title: The role IL-1 in tumor-mediated angiogenesis.
abstract: Tumor angiogenesis is one of the hallmarks of tumor progression and is essential for invasiveness and metastasis. Myeloid inflammatory cells, such as immature myeloid precursor cells, also termed myeloid-derived suppressor cells (MDSCs), neutrophils, and monocytes/macrophages, are recruited to the tumor microenvironment by factors released by the malignant cells that are subsequently "educated" in situ to acquire a pro-invasive, pro-angiogenic, and immunosuppressive phenotype. The proximity of myeloid cells to endothelial cells (ECs) lining blood vessels suggests that they play an important role in the angiogenic response, possibly by secreting a network of cytokines/chemokines and inflammatory mediators, as well as via activation of ECs for proliferation and secretion of pro-angiogenic factors. Interleukin-1 (IL-1) is an "alarm," upstream, pro-inflammatory cytokine that is generated primarily by myeloid cells. IL-1 initiates and propagates inflammation, mainly by inducing a local cytokine network and enhancing inflammatory cell infiltration to affected sites and by augmenting adhesion molecule expression on ECs and leukocytes. Pro-inflammatory mediators were recently shown to play an important role in tumor-mediated angiogenesis and blocking their function may suppress tumor progression. In this review, we summarize the interactions between IL-1 and other pro-angiogenic factors during normal and pathological conditions. In addition, the feasibility of IL-1 neutralization approaches for anti-cancer therapy is discussed.
authors.affiliation: The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences and The Cancer Research Center, Ben-Gurion University of the Negev Beer-Sheva, Israel.
authors.forename: Elena
authors.initials: E
authors.lastname: Voronov
authors.affiliation: The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences and The Cancer Research Center, Ben-Gurion University of the Negev Beer-Sheva, Israel.
authors.forename: Yaron
authors.initials: Y
authors.lastname: Carmi
authors.affiliation: The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences and The Cancer Research Center, Ben-Gurion University of the Negev Beer-Sheva, Israel.
authors.forename: Ron N
authors.initials: RN
authors.lastname: Apte
keywords: IL-1α; IL-1β; VEGF; VEGFR1; VEGFR2; angiogenesis; inflammation; myeloid cells
references.citation: FASEB J. 2004 Jan;18(1):161-3
references.pmid: 14597552
references.citation: J Clin Invest. 2005 Nov;115(11):2979-91
references.pmid: 16239969
references.citation: Adv Cancer Res. 2008;100:203-29
references.pmid: 18620097
references.citation: Blood. 2010 Apr 29;115(17):3632-9
references.pmid: 20200351
references.citation: Proc Natl Acad Sci U S A. 2008 May 6;105(18):6620-5
references.pmid: 18443294
references.citation: Cytokine Growth Factor Rev. 2002 Apr;13(2):135-41
references.pmid: 11900989
references.citation: Curr Opin Hematol. 2010 May;17(3):219-24
references.pmid: 20308892
references.citation: Cytokine Growth Factor Rev. 2010 Feb;21(1):3-10
references.pmid: 20005150
references.citation: J Mol Cell Cardiol. 1999 Mar;31(3):607-17
references.pmid: 10198191
references.citation: Trends Immunol. 2009 Sep;30(9):439-46
references.pmid: 19699681
references.citation: Cancer Cell. 2005 Sep;8(3):211-26
references.pmid: 16169466
references.citation: Am J Clin Nutr. 2006 Feb;83(2):447S-455S
references.pmid: 16470011
references.citation: Circulation. 1995 Jul 1;92(1):11-4
references.pmid: 7788904
references.citation: Semin Cancer Biol. 2012 Feb;22(1):33-40
references.pmid: 22210179
references.citation: Int J Cancer. 2005 Mar 1;113(6):911-9
references.pmid: 15514971
references.citation: Cell. 2011 Sep 16;146(6):873-87
references.pmid: 21925313
references.citation: Thromb Haemost. 2009 Sep;102(3):544-54
references.pmid: 19718476
references.citation: Mol Cell. 2011 Oct 21;44(2):265-78
references.pmid: 22017873
