The Extracellular Space of Gliomas: Changes in Volume Geometry and Composition during Malignant Progressions
Abstract
The extracellular space (ECS) of the brain is an important microenvironment of nerve cells and a communication channel between neurons and glial cells. Its composition and volume change dynamically during neuronal activity, development, aging, many pathological states such as ischemia, demyelination or trauma and during neoplastic reconstruction of the tissue.
It has been suggested that changes in ECS volume and composition also affect the biological behavior of brain tumors. ECS size and geometry can be accurately determined by the tetramethylammonium (TMA+) real-time iontophoretic method, which uses TMA+ as an extracellular marker and follows its diffusion in the ECS by the use of ion-selective microelectrodes.
In comparison with unaffected brain cortex, experiments have revealed a dramatic increase in the ECS volume of gliomas, correlating with increases in malignancy. However, the diffusion of small molecules in the enlarged ECS of high-grade gliomas is slowed down due to increased macromolecule content.
In contrast to 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 diffusion barriers in high-grade gliomas is caused by the overproduction of certain components of the extracellular matrix (ECM), mainly of tenascin. These aberrant or "overproduced" ECM glycoproteins not only stabilize the ECS volume, but also serve as a substrate for the adhesion and subsequent migration of tumor cells through the enlarged ECS.
Interestingly, these alterations in ECS volume and structure may hinder the diffusion of neuroactive substances and 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 for the aggressive biological behavior of tumors.