title: Differential regulation of extracellular matrix protein expression in carcinoma-associated fibroblasts by TGF-β1 regulates cancer cell spreading but not adhesion.
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.
authors.affiliation: Department of Pathology, Ghent University and Ghent University Hospital, Ghent, Belgium.
authors.forename: Mieke
authors.initials: M
authors.lastname: Van Bockstal
authors.affiliation: Department of Pathology, Ghent University and Ghent University Hospital, Ghent, Belgium.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Lambein
authors.affiliation: Department of Dermatology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Mireille
authors.initials: M
authors.lastname: Van Gele
authors.affiliation: Department of Radiation Oncology and Experimental Cancer Research, Ghent University and Ghent University Hospital, Ghent, Belgium.
authors.forename: Elly
authors.initials: E
authors.lastname: De Vlieghere
authors.affiliation: Department of Radiation Oncology and Experimental Cancer Research, Ghent University and Ghent University Hospital, Ghent, Belgium.
authors.forename: Ridha
authors.initials: R
authors.lastname: Limame
authors.affiliation: Department of Gynaecology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: Braems
authors.affiliation: Department of Gynaecology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Rudy
authors.initials: R
authors.lastname: Van den Broecke
authors.affiliation: Department of Medical Oncology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Veronique
authors.initials: V
authors.lastname: Cocquyt
authors.affiliation: Department of Medical Oncology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Hannelore
authors.initials: H
authors.lastname: Denys
authors.affiliation: Department of Radiation Oncology and Experimental Cancer Research, Ghent University and Ghent University Hospital, Ghent, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Bracke
authors.affiliation: Department of Pathology, Ghent University and Ghent University Hospital, Ghent, Belgium.
authors.forename: Louis
authors.initials: L
authors.lastname: Libbrecht
authors.affiliation: Department of Radiation Oncology and Experimental Cancer Research, Ghent University and Ghent University Hospital, Ghent, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: De Wever
keywords: Cancer-associated fibroblasts Stromal protein expression TGF-β1 Decorin Versican