title: A cancer stem cell model for studying brain metastases from primary lung cancer.
abstract: BACKGROUND
  Brain metastases are most common in adults with lung cancer, predicting uniformly poor patient outcome, with a median survival of only months. Despite their frequency and severity, very little is known about tumorigenesis in brain metastases.
  
  
  METHODS
  We applied previously developed primary solid tumor-initiating cell models to the study of brain metastases from the lung to evaluate the presence of a cancer stem cell population. Patient-derived brain metastases (n = 20) and the NCI-H1915 cell line were cultured as stem-enriching tumorspheres. We used in vitro limiting-dilution and sphere-forming assays, as well as intracranial human-mouse xenograft models. To determine genes overexpressed in brain metastasis tumorspheres, we performed comparative transcriptome analysis. All statistical analyses were two-sided.
  
  
  RESULTS
  Patient-derived brain metastasis tumorspheres had a mean sphere-forming capacity of 33 spheres/2000 cells (SD = 33.40) and median stem-cell frequency of 1/60 (range = 0-1/141), comparable to that of primary brain tumorspheres (P = .53 and P = .20, respectively). Brain metastases also expressed CD15 and CD133, markers suggestive of a stemlike population. Through intracranial xenotransplantation, brain metastasis tumorspheres were found to recapitulate the original patient tumor heterogeneity. We also identified several genes overexpressed in brain metastasis tumorspheres as statistically significant predictors of poor survival in primary lung cancer.
  
  
  CONCLUSIONS
  For the first time, we demonstrate the presence of a stemlike population in brain metastases from the lung. We also show that NCI-H1915 tumorspheres could be useful in studying self-renewal and tumor initiation in brain metastases. Our candidate genes may be essential to metastatic stem cell populations, where pathway interference may be able to transform a uniformly fatal disease into a more localized and treatable one.
authors: Department of Biochemistry and Biomedical Sciences, Faculty of HealthSciences, McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Canada.
authors: Sara M
authors: SM
authors: Nolte
authors: Chitra
authors: C
authors: Venugopal
authors: Nicole
authors: N
authors: McFarlane
authors: Olena
authors: O
authors: Morozova
authors: Robin M
authors: RM
authors: Hallett
authors: Erin
authors: E
authors: O'Farrell
authors: Branavan
authors: B
authors: Manoranjan
authors: Naresh K
authors: NK
authors: Murty
authors: Paula
authors: P
authors: Klurfan
authors: Edward
authors: E
authors: Kachur
authors: John P
authors: JP
authors: Provias
authors: Forough
authors: F
authors: Farrokhyar
authors: John A
authors: JA
authors: Hassell
authors: Marco
authors: M
authors: Marra
authors: Sheila K
authors: SK
authors: Singh
mesh_terms: D000328:Adult; D000818:Animals; D001932:Brain Neoplasms / Q000401:mortality* / Q000556:secondary*; D045744:Cell Line, Tumor; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008175:Lung Neoplasms / Q000401:mortality* / Q000473:pathology*; D008297:Male; D051379:Mice; D014411:Neoplastic Stem Cells; D012334:RNA, Neoplasm / Q000032:analysis; D017423:Sequence Analysis, RNA; D016019:Survival Analysis; D059467:Transcriptome; D014183:Transplantation, Heterologous
chemical_list: D012334:RNA, Neoplasm