It takes two to tango in the microenvironment!

Josie Ursini-Siegel,Morag Park

doi:10.1186/bcr3388

Abstract

Using mortal non-tumorigenic human mammary epithelial cells and fibroblasts, Fordyce and colleagues show that an epithelial stress response promotes pro-tumorigenic changes in mammary fibroblasts. Fibroblast reprogramming was dependent on activin A or prostaglandin E2 produced by epithelial cells and, in turn, promoted enhanced migration of epithelial cells. These events in epithelial cells in vitro, including telomere loss, heightened DNA damage response, and activin A expression, are observed in breast ductal carcinoma in situ lesions surrounded by stroma bearing hallmarks of activated fibroblasts and immune and endothelial cell infiltration. Thus, reciprocal epithelial-stromal interactions facilitate progression to malignancy and occur even at the earliest stages of mammary tumorigenesis.

Highlights

Using mortal non-tumorigenic human mammary epithelial cells and fibroblasts, Fordyce and colleagues show that an epithelial stress response promotes pro-tumorigenic changes in mammary fibroblasts
Previous work by the Tlsty laboratory has identified activin A, a member of the transforming growth factorbeta (TGF-β) family, as an integrator of tumor/stromal crosstalk [2]. They showed that, while human immortalized mammary epithelial cells (HMECs) undergo senescence in response to DNA damage or telomere erosion, HMECs lacking an intact p16/retinoblastoma protein (Rb) pathway are rendered hyper-proliferative in response to such genotoxic insults as a result of activin A-induced cyclooxygenase-2 (COX2) expression [2]
These data suggest that immortalized mammary epithelial cells that have bypassed the p16/Rb senescence checkpoint are exquisitely sensitive to DNA damage-induced oncogenic transformation as a consequence of both increased genomic instability and the acquisition of a pro-tumorigenic stromal microenvironment

Summary

Introduction

Using mortal non-tumorigenic human mammary epithelial cells and fibroblasts, Fordyce and colleagues show that an epithelial stress response promotes pro-tumorigenic changes in mammary fibroblasts. Extensive evidence supports an integral role for crosstalk between tumor cells and neighboring stromal cells, which promotes the growth of epithelial cancers and their progression toward increasing malignancy. Recent studies have convincingly demonstrated reciprocal crosstalk between the epithelial and stromal compartments, whereby tumor cells engage in paracrine signaling to increase the pro-tumorigenic properties of immune cells and fibroblasts within the stromal microenvironment.

Results

Conclusion