Interleukin-11 Is the Dominant IL-6 Family Cytokine during Gastrointestinal Tumorigenesis and Can Be Targeted Therapeutically

Putoczki, Tracy L.; Thiem, Stefan; Loving, Andrea; Busuttil, Rita A.; Wilson, Nicholas J.; Ziegler, Paul; Nguyen, Paul M.; Preaudet, Adele; Farid, Ryan; Edwards, Kirsten M; Boglev, Yeliz; Luwor, Rodney B; Jarnicki, Andrew G.; Horst, David; Boussioutas, Alex; Heath, Joan K.; Sieber, Oliver M.; Pleines, Irina; Kile, Benjamin T.; Nash, Andrew D.; Greten, Florian R.; McKenzie, Brent; Ernst, Matthias

doi:10.1016/j.ccr.2013.06.017

Cited by 360 publications

(433 citation statements)

References 67 publications

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“…IL11 protein (16) and mRNA (17), along with IL11Ra protein levels are progressively increased with increased endometrial tumor grade (16), which is in line with findings in other tumor types such as ovarian and colorectal (18,19). Studies have reported protumorigenic roles for IL11 in several epithelial cancers, including breast (20) and colorectal cancer (19) and one recent study highlighted a predominant role for IL11 rather than IL6 in mediating gastric cancer (21). We have previously demonstrated that IL11 promotes endometrial cancer cell migration in vitro, via STAT3 (22).…”

Section: Introductionsupporting

confidence: 73%

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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Section: Introductionsupporting

confidence: 73%

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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“…These results indicate the role of COX-2/PGE 2 pathway-induced inflammation in gastric tumorigenesis. In the gastric tumor stroma, proinflammatory cytokines including TNFa, IL1b, and IL11 are expressed and promote tumorigenesis through enhancement of undifferentiated status, recruiting of myeloid-derived suppressor cells and increasing tumor cell survival (9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Myeloid Differentiation Factor 88 Signaling in Bone Marrow–Derived Cells Promotes Gastric Tumorigenesis by Generation of Inflammatory Microenvironment

Maeda

Echizen

Oshima

et al. 2016

Cancer Prevention Research

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It has been established that COX-2 and downstream signaling by prostaglandin E 2 (PGE 2 ) play a key role in tumorigenesis through generation of inflammatory microenvironment. Tolllike receptor (TLR) signaling through myeloid differentiation factor 88 (MyD88) also regulates inflammatory responses in tumors. However, the relationship between these distinct pathways in tumorigenesis is not yet fully understood. We herein investigated the role of MyD88 in gastric tumorigenesis using Gan mice, which develop inflammation-associated gastric tumors due to the simultaneous activation of the COX-2/PGE 2 pathway and Wnt signaling. Notably, the disruption of Myd88 in Gan mice resulted in the significant suppression of gastric tumorigenesis with the inhibition of inflammatory responses, even though COX-2/PGE 2 pathway is constitutively activated. Moreover, Myd88 disruption in bone marrow-derived cells (BMDCs) in Gan mice also suppressed inflammation and tumorigenesis, indicating that MyD88 signaling in BMDCs regulates the inflammatory microenvironment. We also found that expression of Tlr2 and its coreceptor Cd14 was induced in tumor epithelial cells in Gan mice, which was suppressed by the disruption of Myd88. It has already been shown that TLR2/CD14 signaling is important for stemness of intestinal epithelial cells. These results indicate that MyD88 in BMDCs, together with COX-2/PGE 2 pathway, plays an essential role in the generation of the inflammatory microenvironment, which may promote tumorigenesis through induction of TLR2/CD14 pathway in tumor epithelial cells. These results suggest that inhibition of TLR/MyD88 signaling together with COX-2/PGE 2 pathway will be an effective preventive strategy for gastric cancer.Cancer Prev Res; 9(3); 253-63. Ó2016 AACR.

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“…3 F). Because IL-6 and IL-11 can activate STAT3 (Bollrath et al, 2009;Putoczki et al, 2013), increased pSTAT3 observed in Naip1-6 / tumors might be related to the observed up-regulation of those cytokines. Also consistent with STAT3 activation, downstream targets Mmp9 and Timp1, which can act to enhance tumor growth or invasion (Kim et al, 2012;Shuman Moss et al, 2012), as well as Stat3 itself, were elevated (Fig.…”

mentioning

confidence: 98%

Epithelial NAIPs protect against colonic tumorigenesis

Allam¹,

Maillard²,

Tardivel³

et al. 2015

J Cell Biol

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Interleukin-11 Is the Dominant IL-6 Family Cytokine during Gastrointestinal Tumorigenesis and Can Be Targeted Therapeutically

Cited by 360 publications

References 67 publications

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

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

Myeloid Differentiation Factor 88 Signaling in Bone Marrow–Derived Cells Promotes Gastric Tumorigenesis by Generation of Inflammatory Microenvironment

Epithelial NAIPs protect against colonic tumorigenesis

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