Fibronectin is a glycoprotein found in most extracellular matrices as aggregates or fibrils. It consists of two polypeptide chains linked by interchain disulphide bonds. Fibronectin has variety of biological functions involving cell adhesion, migration and invasion. As early as in 1983, Kochi2 et al showed that astrocytomas and glioblastomas did not express fibronectin but is confined to gliomesenchymal junction of tumours and tumour associated proliferating vessel walls.

Hyaluronic acid (HA or hyaluronan) is a high molecular weight proteoglycan found in the extracellular matrix and does not contain a core protein. Apart from its major role in tumour cell invasion, HA has been implicated in many cell functions including neural crest migration. Elevated levels of HA have been correlated with tumour cell invasiveness.3 The role of HA in glioma cell invasion is complicated, however by the fact that astrocytes synthesize HA themselves, rather than tumour cells stimulating host fibroblasts to make HA.

It has been reported that gliomas disseminate along the myelinated fibre tracts of white matter.4 However, the responsible component or molecule of the crude myelin extract has not been identified; and neither neural cell adhesion molecules nor integrins mediate the adhesion of glioma cells to crude myelin extracts.5

Laminin is an adhesion glycoprotein found predominantly in basement membranes and in hyperplastic blood vessels in gliomas.6 It plays a role in migration, neurite outgrowth, proliferation and differentiation.7

Tenascins are also heterodimeric sulphide proteins implicated in adhesion and migration of human glioma cells. These isoforms of Tenascin have been identified - (i) Tenascin-C, (ii) Tenascin-R and (iii) Tenascin-X.

Tenascin C is also known as cytotactin and is present during development of central nervous system and connective tissue.8

It is also prominent and is overexpressed in most carcinomas and gliomas. In CNS, tenascin-C, is found to be synthesized by glial and neural crest cells and by satellite cells of peripheral nervous system. Tenascin-R also known as restriction is only identified in rat and chicken and seems to be specific to the central and peripheral nervous system.9
Tenascin-X, is known to be expressed usually in skeletal and heart muscle but its specific function is not very clear as yet.

As mentioned earlier, human gliomas are highly diffuse infiltrative tumours, for which complete surgical resection is difficult and hence, recurrence is more common. Unlike other tumour types, gliomas rarely metastasize outside the CNS.10 Invasion of the tumour in the surrounding normal brain tissue is a result of highly coordinated complex mechanisms at the cellular levels. These mechanisms include (i) cell-cell adhesions, (ii) cell and extra-cellular matrix interactions leading to migration and (iii) Neovascularization. Cell-cell adhesions and cell spreading are two separable processes mediated by distinct ECM molecules involved in tumour growth and infiltration. Tenascin-C is one such ECM that interacts with other ECM molecules like fibronectin, laminin and collagen, which induce focal adhesion and migration of various cell types including endothelial cells of the blood vessel walls.11 In vitro studies by Giese12 et al observed that glioma cells migrate at a higher rate on TN-C monolayers than on collagen or fibronectin layers. Endothelial cells were also seen to attach TN-C substrates and were able to elongate; in contrast no spread was visible on substrate including fibonectin, collagen or laminin. This indicated, that in gliomas, TN-C plays a critical role in modulating cell adhesion, motility in endothelial proliferation and tumour cell migration.13

Tenascin-C has been shown to be an important component of ECM and it promotes endothelial cell adhesion, spreading and migration; and these are the processes essential for angiogenesis i.e. formation of blood vessels.14 In human gliomas, TN-C accumulation has been correlated with the degree of tumour neovascularization.15 Increased TN-C expression of endothelial cells modify the ECM composition, which facilitate vascular sprouting and migration required for angiogenesis. TN-C expression is upregulated in tumour formation and has been well correlated with the degree of histological malignancy.16 On immunohistochemical studies, TN-C has been shown to be stronger around and within the walls of hyperplastic blood vessels than in non-hyperplastic vessels, suggesting that TN-C does play a role in tumour angiogenesis.17 In literature, data show that in patients with astrocytoma (grade 2), with no TN-C expression, around the vessels of the lesion, had a significant median survival benefit of 16 months, than the patients with TN-C positive astrocytoma.18 Patients with glioblastoma multiforme exhibiting TN-C negativity survived significantly longer compared to patients who had elevated expression of TN-C extracellular matrix of the lesion.19

Furthermore, it has been reported that heterogeneous distribution of TN-C in the ECM and in blood vessels is detected in different brain tumours; but results are only consistent in astrocytomas. Immunohistochemical studies with TN-C labelling on astrocytomas showed following features (i) strong positivity along neovascularization and in the pleomorphic cellular areas; (ii) reduced positivity in less malignant areas and (iii) the lack of TN-C immunostaining in vessels of control brain suggests that the adhesive/non-adhesive function of TN-C promotes endothelial cell motility and plays a crucial role in glioma-induced neoangiogenesis.20

Thus all the above studies indicate that inhibition of neovascularization may present as an important target for glioma treatment. Moreover, because TN-C is up regulated in tumour vasculature of gliomas, antibody-directed therapies targeting TN-C and causing “tumour infarction” may prove to be useful in treating brain tumours.21

I sincerely thank Dr. JJ Nadkarni, Director, Department of Neuropathology and Applied Biology, Bombay Hospital, for her encouragement and guidance in writing this article