The vast majority of brain tumors in adults exhibit glial characteristics. Brain tumors in children are diverse: Many have neuronal characteristics, whereas others have glial features. Here we show that activation of the Gi protein-coupled receptor CXCR4 is critical for the growth of both malignant neuronal and glial tumors. Systemic administration of CXCR4 antagonist AMD 3100 inhibits growth of intracranial glioblastoma and medulloblastoma xenografts by increasing apoptosis and decreasing the proliferation of tumor cells. This reflects the ability of AMD 3100 to reduce the activation of extracellular signal-regulated kinases 1 and 2 and Akt, all of which are pathways downstream of CXCR4 that promote survival, proliferation, and migration. These studies (i) demonstrate that CXCR4 is critical to the progression of diverse brain malignances and (ii) provide a scientific rationale for clinical evaluation of AMD 3100 in treating both adults and children with malignant brain tumors.

The cerebral metabolic rate of oxygen (CMRO 2 ) was dynamically evaluated on a pixel-by-pixel basis in isoflurane-anesthetized and spontaneously breathing rats following graded electrical somatosensory forepaw stimulations (4, 6, and 8mA). In contrast to ␣-chloralose, which is the most widely used anesthetic in forepaw-stimulation fMRI studies of rats under mechanical ventilation, isoflurane (1.1-1.2%) provided a stable anesthesia level over a prolonged period, without the need to adjust the ventilation volume/rate or sample blood gases. Combined cerebral blood flow signals (CBF) and blood oxygenation level-dependent (BOLD) fMRI signals were simultaneously measured with the use of a multislice continuous arterial spin labeling (CASL) technique (two-coil setup). CMRO 2 was calculated using the biophysical BOLD model of Ogawa et al. (Proc Natl Acad Sci USA 1992;89:5951-5955). The stimulus-evoked BOLD percent changes at 4, 6, and 8mA were, respectively, 0.5% ؎ 0.2%, 1.4% ؎ 0.3%, and 2.0% ؎ 0.3% (mean ؎ SD, N ‫؍‬ 6). The CBF percent changes were 23% ؎ 6%, 58% ؎ 9%, and 87% ؎ 14%. The CMRO 2 percent changes were 14% ؎ 4%, 24% ؎ 6%, and 43% ؎ 11%. BOLD, CBF, and CMRO 2 activations were localized to the forepaw somatosensory cortices without evidence of plateau for oxygen consumption, indicative of partial coupling of CBF and CMRO 2 . This study describes a useful forepaw-stimulation model for fMRI, and demonstrate that CMRO 2 Under normal and resting physiological conditions in the brain, almost all (Ͼ99%) of the energy required for adenosine triphosphate (ATP) production is supplied by oxidative metabolism, and the cerebral metabolic rate of oxygen (CMRO 2 ) is tightly coupled to the cerebral blood flow (CBF) and the cerebral metabolic rate of glucose (CMR glucose ) (1). CBF and CMR glucose changes during task-induced increases in neuronal activity have consistently been demonstrated to be similar (ϳ50%) (2,3). However, the magnitude of stimulus-evoked CMRO 2 changes remains controversial. Following Fox et al.'s (2) initial study with positron emission tomography (PET), stimulusevoked CMRO 2 changes were reported as negligible (2,4,5), substantial but smaller than the CBF and CMR glucose increases (6 -10), or markedly increased by 200 -400% (11).CMRO 2 can be measured by various noninvasive techniques, including PET (2,6,12,13), 13 C MR spectroscopy (11,14), direct and indirect H 2 17 O NMR (15), and functional fMRI (fMRI) with biophysical modeling of the blood oxygenation level-dependent (BOLD) signals (7,9,16,17). These techniques all have some unique advantages and disadvantages. PET CMRO 2 measurement is based on the Kety-Schmidt method. Multiple physiological parameters must be deconvolved by the application of complex kinetic models to the data sets that are poor in signal-tonoise ratio (SNR). These measurements also take a long time, and multiple measurements cannot be made dynamically or in a single subject. Although 13 C spectroscopy and H 2 17 O NMR techniques can be quantitative, they have relatively poor...