IL-6 trans-signaling in formation and progression of malignant ascites in ovarian cancer.
Classic signaling by the proinflammatory cytokine interleukin 6 (IL-6) involves its binding to target cells that express the membrane-bound IL-6 receptor α. However, an alternate signaling pathway exists in which soluble IL-6 receptor (sIL-6Rα) can bind IL-6 and activate target cells that lack mIL-6Rα, such as endothelial cells. This alternate pathway, also termed trans-signaling, serves as the major IL-6 signaling pathway in various pathologic proinflammatory conditions including cancer. Here we report that sIL-6Rα is elevated in malignant ascites from ovarian cancer patients, where it is associated with poor prognosis. IL-6 trans-signaling on endothelial cells prevented chemotherapy-induced apoptosis, induced endothelial hyperpermeability, and increased transendothelial migration of ovarian cancer cells. Selective blockade of the MAPK pathway with ERK inhibitor PD98059 reduced IL-6/sIL-6Rα-mediated endothelial hyperpermeability. ERK activation by the IL-6/sIL-6Rα complex increased endothelial integrity via Src kinase activation and Y685 phosphorylation of VE-cadherin. Selective targeting of IL-6 trans-signaling in vivo reduced ascites formation and enhanced the taxane sensitivity of intraperitoneal human ovarian tumor xenografts in mice. Collectively, our results show that increased levels of sIL-6Rα found in ovarian cancer ascites drive IL-6 trans-signaling on endothelial cells, thereby contributing to cancer progression. Selective blockade of IL-6 trans-signaling may offer a promising therapeutic strategy to improve the management of patients with advanced ovarian cancer.
Department of Oncology, National Taiwan University Hospital, Institute of Toxicology, National Taiwan University College of Medicine, Nankang, Taiwan.
Chi-Wen
CW
Lo
Min-Wei
MW
Chen
Michael
M
Hsiao
Shiuan
S
Wang
Chi-An
CA
Chen
Sheng-Mou
SM
Hsiao
Jeng-Shou
JS
Chang
Tsung-Ching
TC
Lai
Stefan
S
Rose-John
Min-Liang
ML
Kuo
Lin-Hung
LH
Wei
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001201:Ascites / Q000378:metabolism / Q000473:pathology; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D004357:Drug Synergism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation; D019947:Receptors, Interleukin-6 / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000378:metabolism; D000099152:Cadherin 5; D000093242:Interleukin-6 Inhibitors
D015703:Antigens, CD; D015820:Cadherins; D015850:Interleukin-6; D020928:Mitogen-Activated Protein Kinases; D017239:Paclitaxel; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins; D019061:src-Family Kinases; D000099152:Cadherin 5; D000093242:Interleukin-6 Inhibitors; C113250:interleukin-6 receptor alpha; C519852:olamkicept