references.citation: Arterioscler Thromb Vasc Biol. 2012 May;32(5):1280-8
references.pmid: 22345171
references.citation: Am J Pathol. 2002 Feb;160(2):537-48
references.pmid: 11839574
references.citation: Clin Exp Rheumatol. 2002 Sep-Oct;20(5 Suppl 27):S1-13
references.pmid: 14989423
references.citation: Cell. 2010 Apr 2;141(1):39-51
references.pmid: 20371344
references.citation: Cell. 2011 Mar 4;144(5):646-74
references.pmid: 21376230
references.citation: J Clin Invest. 1993 Nov;92(5):2408-18
references.pmid: 7693761
references.citation: J Immunol. 2009 Oct 1;183(7):4705-14
references.pmid: 19752225
references.citation: Cancer Lett. 2013 Sep 28;338(2):219-28
references.pmid: 23707856
references.citation: Cell. 2010 Mar 19;140(6):821-32
references.pmid: 20303873
references.citation: BMC Med Genomics. 2010 May 13;3:18
references.pmid: 20465783
references.citation: Cancer Cell. 2002 Apr;1(3):219-27
references.pmid: 12086857
references.citation: Cancer Metastasis Rev. 2006 Sep;25(3):387-408
references.pmid: 17043764
references.citation: Nat Med. 2005 Mar;11(3):261-2
references.pmid: 15723071
references.citation: J Immunol. 2006 Jan 1;176(1):284-90
references.pmid: 16365420
references.citation: Int J Biochem Cell Biol. 1998 Oct;30(10):1075-9
references.pmid: 9785472
references.citation: Cancer Cell. 2008 Nov 4;14(5):408-19
references.pmid: 18977329
references.citation: Trends Immunol. 2001 Oct;22(10):536-7
references.pmid: 11574262
references.citation: J Cell Biol. 1990 Apr;110(4):1417-26
references.pmid: 1691192
references.citation: Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9349-54
references.pmid: 9689083
references.citation: Annu Rev Immunol. 2009;27:229-65
references.pmid: 19302040
references.citation: Br J Cancer. 2011 Jan 4;104(1):128-37
references.pmid: 21139583
references.citation: Eur J Cancer. 2006 Apr;42(6):751-9
references.pmid: 16530403
references.citation: Cytokine Growth Factor Rev. 2010 Feb;21(1):21-6
references.pmid: 20005148
references.citation: Cytokine Growth Factor Rev. 2002 Aug-Oct;13(4-5):323-40
references.pmid: 12220547
references.citation: Int Immunol. 2010 Apr;22(4):245-57
references.pmid: 20181656
references.citation: Immunology. 1990 Apr;69(4):548-53
references.pmid: 2185985
references.citation: Immunobiology. 2013 Nov;218(11):1370-5
references.pmid: 23932437
references.citation: Front Immunol. 2012 Sep 14;3:290
references.pmid: 23049530
references.citation: Am J Physiol Cell Physiol. 2011 Sep;301(3):C550-2
references.pmid: 21677261
references.citation: J Transl Med. 2006 Nov 10;4:48
references.pmid: 17096856
references.citation: Annu Rev Cell Dev Biol. 2011;27:563-84
references.pmid: 21756109
references.citation: Clin Exp Immunol. 1999 Jan;115(1):176-82
references.pmid: 9933439
references.citation: J Invest Dermatol. 2006 Feb;126(2):460-7
references.pmid: 16374459
references.citation: Immunity. 2013 Feb 21;38(2):203-5
references.pmid: 23438818
references.citation: Blood. 1996 Mar 15;87(6):2095-147
references.pmid: 8630372
references.citation: FASEB J. 2002 Sep;16(11):1471-3
references.pmid: 12205052
references.citation: Cancer Res. 2007 Feb 1;67(3):1062-71
references.pmid: 17283139
references.citation: Blood. 1994 Dec 15;84(12):4242-8
references.pmid: 7994038
references.citation: Immunol Rev. 2008 Apr;222:222-41
references.pmid: 18364005
references.citation: J Immunol. 2010 Oct 1;185(7):4457-69
references.pmid: 20805419
references.citation: PLoS One. 2011;6(6):e21467
references.pmid: 21731759
references.citation: Cancer Cell. 2013 Mar 18;23(3):277-86
references.pmid: 23518347
references.citation: Nat Rev Cancer. 2008 Aug;8(8):592-603
references.pmid: 18650835
references.citation: Semin Cancer Biol. 2002 Aug;12(4):277-90
references.pmid: 12147202
references.citation: Nat Immunol. 2009 Mar;10(3):241-7
references.pmid: 19221555
references.citation: Blood. 2004 Sep 15;104(6):1769-77
references.pmid: 15187022
references.citation: Keio J Med. 2012;61(2):47-56
references.pmid: 22760023
references.citation: Hum Immunol. 2009 May;70(5):325-30
