title: Microscopic DTI accurately identifies early glioma cell migration: correlation with multimodal imaging in a new glioma stem cell model.
abstract: Monitoring glioma cell infiltration in the brain is critical for diagnosis and therapy. Using a new glioma Glio6 mouse model derived from human stem cells we show how diffusion tensor imaging (DTI) may predict glioma cell migration/invasion. In vivo multiparametric MRI was performed at one, two and three months of Glio6 glioma growth (Glio6 (n = 6), sham (n = 3)). This longitudinal study reveals the existence of a time window to study glioma cell/migration/invasion selectively. Indeed, at two months only Glio6 cell invasion was detected, while tumor mass formation, edema, blood-brain barrier leakage and tumor angiogenesis were detected later, at three months. To robustly confirm the potential of DTI for detecting glioma cell migration/invasion, a microscopic 3D-DTI (80 μm isotropic spatial resolution) technique was developed and applied to fixed mouse brains (Glio6 (n = 6), sham (n = 3)). DTI changes were predominant in the corpus callosum (CC), a known path of cell migration. Fractional anisotropy (FA) and perpendicular diffusivity (D⊥) changes derived from ex vivo microscopic 3D-DTI were significant at two months of tumor growth. In the caudate putamen an FA increase of +38% (p < 0.001) was observed, while in the CC a - 28% decrease in FA (p < 0.005) and a + 95% increase in D⊥(p < 0.005) were observed. In the CC, DTI changes and fluorescent Glio6 cell density obtained by two-photon microscopy in the same brains were correlated (p < 0.001, r = 0.69), validating FA and D⊥as early quantitative biomarkers to detect glioma cell migration/invasion. The origin of DTI changes was assessed by electron microscopy of the same tract, showing axon bundle disorganization. During the first two months, Glio6 cells display a migratory phenotype without being associated with the constitution of a brain tumor mass. This offers a unique opportunity to apply microscopic 3D-DTI and to validate DTI parameters FA and D⊥as biomarkers for glioma cell invasion.
authors.affiliation: Inserm U1205, Grenoble, France.
authors.forename: Ulysse
authors.initials: U
authors.lastname: Gimenez
authors.affiliation: Inserm U1205, Grenoble, France.
authors.forename: Adriana-T
authors.initials: AT
authors.lastname: Perles-Barbacaru
authors.affiliation: Inserm U1205, Grenoble, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Millet
authors.affiliation: Grenoble Institut des Neurosciences Inserm U836, Grenoble, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Appaix
authors.affiliation: Inserm U1205, Grenoble, France.
authors.forename: Michele
authors.initials: M
authors.lastname: El-Atifi
authors.affiliation: Grenoble Institut des Neurosciences Inserm U836, Grenoble, France.
authors.forename: Karin
authors.initials: K
authors.lastname: Pernet-Gallay
authors.affiliation: Inserm U1205, Grenoble, France.
authors.forename: Boudewijn
authors.initials: B
authors.lastname: van der Sanden
authors.affiliation: Inserm U1205, Grenoble, France.
authors.forename: François
authors.initials: F
authors.lastname: Berger
authors.affiliation: Inserm U1205, Grenoble, France. hana.lahrech@univ-grenoble-alpes.fr.
authors.forename: Hana
authors.initials: H
authors.lastname: Lahrech
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D058948:Cell Tracking / Q000379:methods; D003337:Corpus Callosum / Q000000981:diagnostic imaging / Q000473:pathology*; D056324:Diffusion Tensor Imaging / Q000379:methods*; D005260:Female; D005910:Glioma / Q000000981:diagnostic imaging / Q000473:pathology*; D021621:Imaging, Three-Dimensional / Q000379:methods*; D008137:Longitudinal Studies; D051379:Mice; D008819:Mice, Nude; D036641:Microscopy, Fluorescence, Multiphoton / Q000379:methods; D064847:Multimodal Imaging / Q000379:methods*; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000473:pathology*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013223:Statistics as Topic
keywords: DTI; animal model; axonal disorganization; glioma migration; two photon