https://scholars.lib.ntu.edu.tw/handle/123456789/458234
Title: | IL-6 trans-signaling in formation and progression of malignant ascites in ovarian cancer | Authors: | Lo C.-W Chen M.-W Hsiao M Wang S CHI-AN CHEN Hsiao S.-M Chang J.-S Lai T.-C Rose-John S Kuo M.-L LING-HUNG WEI |
Issue Date: | 2011 | Journal Volume: | 71 | Journal Issue: | 2 | Start page/Pages: | 424-434 | Source: | Cancer Research | 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. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/458234 | ISSN: | 0008-5472 | DOI: | 10.1158/0008-5472.CAN-10-1496 | SDG/Keyword: | 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 |
Appears in Collections: | 醫學系 |
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