title: Circulating fibrocytes prepare the lung for cancer metastasis by recruiting Ly-6C+ monocytes via CCL2.
abstract: Fibrocytes are circulating, hematopoietic cells that express CD45 and Col1a1. They contribute to wound healing and several fibrosing disorders by mechanisms that are poorly understood. In this report, we demonstrate that fibrocytes predispose the lung to B16-F10 metastasis by recruiting Ly-6C(+) monocytes. To do so, we isolated fibrocytes expressing CD45, CD11b, CD13, and Col1a1 from the lungs of wild type (WT) and Ccr5(-/-) mice. WT but not Ccr5(-/-) fibrocytes increased the number of metastatic foci when injected into Ccr5(-/-) mice (73 ± 2 versus 32 ± 5; p < 0.001). This process was MMP9 dependent. Injection of WT enhanced GFP(+) fibrocytes also increased the number of Gr-1(Int), CD11b(+), and enhanced GFP(-) monocytes. Like premetastatic-niche monocytes, these recruited cells expressed Ly-6C, CD117, and CD45. The transfer of these cells into Ccr5(-/-) mice enhanced metastasis (90 ± 8 foci) compared with B cells (27 ± 2), immature dendritic cells (31 ± 6), or alveolar macrophages (28 ± 3; p < 0.05). WT and Ccl2(-/-) fibrocytes also stimulated Ccl2 expression in the lung by 2.07 ± 0.05- and 2.78 ± 0.36-fold compared with Ccr5(-/-) fibrocytes (1.0 ± 0.06; p < 0.05). Furthermore, WT fibrocytes did not increase Ly-6C(+) monocytes in Ccr2(-/-) mice and did not promote metastasis in either Ccr2(-/-) or Ccl2(-/-) mice. These data support our hypothesis that fibrocytes contribute to premetastatic conditioning by recruiting Ly-6C(+) monocytes in a chemokine-dependent process. This work links metastatic risk to conditions that mobilize fibrocytes, such as inflammation and wound repair.
authors.affiliation: Department of Medicine, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599, USA. hvand@med.unc.edu
authors.forename: Hendrik W
authors.initials: HW
authors.lastname: van Deventer
authors.forename: Daniela A
authors.initials: DA
authors.lastname: Palmieri
authors.forename: Qing Ping
authors.initials: QP
authors.lastname: Wu
authors.forename: Everett C
authors.initials: EC
authors.lastname: McCook
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Serody
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism*; D024042:Collagen Type I / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D003713:Dendritic Cells / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism / Q000473:pathology*; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D054390:Receptors, CCR2 / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
references.citation: Exp Mol Med. 2010 Jun 30;42(6):465-72
references.pmid: 20498529
references.citation: J Leukoc Biol. 2010 Jul;88(1):41-55
references.pmid: 20360402
references.citation: Nat Rev Cancer. 2006 May;6(5):392-401
references.pmid: 16572188
references.citation: Semin Cell Dev Biol. 2010 Feb;21(1):40-6
references.pmid: 19944178
references.citation: Cell. 2006 Jan 27;124(2):263-6
references.pmid: 16439202
references.citation: QJM. 2012 Jun;105(6):505-8
references.pmid: 22627257
references.citation: Nature. 2005 Dec 8;438(7069):820-7
references.pmid: 16341007
references.citation: Cancer Res. 2011 Aug 1;71(15):5346-56
references.pmid: 21670082
references.citation: Virchows Arch. 2004 Mar;444(3):231-4
references.pmid: 14758552
references.citation: Nature. 2011 Jun 08;475(7355):222-5
