Cost o f M igration: I nvasion o f M alignant G liomas a nd Implications f or T reatment

Tumors of glial origin consist of a core mass and a penumbra of invasive, single cells, decreasing in numbers towards the periphery and still detectable several centimeters away from the core lesion. Several decades ago, the diffuse nature of malignant gliomas was recog- nized by neurosurgeons when super-radical resections us- ing hemispherectomies failed to eradicate these tumors. Local invasiveness eventually leads to regrowth of a recur- rent tumor predominantly adjacent to the resection cavity, which is not significantly altered by radiation or chemother- apy. This raises the question of whether invasive glioma cells activate cellular programs that render these cells resis- tant to conventional treatments. Clinical and experimental data demonstrate that glioma invasion is determined by several independent mechanisms that facilitate the spread of these tumors along different anatomic and molecular structures. A common denominator of this cellular behavior may be cell motility. Gene-expression profiling showed upregulation of genes related to motility, and functional studies demonstrated that cell motility contributes to the invasive phenotype of malignant gliomas. There is accumu- lating evidence that invasive glioma cells show a decreased proliferation rate and a relative resistance to apoptosis, which may contribute to chemotherapy and radiation resis- tance. Interestingly, interference with cell motility by differ- ent strategies results in increased susceptibility to apopto- sis, indicating that this dynamic relationship can potentially be exploited as an anti-invasive treatment paradigm. In this review, we discuss mechanisms of glioma invasion, charac- teristics of the invasive cell, and consequences of this cellu- lar phenotype for surgical resection, oncologic treatments, and future perspectives for anti-invasive strategies. J Clin Oncol 21:1624-1636. © 2003 by American Society of Clinical Oncology.