期刊
CANCER DISCOVERY
卷 1, 期 5, 页码 430-441出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-11-0100
关键词
-
类别
资金
- NIH [CA085492, A102162, CA126505, CA068485]
- T. J. Martell Foundation
We report that interleukin (IL)-17 significantly increases the secretion of CXC chemokine ligand 1 and 5 (CXCL1/5) from mammary carcinoma cells, and that stimulated secretion of CXCL1/5 by IL-17 is down-regulated by TGF-beta through the type II TGF-beta receptor (T beta RII). Carcinoma cells with conditional knockout of T beta RII (Tgfbr2(KO)) have enhanced sensitivity to IL-17a in the stimulation of chemokine secretion. During polyoma middle T (PyMT)-induced tumor progression, levels of Th17-inducing cytokines TGF-beta, IL-6, and IL-23 were increased in PyMT/Tgfbr2(KO) tumors, which was associated with an increased number of Th17 cells. IL-17 increased the suppressive function of myeloid-derived suppressor cells (MDSC) on T cells through the up-regulation of Arg, IDO, and cyclooxygenase-2. Treatment of PyMT/Tgfbr2KO mice with anti-IL-17 Ab decreased carcinoma growth and metastatic burden. Analysis of human breast cancer transcriptome databases demonstrated a strong association between IL-17 gene expression and poor outcome in lymph node-positive, estrogen receptor-negative, or luminal B subtypes, suggesting potential therapeutic approaches. SIGNIFICANCE: TGF-beta signaling is a major tumor suppressor pathway and is therefore difficult to target therapeutically. Understanding the downstream effects of abrogation of TGF-beta signaling in tumor cells may identify processes that can be targeted therapeutically. We present data indicating that targeting IL-17 signaling, a pathway that is greatly enhanced by loss of TGF-beta signaling, could provide a therapeutic benefit. Analysis of human databases indicated a specific group of patients in whom treatment could be more efficient. Cancer Discovery;1(5):430-41. (C) 2011 AACR.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据