Migration and Invasion in Brain Neoplasms Anna J. Bolteus, MSc, Michael E. Berens, PhD, and Geoffrey J. Pilkington, PhD, FRCPath Address Experimental Neuro-oncology Group, Department of Neuropathology, Institute of Psychiatry, King’s College, London, De Crespigny Park, Denmark Hill, London SE5 8AF, United Kingdom. E-mail: G.Pilkington@iop.kcl.ac.uk Current Neurology and Neuroscience Reports 2001, 1:225–232 Current Science Inc. ISSN 1528-4042 Copyright © 2001 by Current Science Inc. Introduction Brain tumors are thought to occur at an incidence of between six and 10 per 100,000 people, and account for a quarter of all malignancies in people under 15 years of age. Moreover, recent reports suggest that there has been a 35% to 40% increase in incidence of, and mortality from, brain tumors over the past four decades [1,2]. Gains in successful clinical management of these tumors have been marginal. Brain tumors may be primary (or intrinsic), generally thought to be derived from the glial cell population or their progenitor cells within the brain; secondary (meta- static cancers from primary tumors in other organs); or extrinsic, within the cranium but not within the brain tissue itself (eg, meningiomas). Although the brain is a prime site for growth of secondary cancers (25% of all malignant tumors show involvement of the brain), there are only rare reports of intrinsic brain tumors metastasiz- ing to distant organs. Despite this apparent metastatic failure by neoplastic glia, these cells show a marked propensity for local invasion of the normal brain. The phenomenon of brain tumor invasion is arguably the most important biologic feature of this group of neoplasms, and it often hampers effective therapeutic intervention. Definition of Terms The terms migration and invasion are frequently used inter- changeably; however, migration refers strictly to the active movement of cells either along a surface or through a three- dimensional structure (such as brain tissue), whereas invasion implies migration of cells with consequent detriment or damage to the tissue or structure into which the cells are invading. Examples of migration would be the move- ment of leukocytes into tissues or the movement of reactive astrocytes within the brain, whereas neoplastic glial cells, which destroy normal brain tissue elements during their migratory phase, are said to invade the tissue. Migration is, therefore, one facet of the invasion process. For the purpose of clarity in this review, cell migration includes active, directional cell locomotion, and cell invasion encompasses processes of local matrix or cellular remodeling and subsequent cell migration. Within the brain, migration of cells is a phenome- non common to various cell types during development and neuropathogenesis. Neoplastic Cell Migration and Invasion Neoplastic cell migration and invasion can take several different forms. Diffuse individual cell infiltration of the brain by so-called guerilla cells, which is characteristic of glioma, constitutes perhaps the greatest challenge in the context of therapy. Here single cells can travel several milli- meters or even centimeters from the main tumor mass. Because there is evidence that during this form of invasion neoplastic cells transiently arrest from the cell cycle [3,4], their response to radiation therapy and certain forms of chemotherapy is likely to be poor. Moreover, these guerilla cells may be protected from the action of cytotoxic drugs Local invasion of the brain by neoplastic glial cells is a major obstacle to effective treatment of intrinsic brain tumors. Invasion is directly related to histologic malignancy, but occurs to some extent irrespective of tumor grade. Because the brain-to-tumor interface is not well demar- cated, total surgical removal is rarely possible; moreover, as invading cells transiently arrest from cell division they are refractory to radiotherapeutic intervention. Invading cells may also be protected from the action of cytotoxic drugs by the presence of an intact blood-brain barrier. The invading cells, having migrated several millimeters or even centimeters from the main focus of the tumor, return to cycle phase under the control of some as yet unknown microenvironmental cue to form a recurrent tumor adjacent to the original site of presentation. Recent cellular and genetic information concerning factors underlying invasion may not only yield suitable targets for adaptation of existing therapies, but may also lead to novel approaches in glioma management.