Shravan K. Chintala, Ph.D. and Jasti S. Rao, Ph.D.

Department of Neurosurgery, Box 064, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.

Received 9/28/96; Accepted 10/17/96; On-line 11/01/96

4. GLIOMAS

Gliomas, the most common primary brain tumors, account for more than 40% of all CNS neoplasms. Human astrocytic brain tumors have been divided into pilocytic (juvenile) astrocytoma, low-grade astrocytoma, anaplastic astrocytoma, and glioblastoma. Astrocytomas are defined as tumors comprised predominantly neoplastic astrocytes. Pilocytic astrocytoma (World Health Organization [WHO] grade I) is the most common brain tumor in children. These tumors are typically located in midline structures, e.g., the optic nerves, third ventricle, thalamus, medial temporal lobe, brain stem, and cerebellum. Pilocytic astrocytoma very rarely progresses to anaplasia. Low-grade astrocytoma (WHO grade II) shows a consistent tendency to diffusely infiltrate the surrounding brain parenchyma. These neoplasms typically occur in young adults; they may be localized in any CNS region, including the spinal cord, but they tend to localize in cerebral hemispheres. Anaplastic astrocytoma (WHO grade III) is characterized by neoplastic fibrillary or gemistocytic astrocytes. This astrocytoma has an inherent and often rapid tendency to progress to glioblastoma. Glioblastoma multiforme (WHO grade IV) is the most frequently occurring and most malignant brain tumor that typically affects adults. The most common location of glioblastoma is the frontotemporal region, but the parietal lobes are also often affected. Glioblastomas usually infiltrate through the corpus callosum, with extensions into the contralateral hemisphere.

4.1. Invasion

Human gliomas are characterized by highly diffuse infiltrative growth into the surrounding normal brain tissue, which makes surgical resection difficult (28, 85). In contrast to other tumor types, gliomas rarely metastasize outside the central nervous system (28). In an experimental model system using C6 glioma cells, laminin, was shown to be the principal constituent of the basement membrane of the blood vessels (86, 87), and it appeared to be responsible, in part, for the exclusion of glioblastoma cells from blood vessels (88). The role of laminin is, however, still controversial. During invasion, the tumor cells break up their cell-cell and cell-matrix interactions, become motile and subsequently forge a path through the digested ECM. This is accomplished by changes in the expression of cytoskeletal proteins, cell adhesion molecules and matrix-degrading proteases. Whether the tumor cells invade in response to existing ECM components or themselves synthesize autologous ECM and then migrate to the newly laid matrix is still a debated issue. Tumor cell migration is also influenced by migrating signals, such as ECM components, either by chemo-and/or haptotactic mechanisms (89). Liotta (90) proposed a three-step hypothesis for tumor cell migration, suggesting that cellular invasion is the result of highly coordinated and complex mechanism that include a series of cell-matrix interactions: (1) modification of cell-cell and cell-matrix attachments, (2) proteolytic modification of the ECM, and (3) invasion through proteolytically modified ECM.

These events must be coordinated and integrated so that the leading edge of the invasive cells makes new matrix contacts while the trailing edge breaks previously formed ones. ECM proteolysis and cell migration are not mutually independent events. Cell attachment may influence protease production, and protease activity can alter cell attachment and spreading. Understanding how these events are coordinated will bring a better appreciation of the underlying mechanisms of cell invasion and help to identify new targets for therapeutic interventions. In most cases, degradation of the basement membrane results in the solubilization of ECM fragments that may have chemotactic effects.

In many pathological conditions, ECM remodeling is accompanied by a cellular invasion that can compromise matrix organization and disrupt tissue. Under normal conditions, a negative feedback mechanism may limit the behavior of normal cells, such as endothelial cells, and lymphocytes. Although tumor cells use the same mechanism as normal cells, they seem to lack the appropriate feed back mechanism during invasion (91).