title: Expression of the chemokine receptor CXCR7 in CXCR4-expressing human 143B osteosarcoma cells enhances lung metastasis of intratibial xenografts in SCID mice.
abstract: More effective treatment of metastasizing osteosarcoma with a current mean 5-year survival rate of less than 20% requires more detailed knowledge on mechanisms and key regulatory molecules of the complex metastatic process. CXCR4, the receptor of the chemokine CXCL12, has been reported to promote tumor progression and metastasis in osteosarcoma. CXCR7 is a recently deorphanized CXCL12-scavenging receptor with so far not well-defined functions in tumor biology. The present study focused on a potential malignancy enhancing function of CXCR7 in interaction with CXCR4 in osteosarcoma, which was investigated in an intratibial osteosarcoma model in SCID mice, making use of the human 143B osteosarcoma cell line that spontaneously metastasizes to the lung and expresses endogenous CXCR4. 143B osteosarcoma cells stably expressing LacZ (143B-LacZ cells) were retrovirally transduced with a gene encoding HA-tagged CXCR7 (143B-LacZ-X7-HA cells). 143B-LacZ-X7-HA cells co-expressing CXCR7 and CXCR4 exhibited CXCL12 scavenging and enhanced adhesion to IL-1β-activated HUVEC cells compared to 143B-LacZ cells expressing CXCR4 alone. SCID mice intratibially injected with 143B-LacZ-X7-HA cells had significantly (p<0.05) smaller primary tumors, but significantly (p<0.05) higher numbers of lung metastases than mice injected with 143B-LacZ cells. Unexpectedly, 143B-LacZ-X7-HA cells, unlike 143B-LacZ cells, also metastasized with high incidence to the auriculum cordis. In conclusion, expression of the CXCL12 scavenging receptor CXCR7 in the CXCR4-expressing human 143B osteosarcoma cell line enhances its metastatic activity in intratibial primary tumors in SCID mice that predominantly metastasize to the lung and thereby closely mimic the human disease. These findings point to CXCR7 as a target, complementary to previously proposed CXCR4, for more effective metastasis-suppressive treatment in osteosarcoma.
authors.affiliation: Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, Zürich, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Brennecke
authors.forename: Matthias J E
authors.initials: MJ
authors.lastname: Arlt
authors.forename: Roman
authors.initials: R
authors.lastname: Muff
authors.forename: Carmen
authors.initials: C
authors.lastname: Campanile
authors.forename: Ana
authors.initials: A
authors.lastname: Gvozdenovic
authors.forename: Knut
authors.initials: K
authors.lastname: Husmann
authors.forename: Nathalie
authors.initials: N
authors.lastname: Holzwarth
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Cameroni
authors.forename: Felix
authors.initials: F
authors.lastname: Ehrensperger
authors.forename: Marcus
authors.initials: M
authors.lastname: Thelen
authors.forename: Walter
authors.initials: W
authors.lastname: Born
authors.forename: Bruno
authors.initials: B
authors.lastname: Fuchs
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary*; D051379:Mice; D016513:Mice, SCID; D012516:Osteosarcoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D054387:Receptors, CXCR / Q000235:genetics* / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C501896:ACKR3 protein, human; D054377:Chemokine CXCL12; D054387:Receptors, CXCR; D019718:Receptors, CXCR4
references.citation: Mol Cancer Res. 2010 Jan;8(1):1-14
references.pmid: 20068066
references.citation: J Exp Med. 2006 Sep 4;203(9):2201-13
references.pmid: 16940167
references.citation: Mol Cancer. 2011 Jun 14;10:73
references.pmid: 21672222
references.citation: Cytokine. 2013 Oct;64(1):316-21
references.pmid: 23773308
references.citation: Cancer. 2002 Nov 15;95(10):2202-10
references.pmid: 12412175
references.citation: Radiographics. 1999 Nov-Dec;19(6):1421-34
references.pmid: 10555666
references.citation: Support Cancer Ther. 2004 Apr 1;1(3):165-72
references.pmid: 18628138
references.citation: Clin Cancer Res. 2010 Jul 15;16(14):3769-78
references.pmid: 20525755
references.citation: Int J Cancer. 2010 Dec 1;127(11):2554-68
references.pmid: 20162608
references.citation: Oncologist. 2004;9(4):422-41
references.pmid: 15266096
references.citation: Nature. 2001 Mar 1;410(6824):50-6
references.pmid: 11242036
references.citation: Biochem Cell Biol. 2005 Feb;83(1):36-48
references.pmid: 15746965
references.citation: Clin Cancer Res. 2011 Apr 15;17(8):2074-80
references.pmid: 21349998
references.citation: Semin Cancer Biol. 2004 Jun;14(3):171-9
references.pmid: 15246052
references.citation: Nat Rev Drug Discov. 2003 Jul;2(7):581-7
references.pmid: 12815382
references.citation: Orphanet J Rare Dis. 2007 Jan 23;2:6
references.pmid: 17244349
references.citation: J Immunol. 2009 Sep 1;183(5):3204-11
references.pmid: 19641136
references.citation: Clin Cancer Res. 2005 Apr 1;11(7):2561-7
references.pmid: 15814634
references.citation: Clin Cancer Res. 2005 Jan 15;11(2 Pt 1):490-7
references.pmid: 15701832
references.citation: Cell Signal. 2005 Dec;17(12):1578-92
references.pmid: 16005185
references.citation: J Immunol. 2006 Feb 15;176(4):2197-207
references.pmid: 16455976
references.citation: Cancer. 2009 Jun 1;115(11):2580-93
references.pmid: 19309748
references.citation: Turk Kardiyol Dern Ars. 2008 Dec;36(8):546-8
references.pmid: 19223721
references.citation: Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15735-40
references.pmid: 17898181
references.citation: Blood. 2003 Oct 15;102(8):2728-30
references.pmid: 12855591
references.citation: Cancer. 1981 Oct 1;48(7):1569-81
references.pmid: 6945143
references.citation: Bone. 2006 Apr;38(4):497-508
references.pmid: 16337237
references.citation: Nat Rev Cancer. 2004 Jul;4(7):540-50
references.pmid: 15229479
references.citation: Cancer. 1992 Jan 15;69(2):387-95
references.pmid: 1728367
references.citation: Ann Thorac Surg. 2006 Oct;82(4):1465-71; discussion 1471
references.pmid: 16996955
references.citation: PLoS One. 2010 Feb 11;5(2):e9175
references.pmid: 20161793
references.citation: EMBO J. 1997 Dec 1;16(23):6996-7007
references.pmid: 9384579
references.citation: J Clin Oncol. 1993 Mar;11(3):449-53
references.pmid: 8445419
references.citation: Int J Cancer. 1994 Jul 15;58(2):275-84
references.pmid: 7517921
references.citation: Nat Rev Cancer. 2009 Apr;9(4):274-84
references.pmid: 19308067
references.citation: J Biol Chem. 2005 Oct 21;280(42):35760-6
references.pmid: 16107333
references.citation: Mol Carcinog. 2008 Jan;47(1):66-73
references.pmid: 17683065
references.citation: Clin Exp Metastasis. 2008;25(3):201-11
references.pmid: 18071913
references.citation: J Orthop Res. 2011 Jun;29(6):938-46
references.pmid: 21284029
references.citation: J Biol Chem. 2008 Feb 15;283(7):4283-94
references.pmid: 18057003
references.citation: Cancer Metastasis Rev. 1998-1999;17(3):285-94
references.pmid: 10352882
references.citation: Heart Surg Forum. 2010 Oct;13(5):E333-5
references.pmid: 20961837