title: Cell cycle deregulation and mosaic loss of Ext1 drive peripheral chondrosarcomagenesis in the mouse and reveal an intrinsic cilia deficiency.
abstract: Peripheral chondrosarcoma (PCS) develops as malignant transformation of an osteochondroma, a benign cartilaginous outgrowth at the bone surface. Its invasive, lobular growth despite low-grade histology suggests a loss of chondrocyte polarity. The known genetics of osteochondromagenesis include mosaic loss of EXT1 or EXT2 in both hereditary and non-hereditary cases. The most frequent genetic aberrations in human PCS also include disruptions of CDKN2A or TP53. In order to test the sufficiency of either of these to drive progression of an osteochondroma to PCS, we added conditional loss of Trp53 or Ink4a/Arf in an Ext1-driven mouse model of osteochondromagenesis. Each additional tumour suppressor silencing efficiently drove the development of growths that mimic human PCS. As in humans, lobules developed from both Ext1-null and Ext1-functional clones within osteochondromas. Assessment of their orientation revealed an absence of primary cilia in the majority of mouse PCS chondrocytes, which was corroborated in human PCSs. Loss of primary cilia may be responsible for the lost polarity phenotype ascribed to PCS. Cilia deficiency blocks proliferation in physeal chondrocytes, but cell cycle deregulation is sufficient to rescue chondrocyte proliferation following deciliation. This provides a basis of selective pressure for the frequent cell-cycle regulator silencing observed in peripheral chondrosarcomagenesis. Mosaic loss of Ext1 combined with loss of cell cycle regulators promotes peripheral chondrosarcomagenesis in the mouse and reveals deficient ciliogenesis in both the model and the human disease, explaining biological behaviour including lobular and invasive growth.
authors: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.|Department of Histology and Pathology, University of Navarra, Pamplona, Spain.
authors: Carlos E
authors: CE
authors: de Andrea
authors: Department of Orthopaedics, University of Utah, Salt Lake City, Utah, USA.|Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
authors: Ju-Fen
authors: JF
authors: Zhu
authors: Department of Orthopaedics, University of Utah, Salt Lake City, Utah, USA.|Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
authors: Huifeng
authors: H
authors: Jin
authors: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors: Judith V M G
authors: JV
authors: Bovée
authors: Department of Orthopaedics, University of Utah, Salt Lake City, Utah, USA.|Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
authors: Kevin B
authors: KB
authors: Jones
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics*; D063646:Carcinogenesis / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D019902:Chondrocytes / Q000502:physiology; D002813:Chondrosarcoma / Q000235:genetics*; D002923:Cilia / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D004195:Disease Models, Animal; D019426:Integrases / Q000235:genetics; D008822:Mice, Transgenic; D009030:Mosaicism; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics*; D015831:Osteochondroma / Q000235:genetics*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D000099058:Exostosin 1
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D016159:Tumor Suppressor Protein p53; D017351:N-Acetylglucosaminyltransferases; D000099058:Exostosin 1; C045073:Cre recombinase; D019426:Integrases
keywords: chondrosarcoma; mouse genetic model; osteochondroma; primary cilium; tumour suppressor
references: Matrix Biol. 2006 Apr;25(3):158-65
references: 16386413
references: Genes Chromosomes Cancer. 1999 Nov;26(3):237-46
references: 10502322
references: Am J Hum Genet. 1999 Sep;65(3):689-98
references: 10441575
references: Acta Orthop Scand. 1997 Aug;68(4):396-400
references: 9310048
references: Genes Dev. 2003 Dec 15;17(24):3112-26
references: 14681207
references: Clin Orthop Relat Res. 2003 Jun;(411):193-206
references: 12782876
references: Genesis. 2002 May;33(1):48-54
references: 12001069
references: Nat Genet. 2001 Dec;29(4):418-25
references: 11694875
references: Dev Biol. 2007 May 1;305(1):202-16
references: 17359961
references: J Bone Joint Surg Am. 2009 May;91(5):1063-72
references: 19411454
references: Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2054-9
references: 20080592
references: J Orthop Res. 2013 Apr;31(4):651-7
references: 23192691
references: Oncogene. 2013 Nov 21;32(47):5388-96
references: 23246966
references: Oncogene. 2012 Mar 1;31(9):1095-104
references: 21804604
references: Bone. 2012 Jan;50(1):79-84
references: 21930256
references: J Am Acad Orthop Surg. 2010 Oct;18(10):608-15
references: 20889950
references: Am J Pathol. 2010 Oct;177(4):1946-57
references: 20813973
references: Lab Invest. 2010 Jul;90(7):1091-101
references: 20421870
references: Proc Natl Acad Sci U S A. 2010 Jun 15;107(24):10932-7
references: 20534475
references: Mod Pathol. 2012 Sep;25(9):1275-83
references: 22555180