title: Inhibition of breast cancer metastasis by resveratrol-mediated inactivation of tumor-evoked regulatory B cells.
abstract: We reported previously that tumor-evoked regulatory B cells (tBregs) play an essential role in breast cancer lung metastasis by inducing TGF-β-dependent conversion of metastasis-promoting Foxp3(+) regulatory T cells (Tregs). In this article, we show that resveratrol (RSV), a plant-derived polyphenol, at low and noncytotoxic doses for immune cells, can efficiently inhibit lung metastasis in mice. The mechanism of this process is that RSV inactivates Stat3, preventing the generation and function of tBregs, including expression of TGF-β. As a result, it frees antitumor effector immune responses by disabling tBreg-induced conversion of Foxp3(+) Tregs. We propose that low doses of RSV may also benefit humans by controlling cancer escape-promoting tBregs/Tregs without nonspecific inactivation of effector immune cells.
authors.affiliation: Immunoregulation Section, Laboratory of Molecular Biology and Immunology, National Institute on Aging, Baltimore, MD 21224;
authors.forename: Catalina
authors.initials: C
authors.lastname: Lee-Chang
authors.forename: Monica
authors.initials: M
authors.lastname: Bodogai
authors.forename: Alejandro
authors.initials: A
authors.lastname: Martin-Montalvo
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Wejksza
authors.forename: Mitesh
authors.initials: M
authors.lastname: Sanghvi
authors.forename: Ruin
authors.initials: R
authors.lastname: Moaddel
authors.forename: Rafael
authors.initials: R
authors.lastname: de Cabo
authors.forename: Arya
authors.initials: A
authors.lastname: Biragyn
mesh_terms: D000818:Animals; D060151:B-Lymphocytes, Regulatory / Q000187:drug effects*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control* / Q000556:secondary; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D000077185:Resveratrol; D050796:STAT3 Transcription Factor / Q000187:drug effects / Q000378:metabolism; D013267:Stilbenes / Q000627:therapeutic use*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D013267:Stilbenes; D016212:Transforming Growth Factor beta; D000077185:Resveratrol
references.citation: J Immunol. 2011 May 15;186(10):5656-62
references.pmid: 21490155
references.citation: Mol Cancer Ther. 2006 Mar;5(3):621-9
references.pmid: 16546976
references.citation: J Immunol. 2006 Jan 1;176(1):284-90
references.pmid: 16365420
references.citation: Cancer Res. 2008 Apr 15;68(8):2561-3
references.pmid: 18413722
references.citation: Prostate. 2013 May;73(7):754-62
references.pmid: 23192356
references.citation: Cancer Res. 2011 May 15;71(10):3505-15
references.pmid: 21444674
references.citation: J Immunol. 2013 Mar 15;190(6):2575-84
references.pmid: 23408836
references.citation: Science. 1997 Jan 10;275(5297):218-20
references.pmid: 8985016
references.citation: Oncogene. 2013 Oct 17;32(42):5111-22
references.pmid: 23208501
references.citation: J Neurochem. 2011 May;117(4):678-90
references.pmid: 21375533
references.citation: Int Immunopharmacol. 2012 Nov;14(3):328-33
references.pmid: 22884509
references.citation: Blood. 2005 Sep 15;106(6):2018-25
references.pmid: 15914560
references.citation: PLoS One. 2012;7(4):e35650
references.pmid: 22532866
references.citation: Cancer Cell. 2005 May;7(5):411-23
references.pmid: 15894262
references.citation: Cancer Immunol Immunother. 2004 Feb;53(2):64-72
references.pmid: 14593498
references.citation: Nat Med. 1998 May;4(5):627-30
references.pmid: 9585241
references.citation: J Immunol. 2002 May 1;168(9):4272-6
references.pmid: 11970966
references.citation: J Immunol. 2008 Oct 15;181(8):5791-802
references.pmid: 18832739
references.citation: Cancer Res. 2010 Jan 1;70(1):99-108
references.pmid: 19996287
references.citation: Clin Exp Metastasis. 1999 Mar;17(2):163-70
references.pmid: 10411109
references.citation: Am J Respir Crit Care Med. 2011 May 15;183(10):1369-79
references.pmid: 21278302
references.citation: Toxicol Sci. 2004 Dec;82(2):614-9
references.pmid: 15329443
references.citation: Biochem Biophys Res Commun. 2002 Mar 8;291(4):1001-5
references.pmid: 11866465
references.citation: Cancer Res. 2009 Jul 15;69(14):5996-6004
references.pmid: 19567680
references.citation: Cancer Res. 2013 Apr 1;73(7):2127-38
references.pmid: 23365136
references.citation: Arch Biochem Biophys. 2009 Jun 15;486(2):95-102
references.pmid: 19514131
references.citation: Antioxid Redox Signal. 2001 Dec;3(6):969-79
references.pmid: 11813992
references.citation: Oncogene. 2006 Apr 20;25(17):2520-30
references.pmid: 16474852
references.citation: Cancer Res. 2001 Oct 15;61(20):7456-63
references.pmid: 11606380
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2007 Apr 1;848(2):182-7
references.pmid: 17097357
references.citation: J Clin Invest. 2011 Sep;121(9):3645-56
references.pmid: 21821911
references.citation: J Immunol. 2008 Dec 15;181(12):8278-87
references.pmid: 19050244
references.citation: J Invest Dermatol. 2005 Mar;124(3):570-8
references.pmid: 15737198
references.citation: Nat Med. 2004 Sep;10(9):942-9
references.pmid: 15322536
references.citation: Cancer Res. 2013 Apr 15;73(8):2468-79
references.pmid: 23384943
references.citation: J Leukoc Biol. 2012 Sep;92(3):673-82
references.pmid: 22636320
references.citation: Blood. 2007 Mar 15;109(6):2293-302
references.pmid: 17164350
references.citation: Br J Haematol. 2013 Mar;160(5):714-7
references.pmid: 23205612
references.citation: J Immunol. 2005 Jan 15;174(2):636-45
references.pmid: 15634881
references.citation: Neoplasia. 2005 Jan;7(1):37-47
references.pmid: 15736313
references.citation: Diabetes. 2013 Apr;62(4):1186-95
references.pmid: 23193181
references.citation: Drug Metab Dispos. 2004 Dec;32(12):1377-82
references.pmid: 15333514
references.citation: Int Immunopharmacol. 2008 Apr;8(4):542-7
references.pmid: 18328445
references.citation: J Exp Med. 2003 Aug 18;198(4):569-80
references.pmid: 12925674
references.citation: Inflamm Bowel Dis. 2012 Apr;18(4):613-23
references.pmid: 22431488
references.citation: Proc Natl Acad Sci U S A. 2012 May 15;109(20):7765-9
references.pmid: 22547799
references.citation: Ann Oncol. 2004 Jul;15(7):1109-14
references.pmid: 15205206
references.citation: Nature. 2010 Mar 11;464(7286):302-5
references.pmid: 20220849
references.citation: FEBS Lett. 2008 Mar 5;582(5):586-90
references.pmid: 18242191
references.citation: Proc Natl Acad Sci U S A. 2007 Apr 24;104(17):7217-22
references.pmid: 17438283
references.citation: Cell Metab. 2010 Jun 9;11(6):554-65
references.pmid: 20519126
references.citation: Proc Natl Acad Sci U S A. 2005 Mar 15;102(11):4103-8
references.pmid: 15753318
references.citation: Cancer Res. 2008 Jul 1;68(13):5439-49
references.pmid: 18593947