title: Identification of CD146 as a marker enriched for tumor-propagating capacity reveals targetable pathways in primary human sarcoma.
abstract: Tumor-propagating cells (TPCs) are believed to drive cancer initiation, progression and recurrence. These cells are characterized by enhanced tumorigenicity and self-renewal. The ability to identify such cells in primary human sarcomas relies on the dye exclusion ability of tumor side population (SP) cells. Here, we performed a high-throughput cell surface antigen screen and found that CD146 is enriched in the SP population. In vivo serial transplantation assays showed that CD146+ cells are highly tumorigenic, capable of self-renewal and thus enriches for the TPC population. In addition, depletion of SP cells from the CD146+ population show that CD146+ cells and SP cells are a distinct and overlapping TPC populations. Gene expression profiling of CD146+ and SP cells revealed multiple pathways commonly upregulated in both of these populations. Inhibition of one of these upregulated pathways, Notch signaling, significantly reduced tumor growth and self-renewal. Our data demonstrate that CD146 is an effective cell surface marker for enriching TPCs in primary human sarcomas. Targeting differentially activated pathways in TPCs may provide new therapeutic strategies for treating sarcoma.
authors.affiliation: Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Qingxia
authors.initials: Q
authors.lastname: Wei
authors.affiliation: Department of Orthopaedic Surgery, Duke University, Durham, NC, USA.|Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
authors.forename: Yuning J
authors.initials: YJ
authors.lastname: Tang
authors.affiliation: The Donnelly Centre, University of Toronto, Toronto, ON, Canada.
authors.forename: Veronique
authors.initials: V
authors.lastname: Voisin
authors.affiliation: Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Shingo
authors.initials: S
authors.lastname: Sato
authors.affiliation: Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Makoto
authors.initials: M
authors.lastname: Hirata
authors.affiliation: Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Heather
authors.initials: H
authors.lastname: Whetstone
authors.affiliation: Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Ilkyu
authors.initials: I
authors.lastname: Han
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
authors.forename: Laurie
authors.initials: L
authors.lastname: Ailles
authors.affiliation: The Donnelly Centre, University of Toronto, Toronto, ON, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Bader
authors.affiliation: Samuel Lunenfeld Research Institute, Division of Orthopaedic Surgery, Department of Surgery, Mount Sinai Hospital, Toronto, ON, Canada.|University Musculoskeletal Oncology Unit, Division of Orthopaedic Surgery, Department of Surgery, Mount Sinai Hospital, Toronto, ON, Canada.
authors.forename: Jay
authors.initials: J
authors.lastname: Wunder
authors.affiliation: Department of Orthopaedic Surgery, Duke University, Durham, NC, USA.|Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Alman
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D051929:CD146 Antigen / Q000235:genetics* / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D005434:Flow Cytometry; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D012516:Osteosarcoma / Q000235:genetics / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012509:Sarcoma / Q000235:genetics / Q000473:pathology; D058985:Side-Population Cells / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D051929:CD146 Antigen; D004151:Dipeptides; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester
keywords: CD146; cell signaling; human sarcoma; self-renewal; tumor propagating cells