title: Intrinsic Astrocyte Heterogeneity Influences Tumor Growth in Glioma Mouse Models.
abstract: The influence of cellular origin on glioma pathogenesis remains elusive. We previously showed that mutations inactivating Rb and Pten and activating Kras transform astrocytes and induce tumorigenesis throughout the adult mouse brain. However, it remained unclear whether astrocyte subpopulations were susceptible to these mutations. We therefore used genetic lineage tracing and fate mapping in adult conditional, inducible genetically engineered mice to monitor transformation of glial fibrillary acidic protein (GFAP) and glutamate aspartate transporter (GLAST) astrocytes and immunofluorescence to monitor cellular composition of the tumor microenvironment over time. Because considerable regional heterogeneity exists among astrocytes, we also examined the influence of brain region on tumor growth. GFAP astrocyte transformation induced uniformly rapid, regionally independent tumor growth, but transformation of GLAST astrocytes induced slowly growing tumors with significant regional bias. Transformed GLAST astrocytes had reduced proliferative response in culture and in vivo and malignant progression was delayed in these tumors. Recruited glial cells, including proliferating astrocytes, oligodendrocyte progenitors and microglia, were the majority of GLAST, but not GFAP astrocyte-derived tumors and their abundance dynamically changed over time. These results suggest that intrinsic astrocyte heterogeneity, and perhaps regional brain microenvironment, significantly contributes to glioma pathogenesis.
authors.affiliation: Curriculum in Genetics and Molecular Biology, University of North Carolina School of Medicine, Chapel Hill, NC.
authors.forename: David M
authors.initials: DM
authors.lastname: Irvin
authors.affiliation: Pathobiology and Translational Science Graduate Program, University of North Carolina School of Medicine, Chapel Hill, NC.|Division of Neuropathology, Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, NC.
authors.forename: Robert S
authors.initials: RS
authors.lastname: McNeill
authors.affiliation: Division of Neuropathology, Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, NC.
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Bash
authors.affiliation: Curriculum in Genetics and Molecular Biology, University of North Carolina School of Medicine, Chapel Hill, NC.|Pathobiology and Translational Science Graduate Program, University of North Carolina School of Medicine, Chapel Hill, NC.|Division of Neuropathology, Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, NC.|Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC.|Department of Neurology and Neurosciences Center, University of North Carolina School of Medicine, Chapel Hill, NC.
authors.forename: C Ryan
authors.initials: CR
authors.lastname: Miller
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000737:chemistry / Q000145:classification / Q000473:pathology*; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology*; D019070:Cell Lineage; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D018450:Disease Progression; D027341:Excitatory Amino Acid Transporter 1 / Q000032:analysis; D055879:Gene Knock-In Techniques; D016158:Genes, p53; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology*; D007091:Image Processing, Computer-Assisted; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000032:analysis; D059016:Tumor Microenvironment
chemical_list: D027341:Excitatory Amino Acid Transporter 1; D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; C493393:Slc1a3 protein, mouse; C528900:glial fibrillary astrocytic protein, mouse
keywords: astrocytes; genetically engineered mice; glioma; heterogeneity; microenvironment