title: Tumor microenvironmental signaling elicits epithelial-mesenchymal plasticity through cooperation with transforming genetic events.
abstract: Epithelial-to-mesenchymal transition (EMT) facilitates the escape of epithelial cancer cells from the primary tumor site, which is a key event early in metastasis. Here, we explore how extrinsic, tumor microenvironmental cytokines cooperate with intrinsic, genetic changes to promote EMT in human mammary epithelial cells (HMECs). Viral transduction of transforming genetic events into HMECs routinely generated two distinct cell populations. One population retained epithelial characteristics, while an emergent population spontaneously acquired a mesenchymal morphology and properties associated with cancer stem cells (CSCs). Interestingly, the spontaneous mesenchymal/CSCs were unable to differentiate and lacked epithelial-mesenchymal plasticity. In contrast, exposure of the transformed HMECs retaining epithelial characteristics to exogenous transforming growth factor-β (TGF-β) generated a mesenchymal/CSC population with remarkable plasticity. The TGF-β-induced mesenchymal/CSC population was dependent on the continued presence of TGF-β. Removal of TGF-β or pharmacologic or genetic inhibition of TGF-β/SMAD signaling led to the reversion of mesenchymal/CSC to epithelial/non-CSC. Our results demonstrate that targeting exogenous cytokine signaling disrupts epithelial-mesenchymal plasticity and may be an effective strategy to inhibit the emergence of circulating tumor cells. The model of epithelial-mesenchymal plasticity we describe here can be used to identify novel tumor microenvironmental factors and downstream signaling that cooperate with intrinsic genetic changes to drive metastasis. Understanding the interaction between extrinsic and intrinsic factors that regulate epithelial-mesenchymal plasticity will allow the development of new therapies that target tumor microenvironmental signals to reduce metastasis.
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH.
authors.forename: Damian J
authors.initials: DJ
authors.lastname: Junk
authors.forename: Rocky
authors.initials: R
authors.lastname: Cipriano
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Bryson
authors.forename: Hannah L
authors.initials: HL
authors.lastname: Gilmore
authors.forename: Mark W
authors.initials: MW
authors.lastname: Jackson
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D004847:Epithelial Cells / Q000378:metabolism / Q000821:virology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D006801:Humans; D042361:Mammary Glands, Human / Q000378:metabolism* / Q000821:virology; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D051785:Smad Proteins; D016212:Transforming Growth Factor beta
references.citation: Cell. 2008 May 16;133(4):704-15
references.pmid: 18485877
references.citation: Nature. 1998 Mar 12;392(6672):190-3
references.pmid: 9515965
references.citation: Oncogene. 2008 Nov 20;27(54):6791-805
references.pmid: 18762808
references.citation: Mol Cancer. 2010 Jul 07;9:179
references.pmid: 20609236
references.citation: Cancer Res. 1999 Oct 1;59(19):4834-42
references.pmid: 10519393
references.citation: Cell. 2011 Jun 10;145(6):926-40
references.pmid: 21663795
references.citation: Breast Cancer Res. 2003;5(6):R217-22
references.pmid: 14580257
references.citation: Cell. 2012 Jan 20;148(1-2):349-61
references.pmid: 22265420
references.citation: J Biol Chem. 2000 Nov 24;275(47):36803-10
references.pmid: 10969078
references.citation: Science. 2002 Apr 19;296(5567):550-3
references.pmid: 11910072
references.citation: Mol Cell Biol. 2007 Sep;27(17):6012-25
references.pmid: 17562858
references.citation: Cancer Metastasis Rev. 2012 Jun;31(1-2):277-83
references.pmid: 22215472
references.citation: Dev Cell. 2010 Jun 15;18(6):884-901
references.pmid: 20627072
references.citation: Nature. 2003 Oct 9;425(6958):577-84
references.pmid: 14534577
references.citation: Cell. 2011 Mar 4;144(5):646-74
references.pmid: 21376230
references.citation: APMIS. 1993 Apr;101(4):257-68
references.pmid: 8323734
references.citation: Science. 2002 May 31;296(5573):1646-7
references.pmid: 12040180
references.citation: J Clin Invest. 2009 Jun;119(6):1420-8
references.pmid: 19487818
references.citation: Mol Cell Proteomics. 2004 Apr;3(4):327-44
references.pmid: 14754989
references.citation: Acta Anat (Basel). 1995;154(1):8-20
references.pmid: 8714286
references.citation: J Clin Oncol. 2005 Mar 20;23(9):2078-93
references.pmid: 15774796
references.citation: Int J Biol Sci. 2012;8(7):964-78
references.pmid: 22811618
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3983-8
references.pmid: 12629218
references.citation: Cell. 2003 Jun 13;113(6):685-700
references.pmid: 12809600
references.citation: J Cell Biol. 1991 Apr;113(1):173-85
references.pmid: 2007622
references.citation: Nat Rev Cancer. 2003 Jun;3(6):453-8
references.pmid: 12778135
references.citation: Nat Med. 2008 May;14(5):518-27
references.pmid: 18438415
references.citation: Cancer Res. 2009 Oct 1;69(19):7557-68
references.pmid: 19773443
references.citation: PLoS One. 2013;8(2):e53776
references.pmid: 23390492
references.citation: Proc Natl Acad Sci U S A. 2011 May 24;108(21):8668-73
references.pmid: 21555587
references.citation: J Cell Biol. 2007 Jul 30;178(3):437-51
references.pmid: 17646396
references.citation: Dev Cell. 2008 Jun;14(6):818-29
references.pmid: 18539112
references.citation: Cancer Metastasis Rev. 2012 Dec;31(3-4):469-78
references.pmid: 22729277
references.citation: Nat Rev Drug Discov. 2004 Dec;3(12):1011-22
references.pmid: 15573100
references.citation: PLoS One. 2008 Aug 06;3(8):e2888
references.pmid: 18682804
references.citation: Nat Rev Cancer. 2009 Apr;9(4):274-84
references.pmid: 19308067
references.citation: Cells Tissues Organs. 2007;185(1-3):7-19
references.pmid: 17587803
references.citation: J Clin Invest. 2003 Dec;112(12):1776-84
references.pmid: 14679171
references.citation: Science. 2013 Feb 1;339(6119):580-4
references.pmid: 23372014