High Frequency of Putative Ovarian Cancer Stem Cells With CD44/CK19 Coexpression Is Associated With Decreased Progression-Free Intervals In Patients With Recurrent Epithelial Ovarian Cancer
Restricted accessResearch articleFirst published online May, 2013
High Frequency of Putative Ovarian Cancer Stem Cells With CD44/CK19 Coexpression Is Associated With Decreased Progression-Free Intervals In Patients With Recurrent Epithelial Ovarian Cancer
Epithelial ovarian cancer (EOC) cells with CD44 and CK19 coexpression may represent a subset of ovarian cancer stem cells (OCSCs). This study was conducted to evaluate the correlation of the frequency of putative OCSCs (CD44 + CK19 + OCSCs) with the clinicopathologic features and the prognostic value in patients with recurrent advanced stage EOC.
Methods:
A retrospective study was carried out on 33 patients with EOC and a uniformly treated tissue microarray was constructed. A multiplexed, immunofluorescence-based method of automated in situ quantitative measurement of protein analysis was used for evaluation of the frequency or density of CD44 + CK19 + OCSCs in EOC.
Results:
The mean follow-up time was 42.8 ± 27.1 months. High frequency of EOC cells with CD44+ or CD44+/CK19+ was associated with chemoresistance (P = .033 and P = .02, respectively). Using K-M analysis with log-rank test, a high frequency of putative OCSCs was associated with short disease-free interval (7.9 months vs 20.9 months, P = .019). In univariable analysis, the frequency of OCSCs, International Federation of Gynecology and Obstetrics stage and residual tumor volume were significant predictor variables and were entered into multivariable analysis (P = .019, .037, and .005, respectively). Although no independent significant predictor was found, the frequency of putative OCSCs was the most promising predictor variable compared with the other 2 variables (hazard ratio = 2.344, P = .052).
Conclusion:
Our findings suggest that high frequency of OCSCs (CD44+ and CK19+) in epithelial ovarian tumors correlates with short progression-free intervals.
NossovVAmneusMSuFThe early detection of ovarian cancer: from traditional methods to proteomics. Can we really do better than serum CA-125?Am J Obstet Gynecol. 2008;199(3):215–223.
3.
JemalASiegelRXuJWardE. Cancer statistics, 2010. CA Cancer J Clin. 2010;60(5):277–300.
4.
GarvalovBKAckerT. Cancer stem cells: a new framework for the design of tumor therapies. J Mol Med (Berl). 2011;89(2):95–107.
5.
O'BrienCAKresoADickJE. Cancer stem cells in solid tumors: an overview. Semin Radiat Oncol. 2009;19(2):71–77.
6.
BaoSWuQMcLendonREGlioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444(7120):756–760.
7.
HermannPCHuberSLHerrlerTDistinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell. 2007;1(3):313–323.
8.
AlveroABChenRFuHHMolecular phenotyping of human ovarian cancer stem cells unravels the mechanisms for repair and chemoresistance. Cell Cycle. 2009;8(1):158–166.
9.
MorGYinGChefetzIYangYAlveroA.Ovarian cancer stem cells and inflammation. Cancer Biol Ther. 2011;11(8):708–713.
10.
AlveroABFuHHHolmbergJStem-like ovarian cancer cells can serve as tumor vascular progenitors. Stem Cells. 2009;27(10):2405–2413.
11.
CurleyMDTherrienVACummingsCLCD133 expression defines a tumor initiating cell population in primary human ovarian cancer. Stem Cells. 2009;27(12):2875–2883.
12.
KryczekILiuSRohMExpression of aldehyde dehydrogenase and CD133 defines ovarian cancer stem cells. Int J Cancer. 2012;130(1):29–39.
13.
GaoMQChoiYPKangSYounJHChoNH. CD24+ cells from hierarchically organized ovarian cancer are enriched in cancer stem cells. Oncogene. 2010;29(18):2672–2680.
14.
LuoLZengJLiangBOvarian cancer cells with the CD117 phenotype are highly tumorigenic and are related to chemotherapy outcome. Exp Mol Pathol. 2011;91(2):596–602.
15.
NaorDSionovRVIsh-ShalomD. CD44: structure, function, and association with the malignant process. Adv Cancer Res. 1997;71:241–319.
16.
ShipitsinMCampbellLLArganiPMolecular definition of breast tumor heterogeneity. Cancer Cell. 2007;11(3):259–273.
17.
YinGChenRAlveroABTWISTing stemness, inflammation and proliferation of epithelial ovarian cancer cells through MIR199A2/214. Oncogene. 2010;29(24):3545–3553.
18.
ZollerM. CD44: can a cancer-initiating cell profit from an abundantly expressed molecule?Nat Rev Cancer. 2011;11(4):254–267.
19.
SteffensenKDAlveroABYangYPrevalence of epithelial ovarian cancer stem cells correlates with recurrence in early-stage ovarian cancer. J Oncol. 2011;2011:620523.
20.
