title: Macrophage-secreted cytokines drive pancreatic acinar-to-ductal metaplasia through NF-κB and MMPs.
abstract: In response to inflammation, pancreatic acinar cells can undergo acinar-to-ductal metaplasia (ADM), a reprogramming event that induces transdifferentiation to a ductlike phenotype and, in the context of additional oncogenic stimulation, contributes to development of pancreatic cancer. The signaling mechanisms underlying pancreatitis-inducing ADM are largely undefined. Our results provide evidence that macrophages infiltrating the pancreas drive this transdifferentiation process. We identify the macrophage-secreted inflammatory cytokines RANTES and tumor necrosis factor α (TNF) as mediators of such signaling. Both RANTES and TNF induce ADM through activation of nuclear factor κB and its target genes involved in regulating survival, proliferation, and degradation of extracellular matrix. In particular, we identify matrix metalloproteinases (MMPs) as targets that drive ADM and provide in vivo data suggesting that MMP inhibitors may be efficiently applied to block pancreatitis-induced ADM in therapy.
authors.affiliation: Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Jacksonville, FL 32224, USA.
authors.forename: Geou-Yarh
authors.initials: GY
authors.lastname: Liou
authors.forename: Heike
authors.initials: H
authors.lastname: Döppler
authors.forename: Brian
authors.initials: B
authors.lastname: Necela
authors.forename: Murli
authors.initials: M
authors.lastname: Krishna
authors.forename: Howard C
authors.initials: HC
authors.lastname: Crawford
authors.forename: Massimo
authors.initials: M
authors.lastname: Raimondo
authors.forename: Peter
authors.initials: P
authors.lastname: Storz
mesh_terms: D061354:Acinar Cells / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008679:Metaplasia / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*; D010179:Pancreas / Q000378:metabolism* / Q000473:pathology
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D020782:Matrix Metalloproteinases
references.citation: Genes Dev. 2006 Jun 1;20(11):1435-40
references.pmid: 16751181
references.citation: Gastroenterology. 2007 Feb;132(2):745-62
references.pmid: 17258745
references.citation: Nat Genet. 2004 Jan;36(1):83-7
references.pmid: 14702043
references.citation: Development. 2005 Aug;132(16):3767-76
references.pmid: 16020518
references.citation: Int J Dev Biol. 2008;52(7):823-35
references.pmid: 18956314
references.citation: Nat Immunol. 2011 Jul 19;12(8):715-23
references.pmid: 21772280
references.citation: Nature. 2002 Dec 19-26;420(6917):860-7
references.pmid: 12490959
references.citation: Clin Cancer Res. 1999 Jan;5(1):119-27
references.pmid: 9918209
references.citation: J Clin Invest. 2012 Apr;122(4):1519-28
references.pmid: 22406536
references.citation: Pancreatology. 2005;5(4-5):361-9
references.pmid: 15980665
references.citation: Clin Cancer Res. 2005 May 1;11(9):3587-96
references.pmid: 15867264
references.citation: J Surg Res. 2004 May 1;118(1):9-14
references.pmid: 15093710
references.citation: Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12236-41
references.pmid: 12221286
references.citation: Cancer Cell. 2011 Apr 12;19(4):441-55
references.pmid: 21481787
references.citation: J Cell Biochem. 2007 Jul 1;101(4):887-907
references.pmid: 17266048
references.citation: Cell. 1997 Jan 24;88(2):213-22
references.pmid: 9008162
references.citation: Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4437-42
references.pmid: 17360542
references.citation: Nat Rev Cancer. 2002 Dec;2(12):897-909
references.pmid: 12459728
references.citation: Am J Surg Pathol. 2001 May;25(5):579-86
references.pmid: 11342768
references.citation: Neoplasia. 2007 Nov;9(11):979-86
references.pmid: 18030366
references.citation: J Cell Biol. 2001 Nov 12;155(4):519-30
references.pmid: 11696558
references.citation: Dev Cell. 2010 Mar 16;18(3):342-56
references.pmid: 20230744
references.citation: Immunology. 2008 Nov;125(3):344-58
references.pmid: 18422969
references.citation: Cancer Cell. 2012 Sep 11;22(3):304-17
references.pmid: 22975374
references.citation: Am J Physiol. 1998 Dec;275(6):G1402-14
references.pmid: 9843778
references.citation: Gastroenterology. 1998 Nov;115(5):1254-62
references.pmid: 9797382
references.citation: Cancer Res. 2006 Sep 15;66(18):9045-53
references.pmid: 16982746
references.citation: Nat Rev Cancer. 2010 Oct;10(10):683-95
references.pmid: 20814421
references.citation: J Clin Invest. 2012 Feb;122(2):639-53
references.pmid: 22232209
references.citation: Cancer Res. 1999 Mar 1;59(5):987-90
references.pmid: 10070951
references.citation: Cancer Cell. 2007 Mar;11(3):291-302
references.pmid: 17349585
references.citation: Pancreas. 2002 Jul;25(1):26-30
references.pmid: 12131767
references.citation: Mol Cell Biol. 2009 Sep;29(18):4906-17
references.pmid: 19564415
references.citation: Gastroenterology. 1999 Dec;117(6):1416-26
references.pmid: 10579983
references.citation: Methods Mol Med. 2005;103:259-71
references.pmid: 15542912
references.citation: J Clin Invest. 2010 Feb;120(2):508-20
references.pmid: 20071774
references.citation: J Clin Invest. 2002 Jun;109(11):1437-44
references.pmid: 12045257
references.citation: Cancer Cell. 2011 Jun 14;19(6):728-39
references.pmid: 21665147
references.citation: Gastroenterology. 2007 Dec;133(6):1999-2009
references.pmid: 18054571
references.citation: J Cell Biol. 2012 Dec 24;199(7):1117-30
references.pmid: 23266956
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19327-32
references.pmid: 18042722
references.citation: Int J Cancer. 1995 Aug 9;62(4):407-13
references.pmid: 7635566
references.citation: Cancer Res. 2007 Aug 1;67(15):7068-71
references.pmid: 17652141
references.citation: Cancer Cell. 2003 Dec;4(6):437-50
references.pmid: 14706336
references.citation: Am J Pathol. 2007 Jul;171(1):263-73
references.pmid: 17591971