Differential erbB signaling in astrocytes from the cerebral cortex and the hypothalamus of the human brain.

Studies in rodents have shown that astroglial erbB tyrosine kinase receptors are key regulatory elements in neuron-glia communication. Although both astrocytes and deregulation of erbB functions have been implicated in the pathogenesis of many common human brain disorders, erbB signaling in native human brain astrocytes has never been explored. Taking advantage of our ability to perform primary cultures from the cortex and the hypothalamus of human fetuses, we conducted a thorough analysis of erbB signaling in human astrocytes. We showed that human cortical astrocytes express erbB1, erbB2, and erbB3, whereas human hypothalamic astrocytes express erbB1, erbB2, and erbB4 receptors. Ligand-dependent activation of different erbB receptor heterodimeric complexes in these two populations of astrocytes translated into different morphological and proliferative responses. Although morphological plasticity was more pronounced in hypothalamic astrocytes than in cortical astrocytes, the former showed a lower mitogenic potential. Decreasing erbB4 expression via siRNA-mediated gene knockdown revealed that erbB4 constitutively restrains basal proliferative activity in hypothalamic astrocytes. We further show that treatment of human astrocytes with a protein kinase C activator results in rapid tyrosine phosphorylation of erbB receptors that involves cleavage of endogenous membrane bound erbB ligands by metalloproteinases. Together, these results indicate that erbB signaling in primary human brain astrocytes is functional, region-specific, and can be activated in a paracrine and/or autocrine manner. In addition, by revealing that some aspects of astroglial erbB signaling are different between human and rodents, our results provide a molecular framework to explore the potential involvement of astroglial erbB signaling deregulation in human brain disorders.

Differential distribution of erbB receptors in human glioblastoma multiforme: expression of erbB3 in CD133-positive putative cancer stem cells.

Glioblastomas are the most common primary central nervous system tumors in adults, and they remain resistant to current treatments. erbB1 signaling is frequently altered in glioblastomas, suggesting thaterbB receptor family members may represent targets for molecular therapy. We performed a comprehensive analysis of erbB receptor and ligand expression profiles in a panel of 9 glioblastomas andcompared them to nonneoplastic cerebral tissue containing neocortex and adjacent white matter. Quantitative reverse transcription-polymerase chain reaction and Western blot analysis showed that erbB1signaling and erbB2 receptors exhibited highly variable deregulation profiles in the tumors, with patterns ranging from underexpression to overexpression; in contrast, erbB3 and erbB4 were downregulated. We next performed immunohistochemistry to determinethe distribution patterns of erbB receptors among the main neuralcell types in the tumors with special reference to the putative tumor stem cell population. Results revealed intertumoral and intratumoral heterogeneity in all 4 erbB expression profiles, but each receptor exhibited a distinct distribution pattern among glial fibrillary acidic protein-, Olig2-, NeuN-, and CD133-positive populations. Although erbB1 immunoreactivity was detected in only small subsets of CD133-positive putative tumor stem cells, erbB3 immunoreactivity was prominent in this population, suggesting that erbB3 may represent a new potential therapeutic target.

Mature neuroblastic tumors with spinal cord compression: report of five pediatric cases.

BACKGROUND: Neuroblastic tumors cause spinal cord compression when they arise primarily in the spinal canal or invade it through the radicular foramen. Whereas neuroblastomas (NB) are relatively common and are generally treated with chemotherapy, mature neuroblastic tumors (MNT), which include intermixed ganglioneuroblastomas (iGNB) and ganglioneuromas (GN), are less common and the role of surgery is more prominent. Because MNT are rare and have been separated only recently from NB, their clinical and radiological features as well as the role of surgery are poorly defined. MATERIALS AND METHODS: In order to increase our knowledge on MNT, we reviewed our database for cases operated for spinal cord compression in our department since the introduction of magnetic resonance imaging (MRI). We treated four cases of NB and one case of iGNB presenting primarily with spinal cord compression. REPORT OF CASES: MNT represented 10% of spinal tumors and 1.6% of all tumors of the nervous system in our pediatric neurosurgical practice. The neurological and oncological outcomes were generally favorable after surgical resection, followed by orthotic treatment. In one case with neurofibromatosis type 1, the tumor was inoperable and the child died of tumor progression several years later. CONCLUSION: GN, and some iGNB, are chemo-insensitive and can only be cured by surgical removal. Surgery is an emergency in case of rapidly progressing paraplegia and can be challenging because the tumor is often hard and hemorrhagic. In case of subtotal removal, tumor remnants can stay stable without oncological treatment.