title: Identification of three molecular and functional subtypes in canine hemangiosarcoma through gene expression profiling and progenitor cell characterization.
abstract: Canine hemangiosarcomas have been ascribed to an endothelial origin based on histologic appearance; however, recent findings suggest that these tumors may arise instead from hematopoietic progenitor cells. To clarify this ontogenetic dilemma, we used genome-wide expression profiling of primary hemangiosarcomas and identified three distinct tumor subtypes associated with angiogenesis (group 1), inflammation (group 2), and adipogenesis (group 3). Based on these findings, we hypothesized that a common progenitor may differentiate into the three tumor subtypes observed in our gene profiling experiment. To investigate this possibility, we cultured hemangiosarcoma cell lines under normal and sphere-forming culture conditions to enrich for tumor cell progenitors. Cells from sphere-forming cultures displayed a robust self-renewal capacity and exhibited genotypic, phenotypic, and functional properties consistent with each of the three molecular subtypes seen in primary tumors, including expression of endothelial progenitor cell (CD133 and CD34) and endothelial cell (CD105, CD146, and αvβ3 integrin) markers, expression of early hematopoietic (CD133, CD117, and CD34) and myeloid (CD115 and CD14) differentiation markers in parallel with increased phagocytic capacity, and acquisition of adipogenic potential. Collectively, these results suggest that canine hemangiosarcomas arise from multipotent progenitors that differentiate into distinct subtypes. Improved understanding of the mechanisms that determine the molecular and phenotypic differentiation of tumor cells in vivo could change paradigms regarding the origin and progression of endothelial sarcomas.
authors: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota.
authors: Brandi H
authors: BH
authors: Gorden
authors: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota.
authors: Jong-Hyuk
authors: JH
authors: Kim
authors: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors: Aaron L
authors: AL
authors: Sarver
authors: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota.
authors: Aric M
authors: AM
authors: Frantz
authors: Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina; Center for Comparative Medicine and Translational Research, North Carolina State University, Raleigh, North Carolina; Cancer Genetics Program, University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina.
authors: Matthew
authors: M
authors: Breen
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
authors: Kerstin
authors: K
authors: Lindblad-Toh
authors: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota; Department of Veterinary Population Medicine, University of Minnesota, Saint Paul, Minnesota; Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota.
authors: Timothy D
authors: TD
authors: O'Brien
authors: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors: Leslie C
authors: LC
authors: Sharkey
authors: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota; Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota.
authors: Jaime F
authors: JF
authors: Modiano
authors: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota. Electronic address: edickers@umn.edu.
authors: Erin B
authors: EB
authors: Dickerson
mesh_terms: D000818:Animals; D004283:Dog Diseases / Q000235:genetics* / Q000473:pathology; D004285:Dogs; D020869:Gene Expression Profiling; D006394:Hemangiosarcoma / Q000235:genetics / Q000473:pathology / Q000662:veterinary*; D016130:Immunophenotyping; D014411:Neoplastic Stem Cells / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis