have a distinctive ability to infiltrate the brain parenchyma and disrupt the neural extracellular matrix that inhibits motility of axons and normal neural cells.
Chondroitin sulfate proteoglycans (CSPGs) are among the major inhibitory components in the neural matrix, but surprisingly, some are up-regulated in
gliomas and act as pro-invasive signals. In the normal brain, CSPGs are thought to associate with
hyaluronic acid and
glycoproteins such as the tenascins and link
proteins to form the matrix scaffold. Here, we examined for the first time the expression of link
proteins in human brain and
malignant gliomas. Our results indicate that HAPLN4 and HAPLN2 are the predominant members of this family in the adult human brain but are strongly reduced in the
tumor parenchyma. To test if their absence was related to a pro-invasive gain of function of CSPGs, we expressed HAPLN4 in
glioma cells in combination with the CSPG
brevican. Surprisingly, HAPLN4 increased
glioma cell adhesion and migration and even potentiated the motogenic effect of
brevican. Further characterization revealed that HAPLN4 expressed in
glioma cells was largely soluble and did not reproduce the strong,
hyaluronan-independent association of the native
protein to brain subcellular membranes. Taken together, our results suggest that the
tumor parenchyma is rich in CSPGs that are not associated to HAPLNs and could instead interact with other
extracellular matrix proteins produced by
glioma cells. This dissociation may contribute to changes in the matrix scaffold caused by invasive
glioma cells.