references.pmid: 19236898
references.citation: Nature. 2011 May 19;473(7347):298-307
references.pmid: 21593862
references.citation: Proc Am Thorac Soc. 2011 Nov;8(6):508-11
references.pmid: 22052928
references.citation: Nat Rev Cancer. 2006 Nov;6(11):835-45
references.pmid: 17036040
references.citation: Immunol Rev. 2008 Dec;226:10-8
references.pmid: 19161412
references.citation: Nat Rev Drug Discov. 2004 Apr;3(4):330-9
references.pmid: 15060528
references.citation: J Immunother. 2010 May;33(4):335-51
references.pmid: 20386472
references.citation: J Immunol. 2005 Dec 15;175(12):8200-8
references.pmid: 16339559
references.citation: J Mol Med (Berl). 2011 Jul;89(7):635-45
references.pmid: 21365187
references.citation: J Biol Chem. 1996 Jan 12;271(2):603-6
references.pmid: 8557658
references.citation: Eur J Immunol. 2011 May;41(5):1203-17
references.pmid: 21523780
references.citation: Cancer Res. 2003 Sep 15;63(18):5957-61
references.pmid: 14522922
references.citation: Clin Pharmacol Ther. 2010 Apr;87(4):401-6
references.pmid: 20200512
references.citation: J Cell Sci. 2003 Dec 15;116(Pt 24):4871-81
references.pmid: 14625381
references.citation: Arthritis Rheum. 2002 Oct;46(10):2604-12
references.pmid: 12384918
references.citation: Cancer Res. 2011 Nov 15;71(22):6965-75
references.pmid: 21948958
references.citation: Front Immunol. 2013 Jul 08;4:177
references.pmid: 23847618
references.citation: Circ Res. 2004 Feb 6;94(2):230-8
references.pmid: 14656934
references.citation: Trends Immunol. 2012 Mar;33(3):119-26
references.pmid: 22277903
references.citation: Nat Rev Cancer. 2007 Jun;7(6):475-85
references.pmid: 17522716
references.citation: Eur J Clin Invest. 2013 Jan;43(1):100-7
references.pmid: 23083351
references.citation: Circ Res. 1999 Aug 6;85(3):221-8
references.pmid: 10436164
references.citation: J Immunol. 2002 Jul 1;169(1):469-75
references.pmid: 12077278
references.citation: J Immunol. 2013 Apr 1;190(7):3500-9
references.pmid: 23475218
references.citation: J Mol Cell Cardiol. 2004 Apr;36(4):469-80
references.pmid: 15081307
references.citation: Nat Med. 1995 Jan;1(1):27-31
references.pmid: 7584949
references.citation: Cancer Biol Ther. 2011 Nov 15;12(10):872-80
references.pmid: 21989163
references.citation: Clin Exp Immunol. 2012 Feb;167(2):195-205
references.pmid: 22235995
references.citation: Nature. 2005 Dec 15;438(7070):932-6
references.pmid: 16355210
references.citation: Genes Dev. 2006 Sep 15;20(18):2527-38
references.pmid: 16980582
references.citation: Blood. 2007 Oct 15;110(8):2907-15
references.pmid: 17638846
references.citation: Circulation. 2003 Nov 18;108(20):2511-6
references.pmid: 14581410
references.citation: Gynecol Endocrinol. 2006 Sep;22(9):495-500
references.pmid: 17071533
references.citation: Cancer Cell. 2009 Jan 6;15(1):21-34
references.pmid: 19111878
references.citation: J Immunotoxicol. 2010 Mar;7(1):27-38
references.pmid: 20001788
references.citation: Proc Natl Acad Sci U S A. 2011 Dec 20;108(51):20684-9
references.pmid: 22143786
references.citation: Cancer Cell. 2005 Oct;8(4):299-309
references.pmid: 16226705
references.citation: Nat Rev Rheumatol. 2010 Apr;6(4):232-41
references.pmid: 20177398
references.citation: Lancet. 2008 Mar 1;371(9614):771-83
references.pmid: 18275997
references.citation: Am J Pathol. 2010 Apr;176(4):1564-76
references.pmid: 20167863
references.citation: Nature. 2007 Dec 6;450(7171):825-31
references.pmid: 18064003
references.citation: Blood. 2011 Apr 7;117(14):3720-32
references.pmid: 21304099
references.citation: Mol Med. 2011 Sep-Oct;17(9-10):1045-55
references.pmid: 21670847
references.citation: Immunity. 2013 Feb 21;38(2):285-95
references.pmid: 23395675
references.citation: Br J Haematol. 1993 Nov;85(3):514-20
references.pmid: 7510989
references.citation: Nat Rev Drug Discov. 2012 Aug;11(8):633-52
references.pmid: 22850787
references.citation: Curr Top Microbiol Immunol. 2002;270:47-61
references.pmid: 12467243
