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

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

Authors:	Chang, Q.; Bournazou, E.; Sansone, P.; Berishaj, M.; Gao, S. P.; Daly, L.; Wels, J.; Theilen, T.; Granitto, S.; Zhang, X.; Cotari, J. ; Alpaugh, M. L.; de Stanchina, E.; Manova, K.; Li, M.; Bonafe, M.; Ceccarelli, C.; Taffurelli, M.; Santini, D.; Altan-Bonnet, G.; Kaplan, R.; Norton, L.; Nishimoto, N.; Huszar, D.; Lyden, D.; Bromberg, J.
Article Title:	The IL-6/JAK/Stat3 feed-forward loop drives tumorigenesis and metastasis
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. © 2013 Neoplasia Press, Inc. All rights reserved.
Keywords:	immunohistochemistry; signal transduction; human tissue; protein expression; nonhuman; flow cytometry; cd3 antigen; cd8 antigen; cell proliferation; animal cell; mouse; animal tissue; stat3 protein; reverse transcription polymerase chain reaction; green fluorescent protein; animal model; angiogenesis; enzyme linked immunosorbent assay; carcinogenesis; transgenic mouse; janus kinase; cd11b antigen; western blotting; interleukin 6; immunofluorescence test; cd4 antigen; tumor growth; breast metastasis; cd45 antigen; cd33 antigen; interleukin 1; tumor microenvironment; nitric oxide; arginase; puromycin; lymph vessel metastasis; penicillin binding protein 2a
Journal Title:	NeoPlasia
Volume:	15
Issue:	7
ISSN:	1522-8002
Publisher:	Elsevier Science Inc.
Date Published:	2013-07-01
Start Page:	848
End Page:	862
Language:	English
DOI:	10.1593/neo.13706
PROVIDER:	scopus
PMCID:	PMC3689247
PUBMED:	23814496
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84879731392&partnerID=40&md5=cb4b43b9b255737fa553f20b8a189917
Notes:	--- - "Export Date: 1 August 2013" - "CODEN: NEOPF" - "Source: Scopus"