Differential regulation of extracellular matrix protein expression in carcinoma-associated fibroblasts by TGF-β1 regulates cancer cell spreading but not adhesion.

Mieke Van Bockstal,Ridha Limame,Elly De Vlieghere,Olivier De Wever,Rudy Van Den Broecke,Hannelore Denys,Mireille Van Gele,Kathleen Lambein,Louis Libbrecht,Geert Braems,Veronique Cocquyt,Marc Bracke

doi:10.18632/oncoscience.87

Mieke Van Bockstal, Ridha Limame + Show 10 more

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https://doi.org/10.18632/oncoscience.87

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Journal: Oncoscience	Publication Date: Oct 15, 2014
Citations: 40	License type: cc-by

Affiliation: Ghent University, Ghent University Hospital

Abstract

Cancer progression is characterized by a complex reciprocity between neoplastic epithelium and adjacent stromal cells. In ductal carcinoma in situ (DCIS) of the breast, both reduced stromal decorin expression and myxoid stroma are correlated with increased recurrence risk. In this study, we aimed to investigate paracrine regulation of expression of decorin and related extracellular matrix (ECM) proteins in cancer-associated fibroblasts (CAFs). Transforming growth factor-β1 (TGF-β1) was identified as a competent ECM modulator, as it reduced decorin and strongly enhanced versican, biglycan and type I collagen expression. Similar but less pronounced effects were observed when fibroblasts were treated with basic fibroblast growth factor (bFGF). Despite this concerted ECM modulation, TGF-β1 and bFGF differentially regulated alpha-smooth muscle actin (α-SMA) expression, which is often proposed as a CAF-marker. Cancer cell-derived secretomes induced versican and biglycan expression in fibroblasts. Immunohistochemistry on twenty DCIS specimens showed a trend toward periductal versican overexpression in DCIS with myxoid stroma. Cancer cell adhesion was inhibited by decorin, but not by CAF-derived matrices. Cancer cells presented significantly enhanced spreading when seeded on matrices derived from TGF-β1-treated CAF. Altogether these data indicate that preinvasive cancerous lesions might modulate the composition of surrounding stroma through TGF-β1 release to obtain an invasion-permissive microenvironment.

Highlights

The significance of the tumor microenvironment in cancer progression has been increasingly acknowledged
Gene expression profiling of neoplastic epithelium and stroma during breast cancer progression revealed that the expression of molecules involved in extracellular matrix (ECM) remodeling is altered during the transition from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) [3,4,5,6]
Since we previously reported a significant association between periductal myxoid stroma and reduced stromal decorin in DCIS [11], we aimed to investigate whether a correlation existed between myxoid stroma and increased biglycan and versican immunoreactivity

Summary

Introduction

The significance of the tumor microenvironment in cancer progression has been increasingly acknowledged. Gene expression profiling of neoplastic epithelium and stroma during breast cancer progression revealed that the expression of molecules involved in extracellular matrix (ECM) remodeling is altered during the transition from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) [3,4,5,6]. Extensive stromal gene expression alterations occur during the transition from normal breast to DCIS [4]. Gevaert et al reported overexpression of the small leucinrich proteoglycans (SLRP) decorin and fibromodulin in a gene expression signature associated with good www.impactjournals.com/oncoscience prognosis in invasive breast cancer [7]. Immunohistochemical (IHC) analysis showed that stromal decorin expression is highest in normal breast tissue, lower in DCIS and lowest in IDC [9]. A similar trend was noticed in the colon, with strong decorin expression in normal tissue, hyperplastic adenomas and the majority of tubular adenomas, and decreased decorin expression in tubulo-villous adenomas and most adenocarcinomas [10]

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