title: Epithelial-mesenchymal transition: a new target in anticancer drug discovery.
abstract: The conversion of cells with an epithelial phenotype into cells with a mesenchymal phenotype, referred to as epithelial-mesenchymal transition, is a critical process for embryonic development that also occurs in adult life, particularly during tumour progression. Tumour cells undergoing epithelial-mesenchymal transition acquire the capacity to disarm the body's antitumour defences, resist apoptosis and anticancer drugs, disseminate throughout the organism, and act as a reservoir that replenishes and expands the tumour cell population. Epithelial-mesenchymal transition is therefore becoming a target of prime interest for anticancer therapy. Here, we discuss the screening and classification of compounds that affect epithelial-mesenchymal transition, highlight some compounds of particular interest, and address issues related to their clinical application.
authors.affiliation: Scientific Directorate, Regina Elena National Cancer Institute, via Elio Chianesi 53, 00144 Rome, Italy. Present address: Department of Pharmacological and Biomolecular Sciences, University of Milan, via Trentacoste 2, 20133 Milan, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Marcucci
authors.affiliation: Department of Surgical and Oncological Sciences, University of Palermo, Via del Vespro 131, 90127 Palermo, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Stassi
authors.affiliation: Scientific Directorate, Regina Elena National Cancer Institute, via Elio Chianesi 53, 00144 Rome, Italy.
authors.forename: Ruggero
authors.initials: R
authors.lastname: De Maria
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D055808:Drug Discovery; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents
references.citation: Nat Rev Cancer. 2013 Feb;13(2):97-110
references.pmid: 23344542
references.citation: Mol Biol Cell. 2012 Mar;23(5):781-91
references.pmid: 22238361
references.citation: Oncogene. 2015 Feb 5;34(6):681-90
references.pmid: 24531710
references.citation: PLoS One. 2012;7(3):e33183
references.pmid: 22432005
references.citation: Cancer Res. 2010 Sep 1;70(17):6945-56
references.pmid: 20699369
references.citation: Cancer Res. 2013 Jun 15;73(12):3649-60
references.pmid: 23771907
references.citation: Cancer Res. 2010 Jan 15;70(2):752-61
references.pmid: 20068166
references.citation: Nature. 2015 Nov 26;527(7579):472-6
references.pmid: 26560033
references.citation: Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3522-7
references.pmid: 20133717
references.citation: Clin Cancer Res. 2013 Oct 1;19(19):5372-80
references.pmid: 23942093
references.citation: Gastric Cancer. 2016 Jan;19(1):53-62
references.pmid: 25407459
references.citation: Cancer Res. 2006 Mar 1;66(5):2570-5
references.pmid: 16510574
references.citation: Cell Signal. 2014 Apr;26(4):784-96
references.pmid: 24378533
references.citation: Cancer Cell. 2013 Sep 9;24(3):347-64
references.pmid: 24029232
references.citation: Cold Spring Harb Perspect Biol. 2013 Mar 01;5(3):a015081
references.pmid: 23085770
references.citation: J Biol Chem. 2013 Feb 1;288(5):3322-33
references.pmid: 23255596
references.citation: Proc Natl Acad Sci U S A. 2012 Oct 23;109(43):17460-5
references.pmid: 23033492
references.citation: Clin Cancer Res. 2013 May 1;19(9):2310-8
references.pmid: 23388504
references.citation: Hepatology. 2008 May;47(5):1557-66
references.pmid: 18318443
references.citation: Proc Natl Acad Sci U S A. 2013 Apr 23;110(17 ):6700-5
references.pmid: 23569259
references.citation: Integr Biol (Camb). 2013 Feb;5(2):381-9
references.pmid: 23172153
references.citation: Oncotarget. 2014 Sep 15;5(17):7328-41
references.pmid: 25193862
references.citation: J Transl Med. 2013 Oct 24;11:268
references.pmid: 24156349
references.citation: Nat Med. 2013 Jan;19(1):50-6
references.pmid: 23223005
