title: Flow induces epithelial-mesenchymal transition, cellular heterogeneity and biomarker modulation in 3D ovarian cancer nodules.
abstract: Seventy-five percent of patients with epithelial ovarian cancer present with advanced-stage disease that is extensively disseminated intraperitoneally and prognosticates the poorest outcomes. Primarily metastatic within the abdominal cavity, ovarian carcinomas initially spread to adjacent organs by direct extension and then disseminate via the transcoelomic route to distant sites. Natural fluidic streams of malignant ascites triggered by physiological factors, including gravity and negative subdiaphragmatic pressure, carry metastatic cells throughout the peritoneum. We investigated the role of fluidic forces as modulators of metastatic cancer biology in a customizable microfluidic platform using 3D ovarian cancer nodules. Changes in the morphological, genetic, and protein profiles of biomarkers associated with aggressive disease were evaluated in the 3D cultures grown under controlled and continuous laminar flow. A modulation of biomarker expression and tumor morphology consistent with increased epithelial-mesenchymal transition, a critical step in metastatic progression and an indicator of aggressive disease, is observed because of hydrodynamic forces. The increase in epithelial-mesenchymal transition is driven in part by a posttranslational up-regulation of epidermal growth factor receptor (EGFR) expression and activation, which is associated with the worst prognosis in ovarian cancer. A flow-induced, transcriptionally regulated decrease in E-cadherin protein expression and a simultaneous increase in vimentin is observed, indicating increased metastatic potential. These findings demonstrate that fluidic streams induce a motile and aggressive tumor phenotype. The microfluidic platform developed here potentially provides a flow-informed framework complementary to conventional mechanism-based therapeutic strategies, with broad applicability to other lethal malignancies.
authors: Wellman Center for Photomedicine, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors: Imran
authors: I
authors: Rizvi
authors: Umut A
authors: UA
authors: Gurkan
authors: Savas
authors: S
authors: Tasoglu
authors: Nermina
authors: N
authors: Alagic
authors: Jonathan P
authors: JP
authors: Celli
authors: Lawrence B
authors: LB
authors: Mensah
authors: Zhiming
authors: Z
authors: Mai
authors: Utkan
authors: U
authors: Demirci
authors: Tayyaba
authors: T
authors: Hasan
mesh_terms: D001201:Ascites / Q000503:physiopathology; D014408:Biomarkers, Tumor / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D018929:Cell Culture Techniques; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D046210:Microfluidic Analytical Techniques / Q000379:methods*; D008954:Models, Biological; D009375:Neoplasms, Glandular and Epithelial / Q000556:secondary*; D010051:Ovarian Neoplasms / Q000503:physiopathology*; D010534:Peritoneal Neoplasms / Q000556:secondary*
chemical_list: D014408:Biomarkers, Tumor; D015820:Cadherins; D066246:ErbB Receptors
keywords: combination therapies; molecular targets; photodynamic therapy; stress response; tumor microenvironment
references: Curr Cancer Drug Targets. 2010 May;10(3):268-78
references: 20370691
references: Cancer Res. 1972 Aug;32(8):1663-6
references: 5044130
references: Lancet Oncol. 2006 Nov;7(11):925-34
references: 17081918
references: Nat Rev Cancer. 2009 Apr;9(4):274-84
references: 19308067
references: Nat Rev Cancer. 2011 Jun 24;11(7):512-22
references: 21701513
references: J Pathol. 1997 May;182(1):1-8
references: 9227334
references: Cell. 2006 Nov 17;127(4):679-95
references: 17110329
references: Mol Oncol. 2007 Jun;1(1):84-96
references: 18516279
references: Cell Cycle. 2009 Mar 1;8(5):683-8
references: 19221481
references: Proc Natl Acad Sci U S A. 2011 Jul 5;108(27):11115-20
references: 21690404
references: Cell. 2011 Mar 4;144(5):646-74
references: 21376230
references: BMC Cancer. 2012 Mar 19;12:91
references: 22429801
references: J Biomed Opt. 2010 Sep-Oct;15(5):051603
references: 21054077
references: Gynecol Oncol. 2007 Mar;104(3):727-31
references: 17126894
references: Int J Cancer. 2007 Oct 1;121(7):1463-72
references: 17546601
references: Cancer Res. 2008 Jun 15;68(12):4606-13
references: 18559505
references: J Cell Sci. 1999 Dec;112 ( Pt 24):4615-25
references: 10574710
references: Br J Cancer. 1999 Jun;80(7):946-53
references: 10362101
references: Nat Rev Cancer. 2004 Dec;4(12):948-55
references: 15573116
references: Gynecol Oncol. 2004 Apr;93(1):170-81
references: 15047232
references: Crit Rev Oncol Hematol. 2009 Oct;72(1):1-9
references: 19179094
references: J Transl Med. 2006 Jan 24;4:6
references: 16433903
references: Chem Rev. 2010 May 12;110(5):2795-838
references: 20353192
references: Cancer. 2007 Apr 1;109(7):1323-30
references: 17330838
