Elsevier

Neoplasia

Volume 15, Issue 7, July 2013, Pages 848-862, IN40-IN45
Neoplasia

The IL-6/JAK/Stat3 Feed-Forward Loop Drives Tumorigenesis and Metastasis1,2

https://doi.org/10.1593/neo.13706Get rights and content
Under a Creative Commons license
open access

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.

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

Cited by (0)

1

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.

2

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.

3

These authors contributed equally to the manuscript.