references.citation: Circulation. 2001 Feb 6;103(5):634-7
references.pmid: 11156872
references.citation: Curr Mol Med. 2003 Nov;3(7):643-51
references.pmid: 14601638
references.citation: Arteriosclerosis. 1990 Jan-Feb;10(1):129-34
references.pmid: 2105090
references.citation: EMBO Mol Med. 2009 May;1(2):92-8
references.pmid: 20049709
references.citation: N Engl J Med. 2008 May 8;358(19):2039-49
references.pmid: 18463380
references.citation: Adv Exp Med Biol. 2007;601:265-70
references.pmid: 17713014
references.citation: J Cell Sci. 1994 Sep;107 ( Pt 9):2449-57
references.pmid: 7531200
references.citation: Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2645-50
references.pmid: 12598651
references.citation: Invest Ophthalmol Vis Sci. 2012 Mar 21;53(3):1530-8
references.pmid: 22323467
references.citation: Lab Invest. 2006 Jun;86(6):599-609
references.pmid: 16607378
references.citation: Semin Oncol. 2001 Dec;28(6):536-42
references.pmid: 11740806
references.citation: Cell. 2010 Mar 19;140(6):935-50
references.pmid: 20303881
references.citation: J Immunol. 2003 Oct 1;171(7):3385-93
references.pmid: 14500632
references.citation: J Nanobiotechnology. 2009 Oct 30;7:8
references.pmid: 19878566
references.citation: Cell. 1996 Dec 27;87(7):1153-5
references.pmid: 8980221
references.citation: J Immunol. 2006 Oct 1;177(7):4267-70
references.pmid: 16982859
references.citation: J Control Release. 2007 Nov 6;123(2):123-30
references.pmid: 17900737
references.citation: J Immunol. 2008 Jul 1;181(1):62-72
references.pmid: 18566370
references.citation: Stem Cells Dev. 2009 Jun;18(5):703-6
references.pmid: 19186995
references.citation: J Immunol. 2011 Nov 1;187(9):4835-43
references.pmid: 21930960
references.citation: Circ J. 2006 Sep;70(9):1195-9
references.pmid: 16936436
references.citation: Genes Dev. 2008 Mar 1;22(5):559-74
references.pmid: 18316475
references.citation: Cancer Microenviron. 2012 Aug;5(2):133-49
references.pmid: 21948460
references.citation: Biochem Biophys Res Commun. 2005 Jul 29;333(2):328-35
references.pmid: 15961063
references.citation: Endothelium. 2006 Mar-Apr;13(2):63-9
references.pmid: 16728325
references.citation: Thromb Haemost. 1999 Aug;82(2):748-54
references.pmid: 10605778
references.citation: Hum Gene Ther. 2003 Aug 10;14(12):1193-206
references.pmid: 12908970
references.citation: J Biochem Mol Biol. 2006 Sep 30;39(5):469-78
references.pmid: 17002866
references.citation: Curr Drug Targets. 2010 Sep;11(9):1133-46
references.pmid: 20545607
references.citation: Nat Rev Cancer. 2008 Aug;8(8):618-31
references.pmid: 18633355
references.citation: Cell. 2010 Mar 19;140(6):883-99
references.pmid: 20303878
references.citation: J Surg Res. 2009 May 15;153(2):274-81
references.pmid: 18952231
references.citation: Clin Cancer Res. 2006 Feb 15;12(4):1088-96
references.pmid: 16489061
references.citation: Nature. 2000 Sep 14;407(6801):249-57
references.pmid: 11001068
references.citation: Nature. 2005 Dec 15;438(7070):967-74
references.pmid: 16355214
references.citation: Nat Rev Immunol. 2010 Feb;10(2):89-102
references.pmid: 20081871
references.citation: Cell. 2007 Nov 2;131(3):463-75
references.pmid: 17981115
references.citation: Cell Cycle. 2003 May-Jun;2(3):192-3
references.pmid: 12734422
references.citation: Curr Opin Immunol. 2010 Apr;22(2):231-7
references.pmid: 20144856
references.citation: Cancer Metastasis Rev. 2010 Jun;29(2):317-29
references.pmid: 20422276
references.citation: J Exp Med. 2008 Jun 9;205(6):1261-8
references.pmid: 18490490
references.citation: Curr Opin Immunol. 2010 Feb;22(1):28-33
references.pmid: 20060699
references.citation: Annu Rev Immunol. 2009;27:519-50
references.pmid: 19302047
references.citation: Eur J Cancer. 2010 Dec;46(18):3400-8
references.pmid: 20801015
references.citation: J Immunol. 2003 Dec 15;171(12):6448-56
references.pmid: 14662844
references.citation: Nat Rev Immunol. 2012 Mar 22;12(4):253-68
references.pmid: 22437938
references.citation: Nat Med. 2003 Jun;9(6):653-60
references.pmid: 12778163