references: Cancer Metastasis Rev. 2003 Dec;22(4):465-72
references: 12884919
references: Cell. 2002 Oct 4;111(1):29-40
references: 12372298
references: Nat Rev Mol Cell Biol. 2011 Mar;12(3):189-97
references: 21346732
references: Cancer Treat Res. 2007;134:493-514
references: 17633077
references: Methods. 2003 Jul;30(3):256-68
references: 12798140
references: J Cell Sci. 2003 Jun 15;116(Pt 12):2377-88
references: 12766184
references: Science. 2001 May 4;292(5518):929-34
references: 11340206
references: J Cell Physiol. 2005 Oct;205(1):86-96
references: 15880654
references: Cancer Res. 2005 Oct 15;65(20):9455-62
references: 16230409
references: Biotechnol J. 2011 Feb;6(2):204-212
references: 21298805
references: Cell. 2011 Oct 14;147(2):275-92
references: 22000009
references: Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):9064-8
references: 1384042
references: Annu Rev Cell Dev Biol. 2006;22:287-309
references: 16824016
references: Cell Signal. 1998 Jan;10(1):55-63
references: 9502118
references: Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14229-34
references: 14623978
references: Mol Cell. 2003 Oct;12(4):889-901
references: 14580340
references: Curr Med Chem. 2008;15(17):1655-73
references: 18673216
references: Cancer Res. 2008 Apr 1;68(7):2329-39
references: 18381440
references: Nat Rev Mol Cell Biol. 2011 Feb;12(2):104-17
references: 21252999
references: Nat Rev Cancer. 2009 Apr;9(4):239-52
references: 19279573
references: Nanomedicine. 2010 Jun;6(3):399-408
references: 19969103
references: Cancer Res. 2010 Nov 15;70(22):9234-42
references: 21045152
references: Cancer Sci. 2010 Feb;101(2):293-9
references: 19961486
references: J Am Coll Surg. 2004 Jun;198(6):999-1011
references: 15194082
references: Clin Cancer Res. 2005 Dec 15;11(24 Pt 1):8637-43
references: 16361548
references: Oncogene. 2004 Apr 19;23(18):3248-64
references: 15094774
references: Nat Rev Cancer. 2009 Jun;9(6):415-28
references: 19461667
references: Proteomics. 2002 Jan;2(1):69-75
references: 11788993
references: J Oncol. 2012;2012:915140
references: 22235205
references: Proc Natl Acad Sci U S A. 2012 Feb 14;109(7):2358-63
references: 22308459
references: J Cell Biol. 2008 Oct 6;183(1):143-55
references: 18838556
references: Cancer Cell. 2007 Jun;11(6):526-38
references: 17560334
references: Am J Pathol. 2011 Aug;179(2):580-9
references: 21722621
references: Nat Rev Cancer. 2011 Sep 23;11(10):719-25
references: 21941283
references: Br J Cancer. 2004 Aug 2;91(3):470-5
references: 15226774
references: Lab Invest. 1988 Jun;58(6):725-32
references: 3288807
references: J Vis Exp. 2009 Dec 17;(34):
references: 20019656
references: Nat Cell Biol. 2001 Sep;3(9):785-92
references: 11533657
references: Nat Protoc. 2009;4(11):1591-613
references: 19834475
references: Nat Biotechnol. 1999 Oct;17(10):994-9
references: 10504701
references: Nat Methods. 2007 Apr;4(4):359-65
references: 17396127
references: Nat Rev Cancer. 2010 Jan;10(1):9-22
references: 20029421
references: Chem Soc Rev. 2013 Jul 7;42(13):5788-808
references: 23575660
references: J Natl Cancer Inst. 2001 Sep 19;93(18):1375-84
references: 11562388
references: Am J Physiol Cell Physiol. 2006 Jun;290(6):C1532-42
references: 16394028
references: PLoS One. 2011;6(7):e21409
references: 21754988
references: Acta Pathol Microbiol Scand. 1953;33(1):10-21
references: 13113944
references: J Natl Cancer Inst. 2005 Oct 19;97(20):1516-24
references: 16234565
references: J Cell Physiol. 2007 Dec;213(3):581-8
references: 17708542
references: Lab Chip. 2007 Aug;7(8):1041-7
references: 17653347
references: J Biomed Sci. 2012 Feb 14;19:23
references: 22330345
references: Lab Chip. 2011 Nov 21;11(22):3880-7
references: 21975823
references: PLoS One. 2012;7(12):e50809
references: 23226541
references: Nat Rev Mol Cell Biol. 2005 Apr;6(4):318-27
references: 15803138
references: Nat Rev Cancer. 2002 Aug;2(8):563-72
references: 12154349
references: Biochem Pharmacol. 1986 Feb 1;35(3):467-72
references: 3947382
references: Proc Natl Acad Sci U S A. 2008 Mar 11;105(10):3927-32
references: 18310319
references: Cancer Treat Res. 1996;82:79-100
references: 8849945
references: Cancer Res. 2010 Nov 15;70(22):9319-28
references: 21062986
references: PLoS One. 2012;7(3):e34071
references: 22479527
references: FEBS Lett. 2000 Aug 25;480(1):2-16
references: 10967322
references: Nat Rev Drug Discov. 2010 Oct;9(10):804-20
references: 20885411
references: Cancer Biol Ther. 2007 Apr;6(4):490-3
references: 17457044
references: Am J Pathol. 2010 Sep;177(3):1053-64
references: 20651229
references: Science. 2011 Mar 25;331(6024):1559-64
references: 21436443
references: J Oncol. 2010;2010:414676
references: 20066160
references: Exp Cell Res. 1998 Dec 15;245(2):350-9
references: 9851876
references: Nat Rev Cancer. 2005 May;5(5):355-66
references: 15864277
references: Nat Rev Cancer. 2008 Apr;8(4):253-67
references: 18354415