title: Overexpressing the CCL2 chemokine in an epithelial ovarian cancer cell line results in latency of in vivo tumourigenicity.
abstract: The frequent loss of heterozygosity of chromosome (Chr) 17 in epithelial ovarian cancer (EOC), particularly high-grade ovarian serous carcinomas (HGOSCs), has been attributed to the disruption of known tumour suppressor genes, such as TP53 (17p13), as well as other genes on this chromosome that alone or in combination have a role in EOC. In a transcriptome analysis of Chr17 genes, we observed significant underexpression of the chemokine CCL2 (17q12) in a small set of HGOSC samples relative to normal ovarian surface epithelial cells and a significant upregulation of CCL2 in the TP53-mutated OV-90 EOC cell line rendered non-tumourigenic as a consequence of genetic manipulation. Here, we report that overexpressing CCL2 in OV-90 resulted in latency of tumour formation at intraperitoneal (i.p.) but not subcutaneous sites in a mouse xenograft model. Overexpressing CCL2 affected cell morphology and exerted modest, but not significant effects on cell viability, colony formation and cell migration. We report significant underexpression of CCL2 by transcriptome analysis (P=0.015) and by immunohistochemistry in 77% of HGOSC samples (n=65). Absent or a very low level of protein expression by immunohistochemistry was also observed in 71% of additional HGOSC samples (n=122). However, CCL2 protein expression did not significantly correlate with overall or disease-free survival. The epithelial cells of normal fallopian tubes, a purported origin of HGOSC, exhibited expression of CCL2 protein by immunohistochemistry. Our results affirm that CCL2 underexpression is a significant feature of HGOSC samples, and that CCL2 overexpression in an EOC cell line model affects tumourigenic potential in the i.p. setting.
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Wojnarowicz
authors.forename: K
authors.initials: K
authors.lastname: Gambaro
authors.forename: M
authors.initials: M
authors.lastname: de Ladurantaye
authors.forename: M C J
authors.initials: MC
authors.lastname: Quinn
authors.forename: D
authors.initials: D
authors.lastname: Provencher
authors.forename: A-M
authors.initials: AM
authors.lastname: Mes-Masson
authors.forename: P N
authors.initials: PN
authors.lastname: Tonin
references.citation: Int J Cancer. 1995 Dec 20;64(6):434-40
references.pmid: 8550247
references.citation: Gut. 2012 Mar;61(3):427-38
references.pmid: 21930732
references.citation: Int J Gynecol Cancer. 2008 Sep-Oct;18(5):963-75
references.pmid: 18028382
references.citation: Lab Invest. 1990 Jul;63(1):132-6
references.pmid: 2374399
references.citation: Cancer Res. 2000 Oct 1;60(19):5329-33
references.pmid: 11034065
references.citation: Proc Natl Acad Sci U S A. 1994 Mar 29;91(7):2752-6
references.pmid: 8146186
references.citation: Int J Cancer. 1993 May 8;54(2):220-5
references.pmid: 8098014
references.citation: Cell. 1993 Feb 12;72(3):415-25
references.pmid: 7679328
references.citation: Int J Oncol. 2005 Nov;27(5):1315-20
references.pmid: 16211227
references.citation: Mol Carcinog. 2005 Jul;43(3):141-54
references.pmid: 15937959
references.citation: Adv Exp Med Biol. 2007;601:257-64
references.pmid: 17713013
references.citation: J Transl Med. 2009 Jul 06;7:55
references.pmid: 19580657
references.citation: Am J Hum Genet. 1995 Jan;56(1):265-71
references.pmid: 7825587
references.citation: Am J Pathol. 1997 May;150(5):1723-34
references.pmid: 9137096
references.citation: J Immunol. 2001 Jun 1;166(11):6483-90
references.pmid: 11359798
references.citation: Mol Carcinog. 2009 Jul;48(7):648-61
references.pmid: 19123201
references.citation: Methods Mol Biol. 2000;132:365-86
references.pmid: 10547847
references.citation: Neoplasia. 2008 Dec;10(12):1362-72, following 1372
references.pmid: 19048115
references.citation: Int J Oncol. 2012 Jun;40(6):1865-80
references.pmid: 22344671
