The IL-6/JAK/Stat3 feed-forward loop drives tumorigenesis and metastasis

Qing Chang, Eirini Bournazou, Pasquale Sansone, Marjan Berishaj, Sizhi Paul Gao, Laura Daly, Jared Wels, Till Theilen, Selena Granitto, Xinmin Zhang, Jesse Cotari, Mary L. Alpaugh, Elisa de Stanchina, Katia Manova, Ming Li, Massimiliano Bonafe, Claudio Ceccarelli, Mario Taffurelli, Donatella Santini, Gregoire Altan-BonnetRosandra Kaplan, Larry Norton, Norihiro Nishimoto, Dennis Huszar, David Lyden, Jacqueline Bromberg

Research output: Contribution to journalArticlepeer-review

222 Scopus citations

Abstract

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 potential of interrupting this pathway with IL-6 receptor blockade or by inhibiting its downstream effectors JAK1/2 or Stat3. These clinically relevant interventions did not inhibit tumor cell proliferation in vitro but had profound effects in vivo on tumor progression, interfering broadly with tumor-supportive stromal functions, including angiogenesis, fibroblast infiltration, and myeloid suppressor cell recruitment in both the tumor and pre-metastatic niche. This study provides the first evidence for IL-6 expression at the leading edge of invasive human breast tumors and demonstrates mechanistically that IL-6/JAK/Stat3 signaling plays a critical and pharmacologically targetable role in orchestrating the composition of the tumor microenvironment that promotes growth, invasion, and metastasis.

Original languageEnglish (US)
Pages (from-to)848-862
Number of pages15
JournalNeoplasia (United States)
Volume15
Issue number7
DOIs
StatePublished - Jul 2013

All Science Journal Classification (ASJC) codes

  • Cancer Research

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