期刊
NEOPLASIA
卷 15, 期 7, 页码 848-+出版社
NEOPLASIA PRESS
DOI: 10.1593/neo.13706
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资金
- National Institutes of Health [U54: CA148967, R01: CA87637]
- Charles and Marjorie Holloway Foundation
- Sussman Family Fund
- Lerner Foundation
- AstraZeneca
- Breast Cancer Alliance
- Manhasset Women's Coalition Against Breast Cancer
- NYS Women's Bowling Association
- American Hellenic Educational Progressive Association 5th District
- Department of Defense [W81XWH-10-1-1013]
- Fondazione Carisbo di Bologna
- Children's Cancer and Blood Foundation
- Manning Foundation
- Hartwell Foundation
- Pediatric Oncology Experimental Therapeutics Investigators Consortium
- Stavros S. Niarchos Foundation
- Champalimaud Foundation
- Nancy C. and Daniel P. Paduano Foundation
- Mary Kay Foundation
- Malcolm Hewitt Wiener Foundation
- George Best Costacos Foundation
- National Cancer Institute [R01CA 098234-01, U54-CA143836]
- Susan G. Komen
- Beth C. Tortolani Foundation
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.
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