Interleukin-11 Is the Dominant IL-6 Family Cytokine during Gastrointestinal Tumorigenesis and Can Be Targeted Therapeutically

被引：353

作者：

Putoczki, Tracy L. ^{[1
,6
]}

Thiem, Stefan ^{[1
]}

Loving, Andrea ^{[1
]}

Busutti, Rita A. ^{[3
,4
,5
]}

Wilson, Nicholas J. ^{[2
]}

Ziegler, Paul K. ^{[7
]}

Nguyen, Paul M. ^{[1
]}

Preaudet, Adele ^{[1
]}

Farid, Ryan ^{[1
]}

Edwards, Kirsten M. ^{[2
]}

Boglev, Yeliz ^{[1
]}

Luwor, Rodney B. ^{[6
]}

Jarnicki, Andrew ^{[1
]}

Horst, David ^{[8
]}

Boussioutas, Alex ^{[3
,4
,5
]}

Heath, Joan K. ^{[1
]}

Sieber, Oliver M. ^{[1
]}

Pleines, Irina ^{[9
]}

Kile, Benjamin T. ^{[9
]}

Nash, Andrew ^{[2
]}

Greten, Florian R. ^{[7
]}

McKenzie, Brent S. ^{[2
]}

Ernst, Matthias ^{[1
,6
]}

机构：

[1] Ludwig Inst Canc Res, Melbourne, Vic 3050, Australia

[2] CSL Ltd, Melbourne, Vic 3050, Australia

[3] Peter MacCallum Canc Ctr, Canc Genet & Genom Lab, East Melbourne, Vic 3002, Australia

[4] Univ Melbourne, Peter MacCallum Canc Ctr, Sir Peter MacCallum Dept Oncol, Melbourne, Vic 3010, Australia

[5] Univ Melbourne, Royal Melbourne Hosp, Dept Med, Melbourne, Vic 3050, Australia

[6] Univ Melbourne, Royal Melbourne Hosp, Dept Surg, Melbourne, Vic 3050, Australia

[7] Tech Univ Munich, Inst Mol Immunol, D-81675 Munich, Germany

[8] Univ Munich, Inst Pathol, D-80337 Munich, Germany

[9] Walter & Eliza Hall Inst Med Res, Parkville, Vic 3052, Australia

来源：

CANCER CELL | 2013年 / 24卷 / 02期

基金：

澳大利亚国家健康与医学研究理事会;

关键词：

MULTIPLE INTESTINAL NEOPLASIA; LYMPH-NODE METASTASIS; GASTRIC TUMORIGENESIS; SIGNALING PATHWAY; EPITHELIAL-CELLS; RECEPTOR-ALPHA; JAK2; INHIBITOR; MOUSE MODEL; STAT3; CANCER;

D O I：

10.1016/j.ccr.2013.06.017

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Among the cytokines linked to inflammation-associated cancer, interleukin (IL)-6 drives many of the cancer "hallmarks" through downstream activation of the gp130/STAT3 signaling pathway. However, we show that the related cytokine IL-11 has a stronger correlation with elevated STAT3 activation in human gastrointestinal cancers. Using genetic mouse models, we reveal that IL-11 has a more prominent role compared to IL-6 during the progression of sporadic and inflammation-associated colon and gastric cancers. Accordingly, in these models and in human tumor cell line xenograft models, pharmacologic inhibition of IL-11 signaling alleviated STAT3 activation, suppressed tumor cell proliferation, and reduced the invasive capacity and growth of tumors. Our results identify IL-11 signaling as a potential therapeutic target for the treatment of gastrointestinal cancers.

引用

页码：257 / 271

页数：15

共 63 条

[1] Interleukin-6 and cachexia in ApcMin/+ mice [J].

Baltgalvis, Kristen A. ;

Berger, Franklin G. ;

Pena, Maria Marjorette O. ;

Davis, J. Mark ;

Muga, Stephanie J. ;

Carson, James A. .

AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, 2008, 294 (02) :R393-R401

[2] TGF-β suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling [J].

Becker, C ;

Fantini, MC ;

Schramm, C ;

Lehr, HA ;

Wirtz, S ;

Nikolaev, A ;

Burg, J ;

Strand, S ;

Kiesslich, R ;

Huber, S ;

Ito, H ;

Nishimoto, N ;

Yoshizaki, K ;

Nishimoto, N ;

Galle, PR ;

Blessing, M ;

Rose-John, S ;

Neurath, MF .

IMMUNITY, 2004, 21 (04) :491-501

[3] High resolution colonoscopy in live mice [J].

Becker, C. ;

Fantini, M. C. ;

Neurath, M. F. .

NATURE PROTOCOLS, 2006, 1 (06) :2900-2904

[4] Local administration of interleukin-11 ameliorates intestinal radiation injury in rats [J].

Boerma, Marjan ;

Wang, Junru ;

Burnett, Alexander F. ;

Santin, Alessandro D. ;

Roman, Juan J. ;

Hauer-Jensen, Martin .

CANCER RESEARCH, 2007, 67 (19) :9501-9506

[5] gp130-Mediated Stat3 Activation in Enterocytes Regulates Cell Survival and Cell-Cycle Progression during Colitis-Associated Tumorigenesis [J].

Bollrath, Julia ;

Phesse, Toby J. ;

von Burstin, Vivian A. ;

Putoczki, Tracy ;

Bennecke, Moritz ;

Bateman, Trudie ;

Nebelsiek, Tim ;

Lundgren-May, Therese ;

Canli, Oezge ;

Schwitalla, Sarah ;

Matthews, Vance ;

Schmid, Roland M. ;

Kirchner, Thomas ;

Arkan, Melek C. ;

Ernst, Matthias ;

Greten, Florian R. .

CANCER CELL, 2009, 15 (02) :91-102

[6] Identification of a genetic locus controlling bacteria-driven colitis and associated cancer through effects on innate inflammation [J].

Boulard, Olivier ;

Kirchberger, Stefanie ;

Royston, Daniel J. ;

Maloy, Kevin J. ;

Powrie, Fiona M. .

JOURNAL OF EXPERIMENTAL MEDICINE, 2012, 209 (07) :1309-1324

[7] Dependency of Colorectal Cancer on a TGF-β-Driven Program in Stromal Cells for Metastasis Initiation [J].

Calon, Alexandre ;

Espinet, Elisa ;

Palomo-Ponce, Sergio ;

Tauriello, Daniele V. F. ;

Iglesias, Mar ;

Virtudes Cespedes, Maria ;

Sevillano, Marta ;

Nadal, Cristina ;

Jung, Peter ;

Zhang, Xiang H. -F. ;

Byrom, Daniel ;

Riera, Antoni ;

Rossell, David ;

Mangues, Ramon ;

Massague, Joan ;

Sancho, Elena ;

Batlle, Eduard .

CANCER CELL, 2012, 22 (05) :571-584

[8] Pharmacoeconomic analysis of oprelvekin (recombinant human interleukin-11) for secondary prophylaxis of thrombocytopenia in solid tumor patients receiving chemotherapy [J].

Cantor, SB ;

Elting, LS ;

Hudson, DV ;

Rubenstein, EB .

CANCER, 2003, 97 (12) :3099-3106

[9] Inborn Errors of Human JAKs and STATs [J].

Casanova, Jean-Laurent ;

Holland, Steven M. ;

Notarangelo, Luigi D. .

IMMUNITY, 2012, 36 (04) :515-528

[10] MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis [J].

Coussens, LM ;

Tinkle, CL ;

Hanahan, D ;

Werb, Z .

CELL, 2000, 103 (03) :481-490

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