title: Alterations in cerebrospinal fluid proteins in a presymptomatic primary glioma model.
abstract: BACKGROUND
  Understanding the early relationship between brain tumor cells and their environment could lead to more sensitive biomarkers and new therapeutic strategies. We have been using a rodent model of neurocarcinogenesis in which all animals develop brain tumors by six months of age to establish two early landmarks in glioma development: the appearance of a nestin(+) cell at thirty days of age and the appearance of cellular hyperplasia between 60 and 120 days of age. We now report an assessment of the CSF proteome to determine the changes in protein composition that occur during this period.
  
  
  METHODS
  Nestin(+) cell clusters and microtumors were assessed in 63 ethylnitrosourea-exposed rats on 30, 60, and 90 days of age. CSF was obtained from the cisterna magna from 101 exposed and control rats at 30, 60, and 90 days and then analyzed using mass spectrometry. Differentially expressed peaks were isolated and identified.
  
  
  RESULTS
  Nestin(+) cells were noted in all ethylnitrosourea-exposed rats assessed pathologically. Small microtumors were noted in 0%, 18%, and 67% of 30-, 60-, and 90-day old rats, respectively (p<0.05, Chi square). False Discovery Rate analysis of peak intensities showed that the number of true discoveries with p<0.05 increased markedly with increasing age. Isolation and identification of highly differentially detected proteins at 90 days of age revealed increases in albumin and a fragment of α1 macroglobulin and alterations in glutathionylated transthyretin.
  
  
  CONCLUSIONS
  The presence of increased albumin, fragments of cerebrospinal fluid proteins, and glutathione breakdown in temporal association with the development of cellular hyperplasia, suggests that, similar to many other systemic cancers, inflammation and oxidative stress is playing an important early role in the host's response to brain tumor development and may be involved in affecting the early growth of brain tumor.
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: John C
authors.initials: JC
authors.lastname: Whitin
authors.forename: Taichang
authors.initials: T
authors.lastname: Jang
authors.forename: Milton
authors.initials: M
authors.lastname: Merchant
authors.forename: Tom T-S
authors.initials: TT
authors.lastname: Yu
authors.forename: Kenneth
authors.initials: K
authors.lastname: Lau
authors.forename: Benjamin
authors.initials: B
authors.lastname: Recht
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Cohen
authors.forename: Lawrence
authors.initials: L
authors.lastname: Recht
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000473:pathology; D001932:Brain Neoplasms / Q000134:cerebrospinal fluid* / Q000378:metabolism; D002556:Cerebrospinal Fluid Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D005038:Ethylnitrosourea / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000134:cerebrospinal fluid* / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D007381:Intermediate Filament Proteins / Q000096:biosynthesis*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D064231:Nestin; D020543:Proteome; D040901:Proteomics / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D015415:Biomarkers; D002556:Cerebrospinal Fluid Proteins; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577486:Nes protein, rat; D064231:Nestin; D020543:Proteome; D005978:Glutathione; D005038:Ethylnitrosourea