The extracellular space and matrix of gliomas

Changes in the properties of extracellular space (ECS) — its volume, shape, and composition — play an important role in influencing the biological behavior of brain tumors. Experimental methods allowing assessment of the volume and geometry of ECS by means of analyzing the diffusion of molecules within ECS have revealed a dramatic increase in the ECS volume of gliomas when compared with that of unaffected brain cortex, also correlating with increases in malignancy. However, the newly enlarged ECS of high-grade gliomas does not remain empty; ECS shape becomes more complicated than in normal brain tissue. In contrast to the low-grade tumors, where the diffusion of molecules is reduced mainly by the presence of a dense network of tumor cell processes, the increase of ECS barriers in high-grade gliomas is caused by the overproduction of certain components of the extracellular matrix (ECM), mainly of tenascin. These aberrantly or “overproduced” ECM glycoproteins not only stabilize the ECS volume, but also serve as a substrate for adhesion and subsequent migration of the tumor cells through the enlarged ECS. Interestingly, these same alterations in ECS structure may hinder the diffusion of neuroactive substances or even molecules of drugs into the neoplastic tissue. The presence of tenascin in the ECS of the neoplasm correlates significantly with increased malignancy and poor clinical outcome of the disease, which makes its immunohistochemical detection useful as a marker of an aggressive biological behavior of the tumors.