The IL-6/JAK/Stat3 feed-forward loop drives tumorigenesis and metastasis
Open accessAbstract
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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pSTAT3 induces transcription of multiple genes, including IL6 and IL6R, which amplifies IL-6/STAT3 signaling.
“pSTAT3 induces the transcription of multiple genes, including IL6 and IL6R, which has the effect of amplifying IL-6/STAT3 signaling.”
From Dynamic IL-6R/STAT3 signaling leads to heterogeneity of metabolic phenotype in pancreatic ductal adenocarcinoma cells (2024) · cites this paper as [41]
In “Stat3–IL-6 Feed-Forward Loop Regulates Mammary Tumorigenesis” (page not specified), the paper reports Stat3 binding to the IL-6 promoter and proposes a transcriptional feed-forward loop. The Discussion (page not specified) reports that disrupting Stat3 reduces IL-6 expression. The copy does not show that pStat3 induces IL6R transcription; it discusses IL-6R as a receptor in the signaling pathway. (LLM, conf=0.87)
Experimental — accuracy not yet measuredSTAT3 directly binds to the IL-6 promoter to induce IL-6 gene expression.
“STAT3 directly binds to the IL-6 promoter to induce IL-6 gene expression (82, 83).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [83]
IL-6-STAT3 signaling is increased at the leading edge of breast tumors to promote MDSC recruitment, angiogenesis, fibroblast infiltration and metastases.
“Indeed, Chang et al. showed that IL-6–STAT3 signaling is increased at the leading edge of breast tumors to promote MDSC recruitment, angiogenesis, fibroblast infiltration and metastases (83).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [83]
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- 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.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Children's Cancer and Blood Foundation (US)
- Northwell Health (US)
- IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola (IT)
- National Institutes of Health (US)
- Tokyo Medical University (JP)
- AstraZeneca (United States) (US)
- ORCID
- Venue
- Neoplasia
- Publisher
- Elsevier BV
- Published
- 2013-07
- Volume
- 15
- Issue
- 7
- Pages
- 848-IN45
- ISSN
- 1476-5586 (ISSN-L)
- PMC
- PMC3689247
- OpenAlex
- W1931245889
- Cited by
- 494
- References
- 4
- Citations by year
- 2026: 30 · 2025: 36 · 2024: 45 · 2023: 34 · 2022: 43 · 2021: 49 · 2020: 50 · 2019: 34 · 2018: 45 · 2017: 30 · 2016: 37 · 2015: 32 · 2014: 25 · 2013: 3 · 2012: 1
- FWCI
- 17.33
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Neoplasia (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- AstraZeneca
- Memorial Sloan-Kettering Cancer Center
- National Cancer Institute (R01CA087637, R01 CA87637, R01CA098234, U54CA148967, U54CA143836, P30CA008748)
- National Institute of Allergy and Infectious Diseases (T32AI007621)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- interleukin-6, JAK/STAT3 signaling, breast cancer, tumor invasion, metastasis, tumor microenvironment, pre-metastatic niche, myeloid cell recruitment, angiogenesis, cancer-associated fibroblasts, IL-6 receptor inhibition, JAK1/2 inhibition, STAT3 inhibition, stromal support
- MeSH terms
- Animals, Breast Neoplasms, Cell Transformation, Neoplastic, Female, Humans, Neoplasm Metastasis, Neoplasms, Pyrazoles, Pyrimidines, Signal Transduction, Interleukin-6, Gene Expression, Gene Expression Regulation, Neoplastic, Mice, Knockout, Cell Line, Tumor, STAT3 Transcription Factor, Mice, Janus Kinase 3, Tumor Microenvironment
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