references.citation: Cancer Cell. 2013 Dec 9;24(6):695-709
references.pmid: 24332039
references.citation: Nature. 2006 Apr 27;440(7088):1222-6
references.pmid: 16642001
references.citation: Cancer Res. 2008 Dec 15;68(24):10113-20
references.pmid: 19074877
references.citation: Clin Cancer Res. 2014 May 15;20(10):2714-26
references.pmid: 24644001
references.citation: Cancer Cell. 2014 May 12;25(5):605-20
references.pmid: 24823638
references.citation: Nat Biotechnol. 2013 Sep;31(9):775-6
references.pmid: 24022140
references.citation: BMC Biol. 2012 Mar 22;10:29
references.pmid: 22439642
references.citation: J Cell Physiol. 2010 Apr;223(1):14-26
references.pmid: 20049846
references.citation: Clin Cancer Res. 2012 Jun 15;18(12 ):3218-22
references.pmid: 22679179
references.citation: Mol Cancer Ther. 2008 May;7(5):1185-94
references.pmid: 18483306
references.citation: Cancer Res. 2008 Oct 1;68(19):7846-54
references.pmid: 18829540
references.citation: Int J Oncol. 2012 Apr;40(4):1171-9
references.pmid: 22134360
references.citation: Nat Rev Cancer. 2009 Nov;9(11):798-809
references.pmid: 19851315
references.citation: Nat Rev Cancer. 2014 Jun;14 (6):430-9
references.pmid: 24827502
references.citation: Proc Natl Acad Sci U S A. 2014 Dec 2;111(48):17266-71
references.pmid: 25411317
references.citation: Clin Cancer Res. 2015 May 1;21(9):2084-95
references.pmid: 25934888
references.citation: Biochim Biophys Acta. 2013 Mar;1833(3):663-71
references.pmid: 23246564
references.citation: Carcinogenesis. 2013 May;34(5):962-73
references.pmid: 23358852
references.citation: Nat Rev Cancer. 2009 Apr;9(4):265-73
references.pmid: 19262571
references.citation: Cell Death Dis. 2013 Oct 24;4:e875
references.pmid: 24157869
references.citation: Proc Natl Acad Sci U S A. 2008 Apr 29;105(17 ):6392-7
references.pmid: 18427106
references.citation: Cell. 2009 Nov 25;139(5):871-90
references.pmid: 19945376
references.citation: Clin Cancer Res. 2014 Sep 1;20(17):4673-88
references.pmid: 24919570
references.citation: Cancer Res. 2015 Jan 15;75(2):446-55
references.pmid: 25432176
references.citation: Cancer Res. 2012 Apr 1;72 (7):1878-89
references.pmid: 22350410
references.citation: Clin Dev Immunol. 2012;2012:720768
references.pmid: 23227088
references.citation: PLoS One. 2013 Dec 31;8(12):e83991
references.pmid: 24391862
references.citation: Mol Cell Biochem. 2014 Jan;386(1-2):63-71
references.pmid: 24096736
references.citation: Nature. 2014 Jun 26;510(7506):542-6
references.pmid: 24847880
references.citation: Sci Transl Med. 2014 May 21;6(237):237ra68
references.pmid: 24848258
references.citation: Oncogene. 2014 Nov 20;33(47):5405-14
references.pmid: 24240689
references.citation: Eur J Pharmacol. 2014 Apr 15;729:45-53
references.pmid: 24561043
references.citation: Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13820-5
references.pmid: 19666588
references.citation: Int J Oncol. 2014 Feb;44(2):403-11
references.pmid: 24297508
references.citation: Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):1839-44
references.pmid: 25605917
references.citation: Oncol Lett. 2013 Nov;6(5):1234-1240
references.pmid: 24179501
references.citation: Oncogene. 2014 May 8;33(19):2423-31
references.pmid: 23728338
references.citation: Clin Cancer Res. 2014 Dec 15;20(24):6295-303
references.pmid: 25324140
references.citation: J Clin Invest. 2009 Jun;119(6):1417-9
references.pmid: 19487817
references.citation: Oncotarget. 2011 Dec;2(12):896-917
references.pmid: 22203527
references.citation: Nature. 2012 Jun 28;486(7404):537-40
references.pmid: 22722843
references.citation: Proc Natl Acad Sci U S A. 2010 Aug 31;107(35):15449-54
references.pmid: 20713713
references.citation: J Mol Med (Berl). 2007 Feb;85(2):139-48
references.pmid: 17180667
references.citation: Cancer Cell. 2013 Mar 18;23 (3):316-31
references.pmid: 23453623
references.citation: PLoS One. 2012;7(10 ):e46514