references.pmid: 21654748
references.citation: Virchows Arch. 2002 Dec;441(6):564-8
references.pmid: 12461613
references.citation: Nat Rev Cancer. 2004 Jan;4(1):71-8
references.pmid: 14708027
references.citation: Nat Clin Pract Oncol. 2007 Dec;4(12):699-710
references.pmid: 18037874
references.citation: Proc Natl Acad Sci U S A. 1997 Jun 10;94(12):6307-12
references.pmid: 9177213
references.citation: J Clin Endocrinol Metab. 2012 May;97(5):E740-6
references.pmid: 22399514
references.citation: Cancer Cell. 2012 Apr 17;21(4):488-503
references.pmid: 22516258
references.citation: Atherosclerosis. 2003 Mar;167(1):25-32
references.pmid: 12618265
references.citation: J Exp Med. 2003 Nov 17;198(10):1487-93
references.pmid: 14623905
references.citation: Am J Pathol. 2008 Jul;173(1):253-64
references.pmid: 18535183
references.citation: J Mol Med (Berl). 2011 Oct;89(10):997-1013
references.pmid: 21499735
references.citation: Exp Cell Res. 2005 Mar 10;304(1):81-90
references.pmid: 15707576
references.citation: Cancer Cell. 2008 Jan;13(1):23-35
references.pmid: 18167337
references.citation: Exp Dermatol. 2010 Aug;19(8):e142-50
references.pmid: 20100200
references.citation: J Biol Chem. 2007 Aug 3;282(31):22910-20
references.pmid: 17556364
references.citation: Mol Med. 1994 Nov;1(1):71-81
references.pmid: 8790603
references.citation: Arch Dermatol Res. 2012 Oct;304(8):665-71
references.pmid: 22407077
references.citation: Semin Cancer Biol. 2011 Apr;21(2):139-46
references.pmid: 21251983
references.citation: Blood. 2012 Mar 29;119(13):3164-75
references.pmid: 22327225
references.citation: J Orthop Res. 2007 Jan;25(1):44-50
references.pmid: 17001704
references.citation: J Invest Dermatol. 2011 Feb;131(2):529-36
references.pmid: 20962852
references.citation: Cancer Res. 2010 Dec 15;70(24):10161-9
references.pmid: 21159638
references.citation: Scand J Gastroenterol. 2011 Mar;46(3):333-40
references.pmid: 21091093
references.citation: Proc Natl Acad Sci U S A. 2009 Jul 14;106(28):11617-22
references.pmid: 19564624
references.citation: Chest. 2011 Aug;140(2):502-508
references.pmid: 21813529
references.citation: Cancer Res. 2005 Apr 15;65(8):3374-9
references.pmid: 15833871
references.citation: Int J Biochem Cell Biol. 2004 Apr;36(4):598-606
references.pmid: 15010326
references.citation: Ann Thorac Surg. 2011 Aug;92(2):470-7; discussion 477
references.pmid: 21801908
references.citation: Int J Biochem Cell Biol. 2009 Aug-Sep;41(8-9):1708-18
references.pmid: 19433312
references.citation: J Hypertens. 2008 Apr;26(4):780-90
references.pmid: 18327089
references.citation: Cancer Res. 2007 Oct 1;67(19):9518-27
references.pmid: 17909062
references.citation: DNA Cell Biol. 2012 Aug;31(8):1418-24
references.pmid: 22612293
references.citation: Nat Cell Biol. 2006 Dec;8(12):1369-75
references.pmid: 17128264
references.citation: Oral Oncol. 2010 May;46(5):336-42
references.pmid: 20219413
references.citation: Cancer Metastasis Rev. 2006 Dec;25(4):611-9
references.pmid: 17160712
references.citation: Int J Immunopathol Pharmacol. 2010 Jul-Sep;23(3):715-26
references.pmid: 20943041
references.citation: Cancer Cell. 2002 Oct;2(4):289-300
references.pmid: 12398893
references.citation: Cardiovasc Res. 2011 Feb 1;89(2):374-83
references.pmid: 21147810
references.citation: J Allergy Clin Immunol. 2011 Dec;128(6):1303-1309.e2
references.pmid: 21872912