Neural stem cell markers, nestin and musashi proteins, in the progression of human glioma: correlation of nestin with prognosis of patient survival.
BACKGROUND
The IF protein nestin and the RNA-binding protein musashi are expressed by neural progenitor cells during CNS development. Their expression in glial tumors was evaluated by immunohistochemistry, and the histopathological scores correlated with levels of cysteine cathepsins that are known prognostic markers in several tumors.


METHODS
The levels of nestin, musashi, and cathepsins B and L were assessed by immunohistochemical analysis of biopsies from 87 patients with primary CNS tumors. To confirm the immunohistochemical data, nestin expression was analyzed by real-time PCR in 12 brain tumor biopsies. The exact location of nestin-positive cells was determined by mapping the distribution of nestin in a highly invasive human glioma xenograft model.


RESULTS
Immunostaining revealed nestin to be expressed in 95.8% and musashi in 80% of the patient biopsies. The total IHC score for nestin was significantly higher in high- than in low-grade tumors (P < .0001). No difference was observed for musashi (P = .11). Real-time PCR of nestin expression confirmed the immunohistochemical data. Nestin expression was shown to be a strong prognostic marker for decreased overall survival (P = .0001), whereas musashi expression has no prognostic significance. Moreover, nestin was shown by Cox regression analysis to be a stronger prognostic marker than cathepsins B and L. IHC staining of nestin in a xenograft model showed that its expression is localized mainly in the invasive tumor cells at the tumor periphery.


CONCLUSIONS
Nestin is shown to be a strong prognostic marker for glioma malignancy. The presented data links the invasive glioma cells to CNS precursor cells, indicating that the most malignant cells in the gliomas may well be closely related to the glioma stem cells.
Strojnik
Tadej
T
Department of Neurosurgery, Maribor Teaching Hospital, SI-2000 Maribor, Slovenia. t.strojnik@siol.net
Røsland
Gro Vatne
GV
Sakariassen
Per Oystein
PO
Kavalar
Rajko
R
Lah
Tamara
T
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D002401:Cathepsin B / Q000378:metabolism; D056668:Cathepsin L; D002403:Cathepsins / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003546:Cysteine Endopeptidases / Q000378:metabolism; D005260:Female; D005910:Glioma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D064231:Nestin; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D051381:Rats; D015996:Survival Rate
D014408:Biomarkers, Tumor; D007381:Intermediate Filament Proteins; C491297:MSI1 protein, human; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577486:Nes protein, rat; D064231:Nestin; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L; C534280:Ctsl protein, rat