references.pmid: 23094026
references.citation: Clin Cancer Res. 2014 Feb 15;20(4):938-50
references.pmid: 24284055
references.citation: BMC Syst Biol. 2013 Sep 03;7:85
references.pmid: 24004452
references.citation: Mol Biol Cell. 2009 Apr;20(8):2207-17
references.pmid: 19225155
references.citation: Nat Rev Clin Oncol. 2009 Oct;6(10):587-95
references.pmid: 19787002
references.citation: Biochim Biophys Acta. 2014 Jun;1843(6):1043-53
references.pmid: 24440856
references.citation: Mol Cancer Ther. 2013 Dec;12(12):2864-73
references.pmid: 24130049
references.citation: Cell Death Differ. 2012 Oct;19(10):1644-54
references.pmid: 22539003
references.citation: Cell Cycle. 2013 Jun 1;12 (11):1791-801
references.pmid: 23656776
references.citation: Nat Med. 2005 Dec;11(12):1314-21
references.pmid: 16288283
references.citation: Curr Cancer Drug Targets. 2013 Nov;13(9):957-62
references.pmid: 24168187
references.citation: Oncol Rep. 2013 Feb;29(2):541-8
references.pmid: 23165370
references.citation: Cancer Res. 2014 Jan 1;74(1):309-19
references.pmid: 24108744
references.citation: Cancer Res. 2009 Mar 15;69(6):2400-7
references.pmid: 19276344
references.citation: Oncol Res. 2013;21(2):67-72
references.pmid: 24406042
references.citation: Cell Cycle. 2010 Apr 15;9(8):1647-59
references.pmid: 20404485
references.citation: Oncogene. 2007 Feb 1;26(5):711-24
references.pmid: 16862183
references.citation: Nat Med. 2014 Oct;20(10):1199-205
references.pmid: 25194568
references.citation: Toxicol Pathol. 2011 Oct;39(6):916-24
references.pmid: 21859884
references.citation: Cell Stem Cell. 2014 Dec 4;15(6):692-705
references.pmid: 25479747
references.citation: Science. 1994 Apr 1;264(5155):95-8
references.pmid: 8140422
references.citation: Nat Rev Drug Discov. 2014 Jan;13(1):63-79
references.pmid: 24336504
references.citation: J Biol Chem. 2001 Dec 14;276(50):46707-13
references.pmid: 11590169
references.citation: Cell Death Dis. 2013 Nov 07;4:e915
references.pmid: 24201814
references.citation: Clin Cancer Res. 2013 Apr 1;19(7):1884-93
references.pmid: 23403636
references.citation: Cell. 2011 Jul 8;146(1):148-63
references.pmid: 21729786
references.citation: Cancer Res. 2011 May 1;71(9):3246-56
references.pmid: 21430067
references.citation: Oncogene. 2012 May 3;31(18):2309-22
references.pmid: 21909139
references.citation: Cancer Res. 2014 Sep 1;74(17 ):4783-95
references.pmid: 24994714
references.citation: Cancer Cell. 2014 Jun 16;25(6):846-59
references.pmid: 24898549
references.citation: Mol Cancer Res. 2012 Dec;10 (12 ):1597-606
references.pmid: 23071104
references.citation: Int J Oncol. 2014 Jul;45(1):411-8
references.pmid: 24820265
references.citation: Cancer Res. 2008 May 15;68(10 ):3645-54
references.pmid: 18483246
references.citation: Nature. 2015 Nov 26;527(7579):525-30
references.pmid: 26560028
references.citation: Breast Cancer Res Treat. 2014 Jan;143(1):99-111
references.pmid: 24305977
references.citation: Cell. 2008 May 16;133(4):704-15
references.pmid: 18485877
references.citation: Int J Cancer. 2014 Dec 15;135(12):2972-83
references.pmid: 24789676
references.citation: Proc Natl Acad Sci U S A. 2014 Apr 29;111(17):E1731-9
references.pmid: 24733940
references.citation: Oncogene. 2012 Jan 26;31(4):432-45
references.pmid: 21725369
references.citation: Neoplasia. 2011 May;13(5):406-18
references.pmid: 21532881
references.citation: Mol Cancer. 2013 Oct 05;12(1):114
references.pmid: 24093956
references.citation: Cancer Cell. 2008 Jul 8;14 (1):79-89
references.pmid: 18598946
references.citation: Nat Rev Cancer. 2014 Jul;14(7):455-67
references.pmid: 24957944
references.citation: J Mol Med (Berl). 2012 Jul;90(7):803-15
references.pmid: 22231744
references.citation: Mol Biol Cell. 2007 Nov;18(11):4615-24
references.pmid: 17855508
references.citation: Clin Exp Metastasis. 2013 Feb;30(2):143-54
