Epithelial to mesenchymal transition is mechanistically linked with stem cell signatures in prostate cancer cells.
BACKGROUND
Current management of patients diagnosed with prostate cancer (PCa) is very effective; however, tumor recurrence with Castrate Resistant Prostate Cancer (CRPC) and subsequent metastasis lead to poor survival outcome, suggesting that there is a dire need for novel mechanistic understanding of tumor recurrence, which would be critical for designing novel therapies. The recurrence and the metastasis of PCa are tightly linked with the biology of prostate cancer stem cells or cancer-initiating cells that is reminiscent of the acquisition of Epithelial to Mesenchymal Transition (EMT) phenotype. Increasing evidence suggests that EMT-type cells share many biological characteristics with cancer stem-like cells.


RESULTS
In this study, we found that PCa cells with EMT phenotype displayed stem-like cell features characterized by increased expression of Sox2, Nanog, Oct4, Lin28B and/or Notch1, consistent with enhanced clonogenic and sphere (prostasphere)-forming ability and tumorigenecity in mice, which was associated with decreased expression of miR-200 and/or let-7 family. Reversal of EMT by re-expression of miR-200 inhibited prostasphere-forming ability of EMT-type cells and reduced the expression of Notch1 and Lin28B. Down-regulation of Lin28B increased let-7 expression, which was consistent with repressed self-renewal capability.


CONCLUSIONS
These results suggest that miR-200 played a pivotal role in linking the characteristics of cancer stem-like cells with EMT-like cell signatures in PCa. Selective elimination of cancer stem-like cells by reversing the EMT phenotype to Mesenchymal-Epithelial Transition (MET) phenotype using novel agents would be useful for the prevention of tumor recurrence especially by eliminating those cells that are the "Root Cause" of tumor development and recurrence.
Kong
Dejuan
D
Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, United States of America.
Banerjee
Sanjeev
S
Ahmad
Aamir
A
Li
Yiwei
Y
Wang
Zhiwei
Z
Sethi
Seema
S
Sarkar
Fazlul H
FH
D000818:Animals; D001483:Base Sequence; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D004847:Epithelial Cells / Q000473:pathology*; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D008222:Lymphokines / Q000378:metabolism; D008297:Male; D008648:Mesoderm / Q000473:pathology*; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics; D000071317:Nanog Homeobox Protein; D014411:Neoplastic Stem Cells / Q000473:pathology*; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D010641:Phenotype; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016601:RNA-Binding Proteins; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000378:metabolism
D015415:Biomarkers; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C516326:LIN28B protein, human; D008222:Lymphokines; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; C427493:PDGFD protein, human; C494173:POU5F1 protein, human; D010982:Platelet-Derived Growth Factor; D016601:RNA-Binding Proteins; D051881:Receptor, Notch1; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C487931:mirnlet7 microRNA, human
Cell. 2008 May 16;133(4):704-15
18485877
Prostate. 2006 Nov 1;66(15):1664-73
16902972
Biochim Biophys Acta. 2009 Apr;1792(4):289-96
19264126
Nat Rev Cancer. 2002 Jun;2(6):442-54
12189386
Clin Exp Metastasis. 2009;26(5):433-46
19221883
Nature. 2006 Aug 17;442(7104):823-6
16799564
Nat Genet. 2008 May;40(5):499-507
18443585
Nat Cell Biol. 2008 May;10(5):593-601
18376396
Urol Oncol. 2009 May-Jun;27(3):301-3
19414117
Cancer Res. 2009 Apr 1;69(7):2887-95
19276366
Science. 2007 Dec 21;318(5858):1917-20
18029452
Science. 2008 Apr 4;320(5872):97-100
18292307
Stem Cells. 2008 Mar;26(3):715-23
18055449
Cell. 2007 Dec 14;131(6):1109-23
18083101
Nature. 2009 Sep 24;461(7263):495-500
19741607
Stem Cells. 2009 May;27(5):993-1005
19415763
Science. 2009 May 8;324(5928):797-801
19325077
Oncogene. 2007 May 17;26(23):3395-405
17130832
Cell. 2009 Aug 21;138(4):645-659
19682730
Cell Cycle. 2009 Mar 15;8(6):843-52
19221491
Cell. 2005 Sep 23;122(6):947-56
16153702
J Mammary Gland Biol Neoplasia. 2009 Mar;14(1):29-43
19242781
Trends Cell Biol. 2008 Aug;18(8):357-9
18585040
Cell. 2006 Apr 21;125(2):301-13
16630818
Cancer Res. 2008 Oct 1;68(19):7846-54
18829540
Oncogene. 2003 Mar 13;22(10):1501-10
12629513
Cell. 2009 Aug 7;138(3):592-603
19665978
Cancer Res. 2009 Aug 15;69(16):6704-12
19654291
Cancer Res. 2007 Apr 1;67(7):3310-9
17409440
Trends Mol Med. 2008 Sep;14(9):400-9
18674967
J Cell Physiol. 2008 Aug;216(2):332-6
18459113
Prostate. 2009 Mar 1;69(4):401-10
19058139
EMBO Rep. 2008 Jun;9(6):582-9
18483486
Mol Cell Biol. 2005 Jul;25(14):6279-88
15988036
Nat Cell Biol. 2009 Dec;11(12):1487-95
19935649
Nature. 2010 Feb 4;463(7281):621-6
20054295
Hum Pathol. 2003 Jul;34(7):646-53
12874759
Science. 2008 Aug 1;321(5889):699-702
18276851
Nat Rev Cancer. 2008 Oct;8(10):755-68
18784658
Cancer Res. 2007 Dec 1;67(23):11377-85
18056465
Cancer Res. 2008 Mar 15;68(6):1927-34
18339874
Stem Cells. 2008 Jun;26(6):1425-35
18403754
Stem Cells. 2009 Aug;27(8):1712-21
19544444
Nature. 2006 May 18;441(7091):349-53
16625203
Cancer Res. 2010 May 1;70(9):3606-17
20388782
Cell. 2006 Oct 6;127(1):139-55
17018282
Cancer Res. 2007 May 15;67(10):4807-15
17510410