references.citation: Int J Gynecol Cancer. 2008 May-Jun;18(3):487-91
references.pmid: 17692090
references.citation: Lancet. 1994 Mar 19;343(8899):692-5
references.pmid: 7907678
references.citation: Clin Cancer Res. 2002 Nov;8(11):3324-31
references.pmid: 12429618
references.citation: Oncogene. 2000 Mar 9;19(11):1466-72
references.pmid: 10723138
references.citation: J Leukoc Biol. 2004 Jun;75(6):1079-85
references.pmid: 15020650
references.citation: Nature. 2011 Jun 29;474(7353):609-15
references.pmid: 21720365
references.citation: Int J Gynecol Cancer. 2009 Jan;19(1):58-64
references.pmid: 19258943
references.citation: Mol Carcinog. 2007 Oct;46(10):872-85
references.pmid: 17455221
references.citation: J Neurosci Res. 1996 Aug 15;45(4):382-91
references.pmid: 8872898
references.citation: J Clin Invest. 1995 May;95(5):2391-6
references.pmid: 7738202
references.citation: Mol Cell Biol. 1991 Jun;11(6):3125-31
references.pmid: 2038321
references.citation: Curr Opin Immunol. 2008 Oct;20(5):501-3
references.pmid: 18657612
references.citation: Cancer Genet Cytogenet. 2005 Jun;159(2):114-22
references.pmid: 15899382
references.citation: J Pathol. 2010 May;221(1):49-56
references.pmid: 20229506
references.citation: Nucleic Acids Res. 2003 Jan 1;31(1):51-4
references.pmid: 12519945
references.citation: Clin Cancer Res. 2005 Nov 1;11(21):7629-36
references.pmid: 16278381
references.citation: BMC Cancer. 2008 May 28;8:152
references.pmid: 18507860
references.citation: Gynecol Oncol. 2008 Nov;111(2):320-9
references.pmid: 18757082
references.citation: Hum Reprod. 2005 Jun;20(6):1439-46
references.pmid: 15734755
references.citation: Genome Biol. 2003;4(5):P3
references.pmid: 12734009
references.citation: Breast Cancer Res Treat. 2008 Apr;108(3):399-408
references.pmid: 17541742
references.citation: Oncogene. 2007 Jan 25;26(4):618-32
references.pmid: 16909122
references.citation: Expert Opin Biol Ther. 2002 Aug;2(6):577-84
references.pmid: 12171503
references.citation: Endocr Rev. 2001 Apr;22(2):255-88
references.pmid: 11294827
references.citation: Genomics. 2002 Jan;79(1):104-13
references.pmid: 11827463
references.citation: Exp Cell Res. 1994 Dec;215(2):303-9
references.pmid: 7526992
references.citation: Cytokine. 2003 Jan 21;21(2):98-104
references.pmid: 12670449
references.citation: Oncogene. 1996 May 2;12(9):1895-901
references.pmid: 8649850
references.citation: Clin Cancer Res. 2003 Oct 15;9(13):4811-8
references.pmid: 14581352
references.citation: In Vitro Cell Dev Biol Anim. 2000 Jun;36(6):357-61
references.pmid: 10949993
references.citation: Biotechnol Bioeng. 2003 Jul 20;83(2):173-80
references.pmid: 12768623
references.citation: Gynecol Oncol. 1999 Mar;72(3):437-42
references.pmid: 10053122
references.citation: Int J Cancer. 1999 May 31;81(5):829-34
references.pmid: 10328240
references.citation: Anticancer Res. 2010 Dec;30(12):4791-8
references.pmid: 21187454
references.citation: Blood. 1997 Aug 1;90(3):909-28
references.pmid: 9242519
references.citation: J Natl Cancer Inst. 2000 Feb 2;92(3):205-16
references.pmid: 10655437
references.citation: Br J Cancer. 2005 Jun 6;92(11):2024-31
references.pmid: 15900302
references.citation: Cancer Cell. 2011 Sep 13;20(3):300-14
references.pmid: 21907922
references.citation: Cancer Genet Cytogenet. 2001 Sep;129(2):131-7
references.pmid: 11566343
references.citation: Annu Rev Immunol. 2004;22:329-60
references.pmid: 15032581
references.citation: Science. 1994 Oct 7;266(5182):66-71
references.pmid: 7545954
references.citation: Oncogene. 2003 Mar 13;22(10):1568-79
references.pmid: 12629520
references.citation: Reproduction. 2002 Mar;123(3):341-53
references.pmid: 11882011
references.citation: Clin Cancer Res. 2010 Feb 1;16(3):995-1007
references.pmid: 20103664
references.citation: Mol Carcinog. 2004 Sep;41(1):17-38
references.pmid: 15352123
references.citation: Cancer Res. 2000 Dec 15;60(24):7002-7
references.pmid: 11156403