references.pmid: 22833345
references.citation: Cancer Res. 2012 Nov 15;72 (22):6013-23
references.pmid: 22952217
references.citation: Clin Cancer Res. 2005 Dec 15;11(24 Pt 1):8686-98
references.pmid: 16361555
references.citation: Angew Chem Int Ed Engl. 2014 Feb 24;53(9):2344-8
references.pmid: 24478127
references.citation: Nat Cell Biol. 2014 Jul;16(7):695-707
references.pmid: 24952462
references.citation: EMBO Mol Med. 2014 Sep 11;6(10):1279-93
references.pmid: 25214461
references.citation: Oncotarget. 2014 Dec 30;5(24):12753-68
references.pmid: 25528764
references.citation: Nat Rev Cancer. 2013 Jan;13(1):11-26
references.pmid: 23258168
references.citation: Cancer Metastasis Rev. 2009 Dec;28(3-4):335-44
references.pmid: 20012924
references.citation: Cell. 2012 Jul 6;150(1):165-78
references.pmid: 22770218
references.citation: Nat Cell Biol. 2010 Mar;12 (3):247-56
references.pmid: 20173740
references.citation: Nat Rev Cancer. 2012 Jul 19;12(8):540-52
references.pmid: 22810810
references.citation: Int J Cancer. 2014 Sep 15;135(6):1265-76
references.pmid: 24174383
references.citation: Diabetes Care. 2009 Sep;32(9):1620-5
references.pmid: 19564453
references.citation: Nat Rev Cancer. 2014 Sep;14(9):598-610
references.pmid: 25098269
references.citation: Cancer Cell. 2009 Apr 7;15(4):283-93
references.pmid: 19345327
references.citation: Clin Cancer Res. 2013 Aug 15;19(16):4392-403
references.pmid: 23804423
references.citation: Int J Cancer. 2010 Jul 1;127(1):207-19
references.pmid: 19876915
references.citation: J Clin Invest. 2012 Nov;122(11):4243-56
references.pmid: 23041627
references.citation: PLoS Biol. 2011 Sep;9(9):e1001162
references.pmid: 21980263
references.citation: Cancer Res. 2009 Oct 1;69(19):7507-11
references.pmid: 19752085
references.citation: J Natl Cancer Inst. 2013 Oct 2;105(19):1485-95
references.pmid: 24062525
references.citation: Clin Cancer Res. 2014 Mar 15;20(6):1666-75
references.pmid: 24493831
references.citation: PLoS One. 2012;7(9):e45045
references.pmid: 23024790
references.citation: Med Oncol. 2015 Jan;32(1):393
references.pmid: 25428393
references.citation: Cancer Res. 2009 Apr 1;69(7):2887-95
references.pmid: 19276366
references.citation: Cell. 2011 Jun 10;145(6):926-40
references.pmid: 21663795
references.citation: Clin Exp Metastasis. 2008;25(8):843-54
references.pmid: 18696232
references.citation: Oncogene. 2013 Oct 31;32(44):5210-9
references.pmid: 23208505
references.citation: Br J Cancer. 2009 Jan 13;100(1):134-44
references.pmid: 19088723
references.citation: J Biol Chem. 2008 May 16;283(20):13714-24
references.pmid: 18332144
references.citation: Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20212-7
references.pmid: 24277834
references.citation: Int J Cancer. 2012 Sep 1;131(5):1023-31
references.pmid: 22038895
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):14867-72
references.pmid: 18806226
references.citation: J Biol Chem. 2011 Jul 22;286(29):25992-6002
references.pmid: 21596753
references.citation: Proc Natl Acad Sci U S A. 2012 Oct 9;109(41):16618-23
references.pmid: 22996328
references.citation: Clin Cancer Res. 2010 Feb 15;16(4):1191-205
references.pmid: 20145179
references.citation: Blood. 2014 Apr 17;123(16):2451-9
references.pmid: 24608975
references.citation: Cancer Res. 2014 Mar 15;74(6):1694-704
references.pmid: 24599131
references.citation: Clin Breast Cancer. 2011 Oct;11(5):306-11
references.pmid: 21729667
references.citation: Cancer Res. 2014 Oct 15;74(20):5878-90
references.pmid: 25125659
references.citation: PLoS One. 2013 Jul 30;8(7):e68597
references.pmid: 23935876
references.citation: J Clin Oncol. 2012 May 1;30(13):1527-33
references.pmid: 22454420
references.citation: Int J Cancer. 2012 Apr 15;130(8):1733-44
references.pmid: 21544811
references.citation: Cancer Res. 2014 May 15;74(10):2698-709
references.pmid: 24638980
references.citation: PLoS One. 2011;6(8):e23752
