Paracrine Crosstalk between Fibroblasts and ER+ Breast Cancer Cells Creates an IL1β-Enriched Niche that Promotes Tumor Growth.

Sumanta Chatterjee,Alexei Berdnikov,Janice Safneck,Vasudeva Bhat,Jiahui Liu,Lynne-Marie Postovit,Afshin Raouf,Edward Buchel,Aaron J Marshall,Leigh C Murphy,Guihua Zhang

doi:10.1016/j.isci.2019.07.034

Abstract

SummaryBreast cancer-induced activated fibroblasts support tumor progression. However, the role of normal fibroblasts in tumor progression remains controversial. In this study, we used modified patient-derived organoid cultures and demonstrate that constitutively secreted cytokines from normal breast fibroblasts initiate a paracrine signaling mechanism with estrogen receptor-positive (ER+) breast cancer cells, which results in the creation of an interleukin (IL)-1β-enriched microenvironment. We found that this paracrine signaling mechanism is shared between normal and activated fibroblasts. Interestingly, we observed that in reconstructed tumor microenvironment containing autologous ER+ breast cancer cells, activated fibroblasts, and immune cells, tamoxifen is more effective in reducing tumor cell proliferation when this paracrine signaling is blocked. Our findings then suggest that ER+ tumor cells could create a growth-promoting environment without activating stromal fibroblasts and that in breast-conserving surgeries, normal fibroblasts could be a significant modulator of tumor recurrence by enhancing the proliferation of residual breast cancer cells in the tumor-adjacent breast tissue.

Highlights

Current evidence suggests that cancer initiation and progression is co-mediated by the tissue environment and cancer cells rather than being a cell-autonomous-driven process (Guarnerio et al, 2018; Hanahan and Weinberg, 2011; Plaks et al, 2015)
We demonstrate that the constitutively secreted CCL7 (C-C motif chemokine ligand), IL6, and IL8 from either normal-associated fibroblasts (NAFs) or tumor-associated fibroblasts (TAFs) result in release of platelet-derived growth factor (PDGF)-BB from estrogen receptor-positive (ER+)breast cancer cells (BCCs), but not the normal breast cells, and that the PDGF-BB acts in a paracrine manner causing IL1b production from NAFs and TAFs alike
NAF-Secreted Factors Enhance Primary ER+ Breast Cancer Cell Proliferation in Organoid Cultures To investigate the nature of interaction between NAFs and ER+BCCs, we developed a 3-dimensional (3D) organoid model system initiated with primary malignant human ER+ breast cancer cells (ER+BCCs) and either stromal fibroblast obtained from the matching original tumors or breast reduction samples for up to 10 days (Figure 1A)

Summary

Introduction

Current evidence suggests that cancer initiation and progression is co-mediated by the tissue environment (niche) and cancer cells rather than being a cell-autonomous-driven process (Guarnerio et al, 2018; Hanahan and Weinberg, 2011; Plaks et al, 2015). Extensive studies regarding the interactions between the TAFs and breast cancer cells (BCCs) have revealed a cyclic relationship in which cancer cells stimulate a reactive response in fibroblasts and in turn activated fibroblasts enhance the proliferation and migration of cancer cells. In this regard, the secretion of transforming growth factor (TGF)-b and CXCL12 by the cancer cells has been suggested as one mechanism to confer the activated phenotype in normal stromal fibroblasts. Activated fibroblasts in turn through secretion of fibroblast growth factors, hepatocyte growth factor, interleukin (IL) 6, and TGF-b enhance cancer progression and tumor metastasis (Boimel et al, 2012; Chatterjee et al, 2018; Hugo et al, 2012; Kuperwasser et al, 2004; Pickup et al, 2013; Scherz-Shouval et al, 2014; Sharon et al, 2015)

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