More than a sidekick: the IL-6 family cytokine IL-11 links inflammation to cancer

Putoczki, Tracy L.; Ernst, Matthias

doi:10.1189/jlb.0410226

Cited by 124 publications

(97 citation statements)

References 95 publications

(102 reference statements)

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“…There are two IL-11R␣ isoforms, but only expression of IL-11R␣1 was altered in the BCC model (data not shown). As a member of IL-6 cytokine family, IL-11 can exert both immunomodulatory effects as well as epithelial effects (45). When STAT3 was knocked out in the epidermis, we did not observe any changes in myeloid-derived cell population (CD11b ϩ Gr1 ϩ cells), indicating that the immunomodulatory effects of IL-11 do not play a dominant role in the BCC model.…”

Section: Discussionmentioning

confidence: 73%

“…These results indicate that IL-11R␣ is a critical factor in mediating STAT3 activation and tumor development in this BCC model. IL-11R␣ serves as the specific cytokine receptor for IL-11 by forming a hexamer complex with gp130␤ and IL-11 to activate the downstream effector STAT3 (45). If the IL-11/IL-11R␣ signaling axis is the major contributor for STAT3 activation, we predicted that depleting IL-11 in the tumor microenvironment should reduce tumor size.…”

Section: Smom2mentioning

confidence: 99%

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A Role for Transcription Factor STAT3 Signaling in Oncogene Smoothened-driven Carcinogenesis

Gu¹,

Fan²,

Zhang

et al. 2012

Journal of Biological Chemistry

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Background: Activated Hh signaling drives skin cancer development. Results: Activated Hh signaling in mice increases IL-11, IL-11Ra, and STAT3 phosphorylation. STAT3 or IL-11Ra knockout reduces SmoM2-mediated carcinogenesis. The Smo agonist alone induces STAT3 phosphorylation in an IL11Ra-dependent manner. Conclusion:The IL-11Ra/STAT3 signaling axis is required for Hh-mediated carcinogenesis. Significance: This is the first report to link STAT3 signaling to Hh-mediated carcinogenesis.

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Section: Discussionmentioning

confidence: 73%

Section: Smom2mentioning

confidence: 99%

A Role for Transcription Factor STAT3 Signaling in Oncogene Smoothened-driven Carcinogenesis

Gu¹,

Fan²,

Zhang

et al. 2012

Journal of Biological Chemistry

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“…IL11 is a pleiotropic cytokine that regulates cell cycle, invasion, and migration in numerous cell types (11,12). IL11 is a member of the IL6 family of cytokines, which also includes leukemiainhibitory factor (LIF), oncostatin M, cardiotrophin-1, ciliaryneurotrophic factor, cardiotropin-like cytokine/cytokine-like factor, IL27 and IL31.…”

Section: Introductionmentioning

confidence: 99%

Targeting Interleukin-11 Receptor-α Impairs Human Endometrial Cancer Cell Proliferation and Invasion In Vitro and Reduces Tumor Growth and Metastasis In Vivo

