Breast Cancer Cells Induce Stromal Fibroblasts to Secrete ADAMTS1 for Cancer Invasion through an Epigenetic Change

Shiaw-Wei Tyan,Wen-Hung Kuo,Eva Y.-H P Lee,Chih-Hung Hsu,Li-Jung Juan,Chun-Chin Chen,Jin-Yuh Shew,Wen-Hwa Lee,Kai-Lin Peng,King-Jen Chang,Bernard W Futscher

doi:10.1371/journal.pone.0035128

Abstract

Microenvironment plays an important role in cancer development. We have reported that the cancer-associated stromal cells exhibit phenotypic and functional changes compared to stromal cells neighboring to normal tissues. However, the molecular mechanisms as well as the maintenance of these changes remain elusive. Here we showed that through co-culture with breast cancer cells for at least three to four passages, breast normal tissue-associated fibroblasts (NAFs) gained persistent activity for promoting cancer cell invasion, partly via up-regulating ADAM metallopeptidase with thrombospondin type 1 motif, 1 (ADAMTS1). Furthermore, we demonstrated that the DNA methylation pattern in the ADAMTS1 promoter has no alteration. Instead, the loss of EZH2 binding to the ADAMTS1 promoter and the resulting decrease of promoter-associated histone H3K27 methylation may account for the up-regulation of ADAMTS1. Importantly, the lack of EZH2 binding and the H3K27 methylation on the ADAMTS1 promoter were sustained in cancer cell-precocultured NAFs after removal of cancer cells. These results suggest that cancer cells are capable of inducing stromal fibroblasts to secrete ADAMTS1 persistently for their invasion and the effect is epigenetically inheritable.

Highlights

Cancer development depends on the accumulation of genetic mutations in cancer cells, and the interaction between cancer cells and their surrounding stroma
Similar results were observed when the other breast cancer MDAMB-231 cells were used for invasion assay (Fig. 1B, right panel). These experiments indicate that cancer cells are able to stimulate normal tissue-associated fibroblasts to facilitate cell invasion, and that the effect requires a certain period of time of NAF co-culture with cancer cells before it can be established
The current report demonstrates that cancer-associated fibroblasts (CAFs) secreted ADAMTS1 to promote cancer cell invasion (Fig. 3)

Summary

Introduction

Cancer development depends on the accumulation of genetic mutations in cancer cells, and the interaction between cancer cells and their surrounding stroma. The tumor stroma including extracellular matrix (ECM), endothelial cells, pericytes, inflammatory cells and fibroblasts has been shown to assist cancer progression [1,2,3]. The cancer-associated stromal cells exhibit phenotypic and functional changes, as well as alterations in gene expression, compared to stromal cells neighboring to normal tissues [4,5]. Nor do we understand in details how stromal fibroblasts facilitate cancer cell function. Our previous study suggests that the hepatocyte growth factor (HGF) released by the breast normal tissue-associated fibroblasts (NAFs) co-cultured with breast cancer cells is one of the contributing factors [4]. We demonstrated that the HGF secretion, once established, can be maintained in NAFs without the continued co-culture with cancer cells [4].

Methods

Results

Conclusion