IL-6 trans-signaling in formation and progression of malignant ascites in ovarian cancer
Journal
Cancer Research
Journal Volume
71
Journal Issue
2
Pages
424-434
Date Issued
2011
Author(s)
Lo C.-W
Chen M.-W
Hsiao M
Wang S
Hsiao S.-M
Chang J.-S
Lai T.-C
Rose-John S
Kuo M.-L
Abstract
Classic signaling by the proinflammatory cytokine interleukin 6 (IL-6) involves its binding to target cells that express the membrane-bound IL-6 receptor a. 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. ? 2010 American Association for Cancer Research.
SDGs
Other Subjects
2 (2 amino 3 methoxyphenyl)chromone; cadherin; interleukin 6 receptor alpha; mitogen activated protein kinase; protein tyrosine kinase; taxane derivative; animal cell; animal experiment; animal model; animal tissue; apoptosis; article; ascites; cancer cell; cancer chemotherapy; cancer growth; cancer patient; cell membrane permeability; cell migration; controlled study; drug sensitivity; endothelium cell; female; human; human cell; human tissue; in vivo study; mouse; nonhuman; ovary cancer; priority journal; prognosis; protein blood level; sensitivity analysis; signal transduction; tumor xenograft; Animals; Antigens, CD; Ascites; Cadherins; Cell Adhesion; Cell Line, Tumor; Drug Synergism; Endothelial Cells; Female; Humans; Interleukin-6; MAP Kinase Signaling System; Mice; Mice, Inbred NOD; Mice, SCID; Mitogen-Activated Protein Kinases; Neovascularization, Pathologic; Ovarian Neoplasms; Paclitaxel; Phosphorylation; Receptors, Interleukin-6; Recombinant Fusion Proteins; Signal Transduction; src-Family Kinases; Xenograft Model Antitumor Assays
Type
journal article