title: Mesenchymal Tumors Can Derive from Ng2/Cspg4-Expressing Pericytes with β-Catenin Modulating the Neoplastic Phenotype.
abstract: The cell of origin for most mesenchymal tumors is unclear. One cell type that contributes to this lineages is the pericyte, a cell expressing Ng2/Cspg4. Using lineage tracing, we demonstrated that bone and soft tissue sarcomas driven by the deletion of the Trp53 tumor suppressor, or desmoid tumors driven by a mutation in Apc, can derive from cells expressing Ng2/Cspg4. Deletion of the Trp53 tumor suppressor gene in these cells resulted in the bone and soft tissue sarcomas that closely resemble human sarcomas, while stabilizing β-catenin in this same cell type caused desmoid tumors. Comparing expression between Ng2/Cspg4-expressing pericytes lacking Trp53 and sarcomas that arose from deletion of Trp53 showed inhibition of β-catenin signaling in the sarcomas. Activation of β-catenin inhibited the formation and growth of sarcomas. Thus, pericytes can be a cell of origin for mesenchymal tumors, and β-catenin dysregulation plays an important role in the neoplastic phenotype.
authors.affiliation: Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G1X8, Canada; Department of Orthopaedic Surgery, Tokyo Medical and Dental, University Graduate School and Faculty of Medicine, Tokyo 113-8510, Japan; Department of Physiology and Cell Biology, Graduate School and Faculty of Medicine, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Sato
authors.affiliation: Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G1X8, Canada; Department of Orthopaedic Surgery, Duke University, Durham, NC 27710, USA.
authors.forename: Yuning J
authors.initials: YJ
authors.lastname: Tang
authors.affiliation: Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G1X8, Canada.
authors.forename: Qingxia
authors.initials: Q
authors.lastname: Wei
authors.affiliation: Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G1X8, Canada.
authors.forename: Makoto
authors.initials: M
authors.lastname: Hirata
authors.affiliation: Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G1X8, Canada.
authors.forename: Angela
authors.initials: A
authors.lastname: Weng
authors.affiliation: Department of Orthopaedic Surgery, Seoul National University Hospital, Seoul 151-742, Republic of Korea.
authors.forename: Ilkyu
authors.initials: I
authors.lastname: Han
authors.affiliation: Department of Orthopaedic Surgery, Tokyo Medical and Dental, University Graduate School and Faculty of Medicine, Tokyo 113-8510, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Okawa
authors.affiliation: Department of Physiology and Cell Biology, Graduate School and Faculty of Medicine, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Shu
authors.initials: S
authors.lastname: Takeda
authors.affiliation: Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G1X8, Canada.
authors.forename: Heather
authors.initials: H
authors.lastname: Whetstone
authors.affiliation: Department of Orthopaedic Surgery, Duke University, Durham, NC 27710, USA.
authors.forename: Puvindran
authors.initials: P
authors.lastname: Nadesan
authors.affiliation: Department of Radiation Oncology, Duke University, Durham, NC 27710, USA; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Kirsch
authors.affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
authors.forename: Jay S
authors.initials: JS
authors.lastname: Wunder
authors.affiliation: Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G1X8, Canada; Department of Orthopaedic Surgery, Duke University, Durham, NC 27710, USA. Electronic address: ben.alman@duke.edu.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Alman
mesh_terms: D000818:Animals; D000941:Antigens / Q000378:metabolism*; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000502:physiology; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D008297:Male; D008648:Mesoderm / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000502:physiology; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D020286:Pericytes / Q000378:metabolism*; D010641:Phenotype; D011509:Proteoglycans / Q000378:metabolism*; D012509:Sarcoma / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D000941:Antigens; D011508:Chondroitin Sulfate Proteoglycans; D011509:Proteoglycans; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D000099216:Chondroitin Sulfate Proteoglycan 4