Targeting IL-17B-IL-17RB signaling with an anti-IL-17RB antibody blocks pancreatic cancer metastasis by silencing multiple chemokines
Journal
Journal of Experimental Medicine
Journal Volume
212
Journal Issue
3
Pages
333-349
Date Issued
2015
Author(s)
Wu H.-H.
Hwang-Verslues W.W.
Lee W.-H.
Huang C.-K.
Wei P.-C.
Chen C.-L.
Shew J.-Y.
Lee E.-Y.-H.P.
Ma C.
Lee W.-H.
Abstract
Pancreatic cancer has an extremely high mortality rate due to its aggressive metastatic nature. Resolving the underlying mechanisms will be crucial for treatment. Here, we found that overexpression of IL-17B receptor (IL-17RB) strongly correlated with postoperative metastasis and inversely correlated with progression-free survival in pancreatic cancer patients. Consistently, results from ex vivo experiments further validated that IL-17RB and its ligand, IL-17B, plays an essential role in pancreatic cancer metastasis and malignancy. Signals from IL-17B-IL-17RB activated CCL20/CXCL1/IL-8/TFF1 chemokine expressions via the ERK1/2 pathway to promote cancer cell invasion, macrophage and endothelial cell recruitment at primary sites, and cancer cell survival at distant organs. Treatment with a newly derived monoclonal antibody against IL-17RB blocked tumor metastasis and promoted survival in a mouse xenograft model. These findings not only illustrate a key mechanism underlying the highly aggressive characteristics of pancreatic cancer but also provide a practical approach to tackle this disease. ? 2015 Wu et al.
SDGs
Other Subjects
antineoplastic agent; CXCL1 chemokine; cytokine; interleukin 17B; interleukin 17B receptor; interleukin 17B receptor antibody; interleukin 8; macrophage inflammatory protein 3alpha; mitogen activated protein kinase; monoclonal antibody; unclassified drug; chemokine; interleukin 17; interleukin 17 receptor; monoclonal antibody; adult; animal experiment; animal model; antineoplastic activity; Article; cancer cell; cancer growth; cancer inhibition; cancer localization; cancer survival; cell invasion; drug targeting; endothelium cell; female; gene overexpression; human; macrophage; male; metastasis; mouse; nonhuman; pancreas cancer; priority journal; progression free survival; signal transduction; animal; disease free survival; drug screening; gene expression regulation; genetics; immunology; metabolism; middle aged; mortality; Pancreatic Neoplasms; pathology; SCID mouse; Animals; Antibodies, Monoclonal; Chemokines; Disease-Free Survival; Female; Gene Expression Regulation, Neoplastic; Humans; Interleukin-17; Male; Mice, SCID; Middle Aged; Pancreatic Neoplasms; Receptors, Interleukin-17; Signal Transduction; Xenograft Model Antitumor Assays
Publisher
Rockefeller University Press
Type
journal article