The IL-6/JAK/Stat3 Feed-Forward Loop Drives Tumorigenesis and Metastasis

Neoplasia. 2013 Jul;15(7):848-62. doi: 10.1593/neo.13706.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Female
  • Gene Expression
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism*
  • Janus Kinase 3 / antagonists & inhibitors
  • Janus Kinase 3 / genetics
  • Janus Kinase 3 / metabolism*
  • Mice
  • Mice, Knockout
  • Neoplasm Metastasis
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neoplasms / pathology*
  • Pyrazoles / pharmacology
  • Pyrimidines / pharmacology
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction / drug effects
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / genetics

Substances

  • AZD 1480
  • Interleukin-6
  • Pyrazoles
  • Pyrimidines
  • STAT3 Transcription Factor
  • Janus Kinase 3