title: Silencing of CD44 gene expression in human 143-B osteosarcoma cells promotes metastasis of intratibial tumors in SCID mice.
abstract: Osteosarcoma (OS) is the most frequent primary malignant bone cancer in children and adolescents with a high propensity for lung metastasis. Therefore, it is of great importance to identify molecular markers leading to increased metastatic potential in order to devise more effective therapeutic strategies that suppress metastasis, the major cause of death in OS. CD44, the principal receptor for the extracellular matrix component hyaluronan (HA), is frequently found overexpressed in tumor cells and has been implicated in metastatic spread in various cancer types. Here, we investigated the effects of stable shRNA-mediated silencing of CD44 gene products on in vitro and in vivo metastatic properties of the highly metastatic human 143-B OS cell line. In vitro, CD44 knockdown resulted in a 73% decrease in the adhesion to HA, a 57% decrease in the migration rate in a trans-filter migration assay, and a 28% decrease in the cells' capacity for anchorage-independent growth in soft agar compared to the control cells, implicating that CD44 expression contributes to the metastatic activity of 143-B cells. However, making use of an orthotopic xenograft OS mouse model, we demonstrated that reduced CD44 expression facilitated primary tumor growth and formation of pulmonary metastases. The enhanced malignant phenotype was associated with decreased adhesion to HA and reduced expression of the tumor suppressor merlin in vivo. In conclusion, our study identified CD44 as a metastasis suppressor in this particular experimental OS model.
authors.affiliation: Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, Zurich, Switzerland.
authors.forename: Ana
authors.initials: A
authors.lastname: Gvozdenovic
authors.forename: Matthias J E
authors.initials: MJ
authors.lastname: Arlt
authors.forename: Carmen
authors.initials: C
authors.lastname: Campanile
authors.forename: Patrick
authors.initials: P
authors.lastname: Brennecke
authors.forename: Knut
authors.initials: K
authors.lastname: Husmann
authors.forename: Walter
authors.initials: W
authors.lastname: Born
authors.forename: Roman
authors.initials: R
authors.lastname: Muff
authors.forename: Bruno
authors.initials: B
authors.lastname: Fuchs
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics* / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000556:secondary; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D012516:Osteosarcoma / Q000235:genetics* / Q000473:pathology*; D034622:RNA Interference; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000235:genetics
chemical_list: D018960:Hyaluronan Receptors
references.citation: Cancer Res. 1995 May 1;55(9):1831-5
references.pmid: 7537174
references.citation: Biochim Biophys Acta. 2012 Dec;1826(2):400-6
references.pmid: 22750751
references.citation: J Biol Chem. 1994 Sep 23;269(38):23387-90
references.pmid: 8089100
references.citation: J Orthop Res. 2011 Jun;29(6):938-46
references.pmid: 21284029
references.citation: Neurogenetics. 1998 Dec;2(1):73-4
references.pmid: 9933303
references.citation: Cancer Res. 1993 Oct 15;53(20):4754-6
references.pmid: 7691404
references.citation: Cancer Invest. 2009 May;27(4):435-42
references.pmid: 19212826
references.citation: J Pediatr Hematol Oncol. 2010 Aug;32(6):e213-7
references.pmid: 20562647
references.citation: Orphanet J Rare Dis. 2007 Jan 23;2:6
references.pmid: 17244349
references.citation: Int J Cancer. 1975 Jan 15;15(1):23-9
references.pmid: 165148
references.citation: Cancer Res. 1993 Aug 15;53(16):3830-8
references.pmid: 8339295
references.citation: J Biol Chem. 2010 Oct 1;285(40):30548-57
references.pmid: 20663864
references.citation: J Mol Histol. 2004 Mar;35(3):211-31
references.pmid: 15339042
references.citation: Int J Oncol. 2006 Jul;29(1):175-83
references.pmid: 16773198
references.citation: Proc Natl Acad Sci U S A. 2004 Dec 28;101(52):18081-6
references.pmid: 15596723
references.citation: J Biol Chem. 2011 Nov 18;286(46):40376-85
references.pmid: 21965655
references.citation: Genes Dev. 1998 Apr 15;12(8):1121-33
references.pmid: 9553042
references.citation: Virchows Arch. 2008 Jan;452(1):49-55
references.pmid: 18026989
references.citation: Clin Orthop Relat Res. 2002 Mar;(396):184-90
references.pmid: 11859242
references.citation: J Cancer Res Clin Oncol. 1999 Nov;125(11):646-52
references.pmid: 10541973
references.citation: Cell. 1990 Jun 29;61(7):1303-13
references.pmid: 1694723
references.citation: Int J Cancer. 1994 Jul 15;58(2):275-84
references.pmid: 7517921
references.citation: Nat Rev Mol Cell Biol. 2003 Jan;4(1):33-45
references.pmid: 12511867
references.citation: Prostate. 1998 Feb 15;34(3):162-8
references.pmid: 9492843
references.citation: Exp Cell Res. 2005 Jul 1;307(1):194-203
references.pmid: 15922739
references.citation: Photochem Photobiol. 2012 May-Jun;88(3):721-7
references.pmid: 22268498
references.citation: Cancer Res. 2002 Oct 1;62(19):5543-50
references.pmid: 12359766
references.citation: Cancer Res. 2005 Aug 1;65(15):6755-63
references.pmid: 16061657
references.citation: Mol Cell Biol. 1991 Nov;11(11):5446-53
references.pmid: 1922057
references.citation: Cancer Res. 1994 Mar 1;54(5):1381-7
references.pmid: 7509720
references.citation: Oncologist. 2004;9(4):422-41
references.pmid: 15266096
references.citation: Am J Pathol. 2007 Jul;171(1):274-86
references.pmid: 17591972
references.citation: N Engl J Med. 1986 Jun 19;314(25):1600-6
references.pmid: 3520317
references.citation: Genes Dev. 2001 Apr 15;15(8):968-80
references.pmid: 11316791
references.citation: Curr Protein Pept Sci. 2010 Sep;11(6):471-84
references.pmid: 20491622
references.citation: Cancer Res. 1997 Mar 1;57(5):846-9
references.pmid: 9041184
references.citation: Cancer Res. 1993 Sep 15;53(18):4197-203
references.pmid: 7689929
references.citation: Clin Invest Med. 2009 Apr 01;32(2):E180-8
references.pmid: 19331807