title: Glioma-associated stem cells: a novel class of tumor-supporting cells able to predict prognosis of human low-grade gliomas.
abstract: BACKGROUND
  Translational medicine aims at transferring advances in basic science research into new approaches for diagnosis and treatment of diseases. Low-grade gliomas (LGG) have a heterogeneous clinical behavior that can be only partially predicted employing current state-of-the-art markers, hindering the decision-making process. To deepen our comprehension on tumor heterogeneity, we dissected the mechanism of interaction between tumor cells and relevant components of the neoplastic environment, isolating, from LGG and high-grade gliomas (HGG), proliferating stem cell lines from both the glioma stroma and, where possible, the neoplasm.
  
  
  RESULTS
  We isolated glioma-associated stem cells (GASC) from LGG (n=40) and HGG (n=73). GASC showed stem cell features, anchorage-independent growth, and supported the malignant properties of both A172 cells and human glioma-stem cells, mainly through the release of exosomes. Finally, starting from GASC obtained from HGG (n=13) and LGG (n=12) we defined a score, based on the expression of 9 GASC surface markers, whose prognostic value was assayed on 40 subsequent LGG-patients. At the multivariate Cox analysis, the GASC-based score was the only independent predictor of overall survival and malignant progression free-survival.
  
  
  CONCLUSIONS
  The microenvironment of both LGG and HGG hosts non-tumorigenic multipotent stem cells that can increase in vitro the biological aggressiveness of glioma-initiating cells through the release of exosomes. The clinical importance of this finding is supported by the strong prognostic value associated with the characteristics of GASC. This patient-based approach can provide a groundbreaking method to predict prognosis and to exploit novel strategies that target the tumor stroma.
authors.affiliation: Department of Medical and Biological Sciences, University of Udine, Udine, Italy.
authors.forename: Evgenia
authors.initials: E
authors.lastname: Bourkoula
authors.forename: Damiano
authors.initials: D
authors.lastname: Mangoni
authors.forename: Tamara
authors.initials: T
authors.lastname: Ius
authors.forename: Anja
authors.initials: A
authors.lastname: Pucer
authors.forename: Miriam
authors.initials: M
authors.lastname: Isola
authors.forename: Daniela
authors.initials: D
authors.lastname: Musiello
authors.forename: Stefania
authors.initials: S
authors.lastname: Marzinotto
authors.forename: Barbara
authors.initials: B
authors.lastname: Toffoletto
authors.forename: Marisa
authors.initials: M
authors.lastname: Sorrentino
authors.forename: Anita
authors.initials: A
authors.lastname: Palma
authors.forename: Federica
authors.initials: F
authors.lastname: Caponnetto
authors.forename: Giorgia
authors.initials: G
authors.lastname: Gregoraci
authors.forename: Marco
authors.initials: M
authors.lastname: Vindigni
authors.forename: Stefano
authors.initials: S
authors.lastname: Pizzolitto
authors.forename: Giovanni
authors.initials: G
authors.lastname: Falconieri
authors.forename: Giovanna
authors.initials: G
authors.lastname: De Maglio
authors.forename: Vanna
authors.initials: V
authors.lastname: Pecile
authors.forename: Maria Elisabetta
authors.initials: ME
authors.lastname: Ruaro
authors.forename: Giorgia
authors.initials: G
authors.lastname: Gri
authors.forename: Pietro
authors.initials: P
authors.lastname: Parisse
authors.forename: Loredana
authors.initials: L
authors.lastname: Casalis
authors.forename: Giacinto
authors.initials: G
authors.lastname: Scoles
authors.forename: Miran
authors.initials: M
authors.lastname: Skrap
authors.forename: Carlo Alberto
authors.initials: CA
authors.lastname: Beltrami
authors.forename: Antonio Paolo
authors.initials: AP
authors.lastname: Beltrami
authors.forename: Daniela
authors.initials: D
authors.lastname: Cesselli
mesh_terms: D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002460:Cell Line; D049109:Cell Proliferation; D055354:Exosomes / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D018625:Microscopy, Atomic Force; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D015999:Multivariate Analysis; D000071317:Nanog Homeobox Protein; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment
chemical_list: D018398:Homeodomain Proteins; D008164:Luminescent Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human
keywords: Exosomes; Glioma-associated stem cells; Human glioma; Low-grade glioma; Personalized medicine; Prognostic score