title: Integrin αvβ3 and fibronectin upregulate Slug in cancer cells to promote clot invasion and metastasis.
abstract: The blood clotting cascade is selectively involved in lung metastasis, but the reason for this selectivity is unclear. Here, we show that tumor cells that metastasize predominantly to the lung, such as renal cell carcinoma (RCC) and soft tissue sarcoma (STS), have an inherent capacity to generate extensive invadopodia when embedded in a blood clot. Compared with other metastatic cancer cells tested, RCC and STS cells exhibited increased levels of expression of fibronectin and an activated form of the integrin αvβ3, which coordinately supported the generation of an elaborate fibronectin matrix and actin stress fibers in fibrin-embedded tumor cells. Together, fibronectin and αvβ3 induced upregulation of the transcription factor Slug, which mediates epithelial-mesenchymal transition as well as fibrin invasion and lung metastasis. This mechanism is clinically significant, because primary cancer cells from patients with metastatic RCC strongly invaded fibrin and this correlated with fibronectin matrix formation and Slug expression. In contrast, tumor cells from patients with localized RCC were largely noninvasive. Together, our findings establish that activated integrin αvβ3 and fibronectin promote lung metastasis by upregulating Slug, defining a mechanism through which cancer cells can colonize blood clots in the lung vasculature.
authors: Authors' Affiliations: Department of Urology, University of Pittsburgh School of Medicine, Shadyside Medical Center; and Prostate and Urological Cancers Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors: Lynn M
authors: LM
authors: Knowles
authors: Lisa A
authors: LA
authors: Gurski
authors: Charlotte
authors: C
authors: Engel
authors: James R
authors: JR
authors: Gnarra
authors: Jodi K
authors: JK
authors: Maranchie
authors: Jan
authors: J
authors: Pilch
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D005260:Female; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008819:Mice, Nude; D018613:Microscopy, Confocal; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000097:blood* / Q000378:metabolism / Q000473:pathology*; D000071250:Snail Family Transcription Factors; D013927:Thrombosis / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D005353:Fibronectins; D039302:Integrin alphaVbeta3; C000604407:SNAI1 protein, human; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors
references: Cancer Cell. 2011 Jun 14;19(6):695-7
references: 21665143
references: J Urol. 2011 Feb;185(2):439-44
references: 21167518
references: Oncogene. 2000 Jun 29;19(28):3156-63
references: 10918570
references: Nature. 2005 Jul 28;436(7050):518-24
references: 16049480
references: Cancer Res. 2004 Dec 1;64(23):8613-9
references: 15574768
references: Clin Cancer Res. 2005 Nov 15;11(22):8070-8
references: 16299238
references: Nat Rev Mol Cell Biol. 2006 Feb;7(2):131-42
references: 16493418
references: Proc Natl Acad Sci U S A. 2004 Dec 7;101(49):17210-5
references: 15563590
references: PLoS One. 2013;8(4):e60483
references: 23577117
references: Proc Natl Acad Sci U S A. 2012 Jan 24;109(4):1127-32
references: 22210108
references: Oncogene. 2010 Aug 19;29(33):4658-70
references: 20562906
references: Cancer Res. 1997 Apr 15;57(8):1554-60
references: 9108459
references: Cancer Res. 2007 Jan 15;67(2):659-64
references: 17234776
references: J Cell Sci. 2007 Nov 15;120(Pt 22):3989-98
references: 17971419
references: PLoS One. 2012;7(2):e31557
references: 22363672
references: Cancer Cell. 2010 Jan 19;17(1):53-64
references: 20129247
references: Nat Mater. 2012 Jul 01;11(8):734-41
references: 22751180
references: Oncogene. 2013 Aug 22;32(34):3980-91
references: 22986522
references: Semin Surg Oncol. 1988;4(1):20-6
references: 3353620
references: Cancer Res. 1991 Sep 1;51(17):4549-56
references: 1873799
references: Int J Cancer. 1984 Jan 15;33(1):87-94
references: 6363308
references: Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1853-8
references: 11172040
references: Mol Biol Cell. 2001 Jan;12(1):27-36
references: 11160820
references: Cancer. 2006 Apr 1;106(7):1624-33
references: 16518827
references: Nat Cell Biol. 2002 Aug;4(8):632-8
references: 12134161
references: Science. 1986 Jul 25;233(4762):467-70
references: 3726541
references: J Biol Chem. 2002 Jun 14;277(24):21930-8
references: 11934894
references: Nature. 2000 Aug 3;406(6795):532-5
references: 10952316
references: J Cell Biol. 2012 Feb 6;196(3):363-74
references: 22291038
references: J Angiogenes Res. 2010 Aug 11;2:14
references: 20701757
references: Cancer Cell. 2011 Nov 15;20(5):576-90
references: 22094253
references: Proc Natl Acad Sci U S A. 2012 Oct 9;109(41):16654-9
references: 23011797
references: Nat Med. 2009 Oct;15(10):1163-9
references: 19734908
references: Cancer Res. 2008 Aug 1;68(15):6241-50
references: 18676848
references: Cancer Res. 2010 Jun 1;70(11):4327-34
references: 20501851
references: J Biol Chem. 1999 Jul 30;274(31):21609-16
references: 10419468
references: Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):11832-6
references: 1465406
references: Microvasc Res. 1994 Nov;48(3):259-81
references: 7731392
references: Blood. 2005 Jan 1;105(1):178-85
references: 15367435
references: Cancer Res. 2009 Jun 15;69(12):4962-8
references: 19470770
references: Nat Rev Urol. 2010 Jun;7(6):327-38
references: 20458330
references: Cell. 1995 Dec 1;83(5):715-24
references: 8521488
references: Science. 2013 Feb 1;339(6119):580-4
references: 23372014
references: J Cell Biol. 2003 Nov 24;163(4):847-57
references: 14623871
references: Nat Cell Biol. 2008 Mar;10(3):295-305
references: 18297062
references: Science. 2011 Mar 25;331(6024):1559-64
references: 21436443
references: Cell. 2006 Nov 17;127(4):679-95
references: 17110329
references: Oncogene. 2013 Feb 21;32(8):1041-9
references: 22508482
references: Cell. 2008 Apr 4;133(1):66-77
references: 18394990