Induction of IL-25 secretion from tumour-associated fibroblasts suppresses mammary tumour metastasis.

Mao-Chih Hsieh,Pei-Wen Hsiao,Shu-Yi Yin,Yung-Hsiang Chen,Ning-Sun Yang,Shih-Chang Chien,Feng-Yin Jian,Yueh-Hsiung Kuo,Wen-Hwa Lee

doi:10.1038/ncomms11311

Abstract

Tumour-associated fibroblasts (TAFs), as a functionally supportive microenvironment, play an essential role in tumour progression. Here we investigate the role of IL-25, an endogenous anticancer factor secreted from TAFs, in suppression of mouse 4T1 mammary tumour metastasis. We show that a synthetic dihydrobenzofuran lignan (Q2-3), the dimerization product of plant caffeic acid methyl ester, suppresses 4T1 metastasis by increasing fibroblastic IL-25 activity. The secretion of IL-25 from treated human or mouse fibroblasts is enhanced in vitro, and this activity confers a strong suppressive effect on growth activity of test carcinoma cells. Subsequent in vivo experiments showed that the anti-metastatic effects of Q2-3 on 4T1 and human MDA-MD-231 tumour cells are additive when employed in combination with the clinically used drug, docetaxel. Altogether, our findings reveal that the release of IL-25 from TAFs may serve as a check point for control of mammary tumour metastasis and that phytochemical Q2-3 can efficiently promote such anticancer activities.

Highlights

Tumour-associated fibroblasts (TAFs), as a functionally supportive microenvironment, play an essential role in tumour progression
Our findings indicate that the stromal fibroblasts in the mammary tumour microenvironment can express IL-25 which can in turn mediate an anti-metastatic effect on the companion tumour cells
Our results suggest that the Q2-3-induced IL-25 secretion from fibroblasts plays a critical role in suppressing the growth activity of metastatic mammary tumour cells

Summary

Introduction

Tumour-associated fibroblasts (TAFs), as a functionally supportive microenvironment, play an essential role in tumour progression. We show that a synthetic dihydrobenzofuran lignan (Q2-3), the dimerization product of plant caffeic acid methyl ester, suppresses 4T1 metastasis by increasing fibroblastic IL-25 activity. A series of synthetic dihydrobenzofuran lignans, obtained by biomimetic oxidative dimerization of caffeic and/or ferulic acid methyl ester followed by derivatization reactions have been shown to exhibit potent antiangiogenic activity[14]. Among these synthetic compounds, methyl(E)3-[2-(3,4-dihydroxyphenyl) -7-hydroxy-3-methoxycarbonyl-2,3dihydro-1-benzofuran-5yl]-prop-2-enoate (Q2-3) has been shown to exhibit a significant anti-proliferation effect on various human cancer cell lines, including Jurkat, K562 and MCF-7 cells[15]. We mimicked an in vitro mammary tumour microenvironment by using a three-dimensional (3D) cell co-culture system to assess the regulatory effect of Q2-3 on the expression of specific cytokines and innate immune cell activities in both human and mouse TAFs

Methods

Results

Conclusion