title: Macrophage-derived IL-1beta stimulates Wnt signaling and growth of colon cancer cells: a crosstalk interrupted by vitamin D3.
abstract: Tumor-associated macrophages mediate the link between inflammation and cancer progression. Here, we showed that macrophage-derived soluble factors induce canonical Wnt signaling in colon cancer cells and promote their growth. Tumor cells induced the release of interleukin (IL)-1beta from macrophages, which induced phosphorylation of GSK3beta, stabilized beta-catenin, enhanced T-cell factor (TCF)-dependent gene activation and induced the expression of Wnt target genes in tumor cells. Neutralization experiments using anti-IL-1beta-specific antibodies, or silencing of IL-1beta in THP1 macrophages, showed that IL-1beta was required for macrophages to induce Wnt signaling and to support the growth of tumor cells. Constitutive activation of signal transducer and activator of transcription (STAT)1 in THP1 macrophages was essential for the induction of IL-1beta and thus for the activation of beta-catenin signaling in tumor cells. Vitamin D3, an effective chemopreventive agent, interrupted this crosstalk by blocking the constitutive activation of STAT1 and the production of IL-1beta in macrophages, and therefore-in a vitamin D receptor-dependent manner-inhibited the ability of macrophages to activate Wnt signaling in colon carcinoma cells. Our data therefore established that vitamin D3 exerts its chemopreventive activity by interrupting a crosstalk between tumor epithelial cells and the tumor microenvironment.
authors.affiliation: Department of Oncology, Albert Einstein Cancer Center, Montefiore Medical Center, Bronx, NY10467, USA.
authors.forename: P
authors.initials: P
authors.lastname: Kaler
authors.forename: L
authors.initials: L
authors.lastname: Augenlicht
authors.forename: L
authors.initials: L
authors.lastname: Klampfer
mesh_terms: D000906:Antibodies / Q000494:pharmacology; D002450:Cell Communication / Q000187:drug effects*; D045744:Cell Line, Tumor; D002762:Cholecalciferol / Q000494:pharmacology*; D020868:Gene Silencing; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D018167:Receptors, Calcitriol / Q000378:metabolism; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects*; D014815:Vitamins / Q000494:pharmacology*; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000906:Antibodies; D053583:Interleukin-1beta; D009363:Neoplasm Proteins; D018167:Receptors, Calcitriol; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D014815:Vitamins; D051153:Wnt Proteins; D051176:beta Catenin; D002762:Cholecalciferol; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3
references.citation: Cancer Res. 2007 Sep 15;67(18):8477-85
references.pmid: 17875686
references.citation: Clin Cancer Res. 2000 Sep;6(9):3545-51
references.pmid: 10999742
references.citation: Cancer Res. 1982 Apr;42(4):1530-6
references.pmid: 6949641
references.citation: Oncogene. 2005 Jun 2;24(24):3932-41
references.pmid: 15856030
references.citation: J Cell Biol. 2001 Jul 23;154(2):369-87
references.pmid: 11470825
references.citation: Proc Natl Acad Sci U S A. 2005 Jan 4;102(1):99-104
references.pmid: 15615857
references.citation: J Natl Cancer Inst. 2003 Jun 18;95(12):896-905
references.pmid: 12813173
references.citation: Science. 2005 Feb 4;307(5710):734-8
references.pmid: 15692052
references.citation: Blood. 2006 Mar 1;107(5):2112-22
references.pmid: 16269622
references.citation: Mol Cell. 2006 Mar 17;21(6):799-809
references.pmid: 16543149
references.citation: Pathol Res Pract. 1998;194(10):701-4
references.pmid: 9820866
references.citation: Mol Cancer Res. 2003 Sep;1(11):855-62
references.pmid: 14517348
references.citation: Mol Cell Biol. 1996 May;16(5):2183-94
references.pmid: 8628285
references.citation: Cancer Causes Control. 2004 Mar;15(2):149-58
references.pmid: 15017127
references.citation: Nat Rev Cancer. 2003 Aug;3(8):601-14
references.pmid: 12894248
references.citation: J Clin Invest. 2007 May;117(5):1175-83
references.pmid: 17476347
references.citation: Cancer Cell. 2008 Nov 4;14(5):408-19
references.pmid: 18977329
references.citation: Cancer Res. 1992 Apr 1;52(7 Suppl):2067s-2070s
references.pmid: 1544142
references.citation: Carcinogenesis. 2008 Mar;29(3):666-72
references.pmid: 18204079
references.citation: J Surg Res. 2007 Oct;142(2):239-45
references.pmid: 17574271
references.citation: Anticancer Res. 2008 Sep-Oct;28(5A):2613-23
references.pmid: 19035286
references.citation: Cancer Epidemiol Biomarkers Prev. 2006 Jun;15(6):1126-31
references.pmid: 16775170
references.citation: EMBO J. 2008 Jun 18;27(12):1671-81
references.pmid: 18511911
references.citation: Science. 1993 Apr 2;260(5104):85-8
references.pmid: 8465203
references.citation: Mol Pharmacol. 2006 Mar;69(3):1041-7
references.pmid: 16354768
references.citation: Oncogene. 2007 Feb 15;26(7):1078-87
references.pmid: 16953230
references.citation: Clin Cancer Res. 2007 Mar 1;13(5):1472-9
references.pmid: 17332291
references.citation: J Pathol. 2005 Oct;207(2):147-55
references.pmid: 16104052
references.citation: J Med Food. 2006 Summer;9(2):135-7
references.pmid: 16822196
references.citation: Crit Rev Oncol Hematol. 2008 Apr;66(1):1-9
references.pmid: 17913510
references.citation: J Biol Chem. 2003 Nov 28;278(48):48137-45
references.pmid: 12972427
references.citation: Cancer Cell. 2005 Jan;7(1):17-23
references.pmid: 15652746
references.citation: Cancer Res. 2008 Jul 1;68(13):5086-95
references.pmid: 18593907
references.citation: J Biol Chem. 2004 Aug 27;279(35):36680-8
references.pmid: 15213223
references.citation: Nat Rev Cancer. 2007 Feb;7(2):139-47
references.pmid: 17218951
references.citation: J Immunol. 2005 Apr 15;174(8):4880-91
references.pmid: 15814715
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19977-82
references.pmid: 18077429
references.citation: Cancer Causes Control. 2000 May;11(5):459-66
references.pmid: 10877339
references.citation: Nat Med. 2004 Sep;10(9):917-9
references.pmid: 15322538
references.citation: Lancet. 1989 Nov 18;2(8673):1176-8
references.pmid: 2572900
references.citation: Nat Genet. 2004 Apr;36(4):417-22
references.pmid: 15034581
references.citation: Nat Rev Cancer. 2004 Jan;4(1):71-8
references.pmid: 14708027
references.citation: Nature. 2006 Jun 22;441(7096):1015-9
references.pmid: 16791201
references.citation: Cell. 2006 Oct 6;127(1):139-55
references.pmid: 17018282
references.citation: Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10356-61
references.pmid: 11526241
references.citation: Nature. 1995 Dec 21-28;378(6559):785-9
references.pmid: 8524413
references.citation: J Exp Med. 2008 Jun 9;205(6):1261-8
references.pmid: 18490490
references.citation: Science. 2002 May 31;296(5573):1644-6
references.pmid: 12040179
references.citation: Cancer. 1991 Sep 1;68(5):1035-44
references.pmid: 1655212
references.citation: Nat Genet. 2004 Apr;36(4):320-2
references.pmid: 15054482
references.citation: Nat Genet. 2008 May;40(5):650-5
references.pmid: 18408720