Aberrant nestin expression during ethylnitrosourea-(ENU)-induced neurocarcinogenesis.
Nestin is a unique intermediate filament protein. While it is robustly expressed in developing brain, postnatal expression is limited to the brain's subventricular zone (SVZ) and endothelial cells. Reexpression occurs, however, under several pathological conditions, including injury and neoplasia. We hypothesized that nestin would be a sensitive marker of early neoplasia after transplacental exposure of rats to ethylnitrosourea (ENU). Rats of various ages were administered bromodeoxyuridine (BudR) before sacrifice, and brain sections were examined for proliferative cells and several immunohistochemical markers, including nestin. Additional rats were examined after a stab wound injury to assess the expression of two of these markers, GFAP and nestin, in reactive astrocytes. All ENU-induced brain tumors (n = 9) were classified as gliomas (astrocytomas or oligoastrocytomas) based on their histology and immunophenotype. Nestin expression was noted in all tumors examined and was present in tumor cells as well as endothelial cells. During tumor development, we consistently noted nestin-expressing cells bearing multiple processes distributed throughout brain parenchyma. Both single cells and multiple cell clusters were observed as early as postnatal day 30 in all ENU-exposed brains examined (n = 11). Such distinctive nestin-expressing cells were not seen in nestin-stained control brains or ENU-exposed brains stained for GFAP or vimentin, nor was such a cell seen in a stab wound model used to assess reactive astrocytosis. While the number of these clusters was highly variable among rats, their size increased between 30 and 90 days. The data suggest that these nestin-expressing cells represent an early stage of the neoplastic process. It remains to be determined whether these cells become apparent at 30 days of age due to "dedifferentiation" of a local resident astrocyte or astrocyte precursor cell or migration of a relatively undifferentiated precursor/stem cell from the SVZ.
Jang
Taichang
T
Department of Surgery (Neurosurgery), University of Massachusetts Medical School, Worcester, MA 01655, USA.
Litofsky
N Scott
NS
Smith
Thomas W
TW
Ross
Alonzo H
AH
Recht
Lawrence D
LD
D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis*; D001930:Brain Injuries / Q000378:metabolism; D001932:Brain Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D002273:Carcinogens / Q000633:toxicity; D019070:Cell Lineage; D005038:Ethylnitrosourea / Q000633:toxicity; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D007381:Intermediate Filament Proteins / Q000096:biosynthesis*; D018613:Microscopy, Confocal; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D064231:Nestin; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D014408:Biomarkers, Tumor; D002273:Carcinogens; D005904:Glial Fibrillary Acidic Protein; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577486:Nes protein, rat; D064231:Nestin; D005038:Ethylnitrosourea