The role of the extracellular matrix in neoplastic glial invasion of the nervous system.

Intrinsic tumours of the central nervous system (CNS) are generally derived from the glial cells: the astrocytes, oligodendrocytes and ependymal cells. Although such tumours rarely metastasize to distant organs, they show a marked propensity for local invasion of the surrounding nervous tissue. Sub-populations of neoplastic glia may migrate several millimetres away from main tumour mass into the contiguous CNS parenchyma, resulting in poor demarcation of the tumour. These migratory, so-called "guerrilla" cells give rise to recurrent tumours following surgical debulking and adjuvant radio- and chemo-therapeutic intervention. As in other organs, tumour cell invasion is, in part, facilitated by interaction with the extracellular matrix (ECM); however, apart from the vascular basal lamina and the glia limitans externa, the CNS lacks a well-defined ECM. Invading neoplastic cells must, therefore, provide their own ECM, a process which may be stimulated by such agents as gangliosides or growth factors. Glioma cell-derived laminin and hyaluronic acid may provide the most important substrates for invasion, cell adhesion to these substrates being achieved largely through integrin receptors (the function of which may be determined by interaction with cell surface gangliosides) and CD44, respectively. Modulation of these ECM components is facilitated by a variety of proteinases including the matrix metalloproteinases and hyaluronidase, the activity of which is also thought to stimulate angiogenesis. Interference with the mechanisms which promote glioma cell adhesive properties may provide suitable targets for novel anti-invasive therapies. These might include ECM components, growth factors, gangliosides, integrin receptors and proteases and their inhibitors.