title: Targeting Interleukin-11 Receptor-α Impairs Human Endometrial Cancer Cell Proliferation and Invasion In Vitro and Reduces Tumor Growth and Metastasis In Vivo.
abstract: 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) α 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 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 tumor growth, suggesting that cancer epithelial cell IL11 signaling is required for tumor 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 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 IL11Rα could inhibit endometrial cancer growth and dissemination. Mol Cancer Ther; 15(4); 720-30. ©2016 AACR.
authors: Centre for Reproductive Health, The Hudson Institute of Medical Research, Clayton, Victoria, Australia. Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia.
authors: Amy L
authors: AL
authors: Winship
authors: Centre for Reproductive Health, The Hudson Institute of Medical Research, Clayton, Victoria, Australia. Department of Molecular and Translational Medicine, Monash University, Clayton, Victoria, Australia.
authors: Michelle
authors: M
authors: Van Sinderen
authors: Department of Molecular and Translational Medicine, Monash University, Clayton, Victoria, Australia. Centre for Cancer Research, The Hudson Institute of Medical Research, Clayton, Victoria, Australia.
authors: Jacqueline
authors: J
authors: Donoghue
authors: Centre for Reproductive Health, The Hudson Institute of Medical Research, Clayton, Victoria, Australia. Department of Molecular and Translational Medicine, Monash University, Clayton, Victoria, Australia.
authors: Kate
authors: K
authors: Rainczuk
authors: Centre for Reproductive Health, The Hudson Institute of Medical Research, Clayton, Victoria, Australia. Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia. Department of Molecular and Translational Medicine, Monash University, Clayton, Victoria, Australia. evdokia.dimitriadis@hudson.org.au.
authors: Evdokia
authors: E
authors: Dimitriadis
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D016889:Endometrial Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D006801:Humans; D017370:Interleukin-11 / Q000378:metabolism / Q000494:pharmacology; D053703:Interleukin-11 Receptor alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D017370:Interleukin-11; D053703:Interleukin-11 Receptor alpha Subunit; D015850:Interleukin-6; D050796:STAT3 Transcription Factor