The IL-6 / JAK / Stat 3 Feed-Forward Loop Drives Tumorigenesis and Metastasis 1 , 2

We have investigated the importance of interleukin-6 (IL-6) in promoting tumor growth and metastasis. In human primary breast cancers, increased levels of IL-6 were found at the tumor leading edge and positively correlated with advanced stage, suggesting a mechanistic link between tumor cell production of IL-6 and invasion. In support of this hypothesis, we showed that the IL-6/Janus kinase (JAK)/signal transducer and activator of transcription 3 (Stat3) pathway drives tumor progression through the stroma and metastatic niche. Overexpression of IL-6 in tumor cell lines promoted myeloid cell recruitment, angiogenesis, and induced metastases. We demonstrated the therapeutic Abbreviations: IL-6, interleukin-6; JAK, Janus kinase; LVI, lymphovascular invasion; MFP, mammary fat pad; MDSCs, myeloid-derived suppressor cells; Stat3, signal transducer and activator of transcription 3; TN, triple negative Address all correspondence to: Jacqueline Bromberg, MD, PhD, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 397, New York, NY 10021. E-mail: bromberj@mskcc.org or David Lyden, MD, PhD, Departments of Pediatrics and Cell Biology, Weill Cornell Medical College, 515 E. 71st Street, S726, Box 284, New York, NY 10021. E-mail: dcl2001@med.cornell.edu Our work was supported by grants from the National Institutes of Health [U54: CA148967 (J.B. and G.A.-B.) and R01: CA87637 (J.B.)], Charles and Marjorie Holloway Foundation (J.B.), Sussman Family Fund (J.B.), Lerner Foundation (J.B.), AstraZeneca (J.B.), Breast Cancer Alliance (J.B.), Manhasset Women’s Coalition Against Breast Cancer (J.B.), NYS Women’s Bowling Association (J.B.), American Hellenic Educational Progressive Association 5th District (E.B. and D.L.), Department of Defense (Postdoctoral Award W81XWH-10-1-1013) and Fondazione Carisbo di Bologna (P.S.), Children’s Cancer and Blood Foundation (D.L.), The Manning Foundation (D.L.), The Hartwell Foundation (D.L.), Pediatric Oncology Experimental Therapeutics Investigators Consortium (D.L.), Stavros S. Niarchos Foundation (D.L.), Champalimaud Foundation (D.L.), The Nancy C. and Daniel P. Paduano Foundation (D.L.), The Mary Kay Foundation (D.L.), The Malcolm Hewitt Wiener Foundation (D.L.), The George Best Costacos Foundation (D.L.), National Cancer Institute [R01CA 098234-01 and U54-CA143836 PSOC training grant (D.L.)], Susan G. Komen for the Cure (D.L.), and The Beth C. Tortolani Foundation (J.B. and D.L.). J.B. has consulted for Roche, Medimmune, and Bristol-Myers Squibb and has received research support from AstraZeneca. No potential conflicts of interest were disclosed by the other authors. This article refers to supplementary materials, which are designated by Table W1 and Figures W1 to W4 and are available online at www.neoplasia.com. These authors contributed equally to the manuscript. Received 26 March 2013; Revised 19 April 2013; Accepted 22 April 2013 Copyright © 2013 Neoplasia Press, Inc. All rights reserved 1522-8002/13/$25.00 DOI 10.1593/neo.13706 *Department of Medicine, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, NY; Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, Cell and Developmental Biology,Weill Cornell Medical College (WCMC), New York, NY; Hofstra North Shore-LIJ School of Medicine, Manhasset, NY; Computational Biology Program, MSKCC, NewYork, NY; Department ofMolecular Pharmacology, MSKCC, New York, NY; Antitumor Assessment,MSKCC, NewYork, NY; **Molecular Cytology, MSKCC, New York, NY; Immunology Program, Sloan-Kettering Institute, MSKCC, New York, NY; Department of Experimental, Diagnostic and Specialty Medicine, Policlinico Universitario S. Orsola-Malpighi, Bologna, Italy; Department of Medical and Surgical Sciences, Policlinico Universitario S. Orsola-Malpighi, Bologna, Italy; Department of Anatomy and Histological Pathology, Policlinico Universitario S. Orsola-Malpighi, Bologna, Italy; Tumor Microenvironment Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD; ***Champalimaud Metastasis Programme, Lisbon, Portugal; TokyoMedical University, Tokyo, Japan; Oncology iMED, AstraZeneca, Waltham, MA; Department of Pediatrics, MSKCC, New York, NY; WCMC, New York, NY www.neoplasia.com Volume 15 Number 7 July 2013 pp. 848–862 848