Analysis of epithelial and mesenchymal markers in ovarian cancer reveals phenotypic heterogeneity and plasticity.
In our studies of ovarian cancer cells we have identified subpopulations of cells that are in a transitory E/M hybrid stage, i.e. cells that simultaneously express epithelial and mesenchymal markers. E/M cells are not homogenous but, in vitro and in vivo, contain subsets that can be distinguished based on a number of phenotypic features, including the subcellular localization of E-cadherin, and the expression levels of Tie2, CD133, and CD44. A cellular subset (E/M-MP) (membrane E-cadherin(low)/cytoplasmic E-cadherin(high)/CD133(high), CD44(high), Tie2(low)) is highly enriched for tumor-forming cells and displays features which are generally associated with cancer stem cells. Our data suggest that E/M-MP cells are able to differentiate into different lineages under certain conditions, and have the capacity for self-renewal, i.e. to maintain a subset of undifferentiated E/M-MP cells during differentiation. Trans-differentiation of E/M-MP cells into mesenchymal or epithelial cells is associated with a loss of stem cell markers and tumorigenicity. In vivo xenograft tumor growth is driven by E/M-MP cells, which give rise to epithelial ovarian cancer cells. In contrast, in vitro, we found that E/M-MP cells differentiate into mesenchymal cells, in a process that involves pathways associated with an epithelial-to-mesenchymal transition. We also detected phenotypic plasticity that was dependent on external factors such as stress created by starvation or contact with either epithelial or mesenchymal cells in co-cultures. Our study provides a better understanding of the phenotypic complexity of ovarian cancer and has implications for ovarian cancer therapy.
Division of Medical Genetics, University of Washington, Seattle, Washington, United States of America.
Robert
R
Strauss
Zong-Yi
ZY
Li
Ying
Y
Liu
Ines
I
Beyer
Jonas
J
Persson
Pavel
P
Sova
Thomas
T
Möller
Sari
S
Pesonen
Akseli
A
Hemminki
Petra
P
Hamerlik
Charles
C
Drescher
Nicole
N
Urban
Jiri
J
Bartek
André
A
Lieber
D014408:Biomarkers, Tumor / Q000032:analysis; D000077216:Carcinoma, Ovarian Epithelial; D054338:Cell Transdifferentiation; D004847:Epithelial Cells / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000473:pathology*; D009375:Neoplasms, Glandular and Epithelial / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000473:pathology; D010051:Ovarian Neoplasms / Q000473:pathology; D010641:Phenotype
D014408:Biomarkers, Tumor
Int J Cancer. 1997 Jun 20;74(3):275-80
9221804
Dev Cell. 2005 Apr;8(4):456-8
15809027
Vaccine. 2007 Aug 29;25(35):6501-10
17646036
Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3983-8
12629218
Nat Immunol. 2004 Jul;5(7):738-43
15170211
Nature. 2010 Dec 9;468(7325):829-33
21102433
Cancer Res. 2005 Oct 15;65(20):9328-37
16230395
PLoS One. 2010 Aug 27;5(8):e12445
20805998
Cancer Treat Res. 2002;107:161-83
11775449
Cancer Res. 2006 Sep 1;66(17):8319-26
16951136
Cancer Cell. 2010 Apr 13;17(4):362-75
20385361
J Immunol Methods. 2009 Aug 15;347(1-2):70-8
19567251
Cell. 2008 May 16;133(4):704-15
18485877
Nature. 2008 Dec 4;456(7222):593-8
19052619
Int J Gynecol Cancer. 2002 Nov-Dec;12(6):691-703
12445245
Pathol Int. 2006 Feb;56(2):62-70
16445817
J Clin Pathol. 2006 May;59(5):460-7
16461565
Nat Clin Pract Oncol. 2008 May;5(5):280-90
18349857
Hum Pathol. 1997 Jun;28(6):734-9
9191009
Oncogene. 2009 Jun 18;28(24):2358-63
19421150
Cancer Res. 2009 Jun 15;69(12):5115-25
19491256
Stem Cells. 2009 Dec;27(12):2875-83
19816957
PLoS One. 2008;3(10):e3469
18941626
Cancer Res. 2008 Jun 1;68(11):4311-20
18519691
Nat Med. 2009 Sep;15(9):1010-2
19734877
Mol Ther. 2004 May;9(5):650-7
15120325
Int J Cancer. 2003 Aug 20;106(2):172-7
12800191
Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):973-8
17210912
J Cell Sci. 2004 Jul 15;117(Pt 16):3539-45
15226377
Clin Cancer Res. 2006 Sep 15;12(18):5395-402
17000672
Nature. 2010 Dec 9;468(7325):824-8
21102434
Cancer Res. 2005 Apr 15;65(8):3025-9
15833827
Cancer Res. 2005 Dec 1;65(23):10946-51
16322242
Cell. 2008 Feb 22;132(4):583-97
18295577
Hum Pathol. 2004 Dec;35(12):1469-76
15619205
Stem Cells Dev. 2009 Oct;18(8):1127-34
19409053
Nat Rev Cancer. 2005 Sep;5(9):744-9
16148886
Cancer Res. 2006 Oct 1;66(19):9339-44
16990346
Am J Physiol Cell Physiol. 2006 Jun;290(6):C1532-42
16394028
Proc Natl Acad Sci U S A. 2003 Sep 30;100 Suppl 1:11842-9
14504387
Oncogene. 2009 Jan 15;28(2):209-18
18836486
Histol Histopathol. 2008 Jun;23(6):773-80
18366015
Histol Histopathol. 2010 Jan;25(1):113-20
19924647
Nature. 2007 Jan 4;445(7123):106-10
17122772
Clin Exp Metastasis. 2008;25(6):643-55
18398687
Cancer Res. 2004 Oct 1;64(19):7011-21
15466194