Winship

Sinderen

Donoghue

et al. 2016

Molecular Cancer Therapeutics

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Endometrial cancer contributes to significant morbidity and mortality in women with advanced stage or recurrent disease. IL11 is a cytokine that regulates cell cycle, invasion, and migration, all hallmarks of cancer. IL11 is elevated in endometrial tumors and uterine lavage fluid in women with endometrial cancer, and alters endometrial epithelial cancer cell adhesion and migration in vitro, but its role in endometrial tumorigenesis in vivo is unknown. We injected mice subcutaneously with human-derived Ishikawa or HEC1A endometrial epithelial cancer cells (ectopic), or HEC1A cells into the uterus (orthotopic) to develop endometrial cancer mouse models. Administration of anti-human IL11 receptor (R) a blocking antibody dramatically reduced HEC1A-derived tumor growth in both models and reduced peritoneal metastatic lesion spread in the orthotopic model, compared with IgG. Anti-human IL11Ra retained a well-differentiated, endometrial epithelial phenotype in the HEC1A ectopic mice, suggesting it prevented epithelial-to-mesenchymal transition. Blockade of mouse IL11Ra with anti-mouse IL11Ra antibody did not alter tumor growth, suggesting that cancer epithelial cell IL11 signaling is required for tumor progression. In vitro, anti-human IL11Ra antibody significantly reduced Ishikawa and HEC1A cell proliferation and invasion and promoted apoptosis. Anti-human, but not anti-mouse, IL11Ra antibody reduced STAT3, but not ERK, activation in HEC1A cells in vitro and in endometrial tumors in xenograft mice. We demonstrated that targeted blockade of endometrial cancer epithelial cell IL11 signaling reduced primary tumor growth and impaired metastasis in ectopic and orthotopic endometrial cancer models in vivo. Our data suggest that therapeutically targeting IL11Ra could inhibit endometrial cancer growth and dissemination. Mol Cancer Ther; 15(4); 720-30. Ó2016 AACR.

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“…Tumor development is prevented by systemic restriction of Stat3 expression in gp130 FF Stat3 +/-mice or by the absence of the ligand-binding IL-11 receptor α (Il11ra) subunit in compound gp130 FF Il11ra -/-mice but not by Il6 gene ablation (10). Similarly, therapeutic inhibition of STAT3 or IL-11, but not IL-6, reduces tumor burden in gp130 FF mice (10,14). These observations indicate that epithelial tumor promotion can be dependent upon continuous cytokine activation of the GP130/STAT3 signaling cascade.…”

Section: Introductionmentioning

confidence: 99%

mTORC1 inhibition restricts inflammation-associated gastrointestinal tumorigenesis in mice

Thiem¹,

Pierce²,

Palmieri³

et al. 2013

J. Clin. Invest.

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Gastrointestinal cancers are frequently associated with chronic inflammation and excessive secretion of IL-6 family cytokines, which promote tumorigenesis through persistent activation of the GP130/JAK/STAT3 pathway. Although tumor progression can be prevented by genetic ablation of Stat3 in mice, this transcription factor remains a challenging therapeutic target with a paucity of clinically approved inhibitors. Here, we uncovered parallel and excessive activation of mTOR complex 1 (mTORC1) alongside STAT3 in human intestinal-type gastric cancers (IGCs). Furthermore, in a preclinical mouse model of IGC, GP130 ligand administration simultaneously activated mTORC1/S6 kinase and STAT3 signaling. We therefore investigated whether mTORC1 activation was required for inflammation-associated gastrointestinal tumorigenesis. Strikingly, the mTORC1-specific inhibitor RAD001 potently suppressed initiation and progression of both murine IGC and colitis-associated colon cancer. The therapeutic effect of RAD001 was associated with reduced tumor vascularization and cell proliferation but occurred independently of STAT3 activity. We analyzed the mechanism of GP130-mediated mTORC1 activation in cells and mice and revealed a requirement for JAK and PI3K activity but not for GP130 tyrosine phosphorylation or STAT3. Our results suggest that GP130-dependent activation of the druggable PI3K/mTORC1 pathway is required for inflammation-associated gastrointestinal tumorigenesis. These findings advocate clinical application of PI3K/mTORC1 inhibitors for the treatment of corresponding human malignancies.

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More than a sidekick: the IL-6 family cytokine IL-11 links inflammation to cancer

Cited by 124 publications

References 95 publications

A Role for Transcription Factor STAT3 Signaling in Oncogene Smoothened-driven Carcinogenesis

A Role for Transcription Factor STAT3 Signaling in Oncogene Smoothened-driven Carcinogenesis

Targeting Interleukin-11 Receptor-α Impairs Human Endometrial Cancer Cell Proliferation and Invasion In Vitro and Reduces Tumor Growth and Metastasis In Vivo

mTORC1 inhibition restricts inflammation-associated gastrointestinal tumorigenesis in mice

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