Differential regulation of extracellular matrix protein expression in carcinoma-associated fibroblasts by TGF-β1 regulates cancer cell spreading but not adhesion
Mieke Van Bockstal1, Kathleen Lambein1, Mireille Van Gele2, Elly De Vlieghere3, Ridha Limame3, Geert Braems4, Rudy Van den Broecke4, Veronique Cocquyt5, Hannelore Denys5, Marc Bracke3, Louis Libbrecht1 and Olivier De Wever3
1 Department of Pathology, Ghent University and Ghent University Hospital, Ghent, Belgium
2 Department of Dermatology, Ghent University Hospital, Ghent, Belgium
3 Department of Radiation Oncology and Experimental Cancer Research, Ghent University and Ghent University Hospital, Ghent, Belgium
4 Department of Gynaecology, Ghent University Hospital, Ghent, Belgium
5 Department of Medical Oncology, Ghent University Hospital, Ghent, Belgium
Correspondence:
Mieke Van Bockstal, email:
Keywords: Cancer-associated fibroblasts Stromal protein expression TGF-β1 Decorin Versican
Received: September 17, 2014 Accepted: October 14, 2014 Published: October 15, 2014
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 (CAF). Transforming growth factor-β1 (TGF-β1) was identified as a competent ECM modulator, as it reduced decorin and strongly enhanced versican, biglycan and collagen expression. Similar but less pronounced effects were observed when fibroblasts were treated with bFGF. Despite this concerted ECM modulation, TGF-β1 and bFGF differentially regulated α-SMA expression, which is often proposed as a CAF-marker. Cancer cell-derived conditioned medium 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.