LimRLappasMAhmedNPermezelMQuinnMA, Rice GE. 2D-PAGE of ovarian cancer: analysis of soluble and insoluble fractions using medium-range immobilized pH gradients. Biochem Biophys Res Commun. 2011;406(3):408–413.
21.
McCabeADolled-FilhartMCampRLRimmDL. Automated quantitative analysis (AQUA) of in situ protein expression, antibody concentration, and prognosis. J Natl Cancer Inst. 2005;97(24):1808–1815.
22.
KlugerHMDolled-FilhartMRodovSKacinskiBMCampRLRimmDL. Macrophage colony-stimulating factor-1 receptor expression is associated with poor outcome in breast cancer by large cohort tissue microarray analysis. Clin Cancer Res. 2004;10(1 pt 1):173–177.
23.
PsyrriAKountourakisPYuZAnalysis of p53 protein expression levels on ovarian cancer tissue microarray using automated quantitative analysis elucidates prognostic patient subsets. Ann Oncol. 2007;18(4):709–715.
24.
CampRLChungGGRimmDL. Automated subcellular localization and quantification of protein expression in tissue microarrays. Nat Med. 2002;8(11):1323–1327.
25.
GustavsonMDBourke-MartinBReillyDStandardization of HER2 immunohistochemistry in breast cancer by automated quantitative analysis. Arch Pathol Lab Med. 2009;133(9):1413–1419.
26.
GustavsonMDBourke-MartinBReillyDMDevelopment of an unsupervised pixel-based clustering algorithm for compartmentalization of immunohistochemical expression using Automated QUantitative Analysis. Appl Immunohistochem Mol Morphol. 2009;17(4):329–337.
27.
CampRLChungGGRimmDL. Automated subcellular localization and quantification of protein expression in tissue microarrays. Nat Med. 2002;8(11):1323–1327.
28.
GustavsonMDMolinaroAMTedeschiGCampRLRimmDL. AQUA analysis of thymidylate synthase reveals localization to be a key prognostic biomarker in 2 large cohorts of colorectal carcinoma. Arch Pathol Lab Med. 2008;132(11):1746–1752.
29.
CampRLDolled-FilhartMRimmDL. X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clin Cancer Res. 2004;10(21):7252–7259.
30.
RustinGJQuinnMThigpenTRe: New guidelines to evaluate the response to treatment in solid tumors (ovarian cancer). J Natl Cancer Inst. 2004;96(6):487–488.
31.
RustinGJ. Can we now agree to use the same definition to measure response according to CA-125?J Clin Oncol. 2004;22(20):4035–4036.
32.
NeumeisterVAgarwalSBordeauxJCampRLRimmDL.In situ identification of putative cancer stem cells by multiplexing ALDH1, CD44, and cytokeratin identifies breast cancer patients with poor prognosis. Am J Pathol. 2010;176(5):2131–2138.
33.
JainRFischerSSerraSChettyR. The use of Cytokeratin 19 (CK19) immunohistochemistry in lesions of the pancreas, gastrointestinal tract, and liver. Appl Immunohistochem Mol Morphol. 2010;18(1):9–15.
34.
LacroixM. Significance, detection and markers of disseminated breast cancer cells. Endocr Relat Cancer. 2006;13(4):1033–1067.
35.
MertzKDDemichelisFSbonerAAssociation of cytokeratin 7 and 19 expression with genomic stability and favorable prognosis in clear cell renal cell cancer. Int J Cancer. 2008;123(3):569–576.
36.
PontaHShermanLHerrlichPA. CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol. 2003;4(1):33–45.
YinGAlveroABCraveiroVConstitutive proteasomal degradation of TWIST-1 in epithelial-ovarian cancer stem cells impacts differentiation and metastatic potential [published online February 20, 2012]. Oncogene. 2012.
39.
CasagrandeFCoccoEBelloneSEradication of chemotherapy-resistant CD44+ human ovarian cancer stem cells in mice by intraperitoneal administration of clostridium perfringens enterotoxin. Cancer. 2011;117(24):5519–5528.
40.
KayasthaSFreedmanANPiverMSMukkamallaJRomero-GuittierezMWernessBA.Expression of the hyaluronan receptor, CD44S, in epithelial ovarian cancer is an independent predictor of survival. Clin Cancer Res. 1999;5(5):1073–1076.
41.
Rodriguez-RodriguezLSancho-TorresIMesoneroCGibbonDGShihWJZotalisG. The CD44 receptor is a molecular predictor of survival in ovarian cancer. Med Oncol. 2003;20(3):255–263.
42.
BernerHSDavidsonBBernerAExpression of CD44 in effusions of patients diagnosed with serous ovarian carcinoma—diagnostic and prognostic implications. Clin Exp Metastasis. 2000;18(2):197–202.
43.
SillanpaaSAnttilaMAVoutilainenKCD44 expression indicates favorable prognosis in epithelial ovarian cancer. Clin Cancer Res. 2003;9(14):5318–5324.
44.
Dolled-FilhartMGustavsonMCampRLRimmDLTonkinsonJLChristiansenJ. Automated analysis of tissue microarrays. Methods Mol Biol. 2010;664:151–162.
