Endometrial cancer contributes to significant morbidity and mortality in women with advanced stage or recurrent disease. Interleukin (IL)11 is a cytokine that regulates cell cycle, invasion and migration, all hallmarks of cancer. IL11 is elevated in endometrial tumours and uterine lavage fluid in women with endometrial cancer, alters endometrial epithelial cancer cell adhesion and migration in vitro but its role in endometrial tumourigenesis 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) α blocking antibody dramatically reduced HEC1A-derived tumour growth in both models and reduced peritoneal metastatic lesion spread in the orthotopic model, compared to IgG. Anti-human IL11Rα retained a well-differentiated, endometrial epithelial phenotype in the HEC1A ectopic mice suggesting it prevented epithelial-to-mesenchymal transition. Blockade of mouse IL11Rα with anti-mouse IL11Rα antibody did not alter tumour growth, suggesting that cancer epithelial cell IL11 signalling is required for tumour progression. In vitro, anti-human IL11Rα antibody significantly reduced Ishikawa and HEC1A cell proliferation and invasion and promoted apoptosis. Anti-human, but not anti-mouse IL11Rα antibody reduced STAT3, but not ERK activation in HEC1A cells in vitro and in endometrial tumours in xenograft mice. We demonstrated that targeted blockade of endometrial cancer epithelial cell IL11 signalling reduced primary tumour growth and impaired metastasis in ectopic and orthotopic endometrial cancer models in vivo. Our data suggest that therapeutically targeting IL11Rα could inhibit endometrial cancer growth and dissemination.
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