references.pmid: 21887310
references.citation: Clin Cancer Res. 2010 Dec 15;16(24):5928-35
references.pmid: 20962028
references.citation: Cancer Cell. 2013 Feb 11;23 (2):249-62
references.pmid: 23410977
references.citation: Cancer Res. 2014 Dec 15;74(24):7546-59
references.pmid: 25320014
references.citation: Clin Cancer Res. 2013 Jan 1;19(1):279-90
references.pmid: 23091115
references.citation: Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7319-24
references.pmid: 11404481
references.citation: Cancer Res. 2014 May 15;74(10):2869-81
references.pmid: 24686166
references.citation: Oncogene. 2013 Apr 4;32(14):1843-53
references.pmid: 22614007
references.citation: Histopathology. 2012 May;60(6B):E87-95
references.pmid: 22439911
references.citation: J Cell Physiol. 2014 Nov;229(11):1647-59
references.pmid: 24610459
references.citation: Cancer Res. 2013 Sep 1;73(17):5336-46
references.pmid: 23856251
references.citation: Proc Natl Acad Sci U S A. 2012 Jul 17;109(29):11717-22
references.pmid: 22753465
references.citation: Cancer Cell. 2006 Apr;9(4):261-72
references.pmid: 16616332
references.citation: Nat Rev Drug Discov. 2013 Nov;12(11):847-65
references.pmid: 24172333
references.citation: Nature. 2004 Nov 18;432(7015):332-7
references.pmid: 15549095
references.citation: Clin Exp Metastasis. 2011 Feb;28(2):137-55
references.pmid: 21194007
references.citation: Proc Natl Acad Sci U S A. 2014 Apr 8;111(14):5349-54
references.pmid: 24706870
references.citation: Proc Natl Acad Sci U S A. 2010 Jan 19;107(3):1124-9
references.pmid: 20080645
references.citation: Cancer Res. 2013 Apr 1;73(7):2059-69
references.pmid: 23378342
references.citation: Proc Natl Acad Sci U S A. 2013 Aug 6;110(32):13091-6
references.pmid: 23878224
references.citation: Cancer Biol Ther. 2010 Dec 15;10(12):1224-32
references.pmid: 21139417
references.citation: Cancer Cell. 2012 Dec 11;22(6):725-36
references.pmid: 23201165
references.citation: Clin Cancer Res. 2015 Feb 1;21(3):553-60
references.pmid: 25424852
references.citation: Nat Med. 2013 Nov;19(11):1438-49
references.pmid: 24202396
references.citation: Cancer Res. 2011 May 1;71(9):3364-76
references.pmid: 21415165
references.citation: Cell. 2011 Nov 11;147(4):759-72
references.pmid: 22078877
references.citation: J Biol Chem. 2012 Feb 17;287(8):5819-32
references.pmid: 22205702
references.citation: J Clin Invest. 2006 Jun;116(6):1561-70
references.pmid: 16741576
references.citation: Gastroenterology. 2011 Jan;140(1):297-309
references.pmid: 20951698
references.citation: Mol Biol Cell. 2013 Nov;24(21):3449-59
references.pmid: 24006485
references.citation: Cancer Res. 2013 Oct 15;73(20):6299-309
references.pmid: 23943797
references.citation: J Biol Chem. 2011 Sep 2;286(35):30393-400
references.pmid: 21730052
references.citation: Clin Exp Metastasis. 1996 Mar;14(2):176-86
references.pmid: 8605731
references.citation: Cell Stem Cell. 2014 Mar 6;14(3):342-56
references.pmid: 24607406
references.citation: Cancer Microenviron. 2012 Apr;5(1):29-38
references.pmid: 21748438
references.citation: Oncologist. 2011;16(5):566-78
references.pmid: 21521831
references.citation: Cancer Res. 2013 Sep 1;73(17):5519-31
references.pmid: 23811941
references.citation: Cancer Cell. 2013 Nov 11;24(5):589-602
references.pmid: 24209604
references.citation: Genes Dev. 2004 May 15;18(10 ):1131-43
references.pmid: 15155580
references.citation: Cancer Res. 2014 Apr 1;74(7):1890-4
references.pmid: 24638984
references.citation: Science. 1995 Jul 7;269(5220):81-3
references.pmid: 7541555
references.citation: PLoS One. 2012;7(5):e36402
references.pmid: 22570710
references.citation: Cancer Cell. 2012 Mar 20;21(3):309-22
references.pmid: 22439926
references.citation: PLoS One. 2011;6(9):e23943
references.pmid: 21912653
references.citation: J Clin Invest. 2013 Mar;123(3):1348-58
references.pmid: 23391723