Syndecan-1 in Breast Cancer Stroma Fibroblasts Regulates Extracellular Matrix Fiber Organization and Carcinoma Cell Motility

Abstract

Stromal fibroblasts of breast carcinomas frequently express the cell surface proteoglycan syndecan-1 (Sdc1). In human breast carcinoma samples, stromal Sdc1 expression correlates with an organized, parallel, extracellular matrix (ECM) fiber architecture. To examine a possible link between stromal Sdc1 and the fiber architecture, we generated bioactive cell-free three-dimensional ECMs from cultures of Sdc1-positive and Sdc1-negative murine and human mammary fibroblasts (termed ECM-Sdc1 and ECM-mock, respectively). Indeed, ECM-Sdc1 showed a parallel fiber architecture that contrasted markedly with the random fiber arrangement of ECM-mock. When breast carcinoma cells were seeded into the fibroblast-free ECMs, ECM-Sdc1, but not ECM-mock, promoted their attachment, invasion, and directional movement. We further evaluated the contribution of the structural/compositional modifications in ECM-Sdc1 on carcinoma cell behavior. By microcontact printing of culture surfaces, we forced the Sdc1-negative fibroblasts to produce ECM with parallel fiber organization, mimicking the architecture observed in ECM-Sdc1. We found that the fiber topography governs carcinoma cell migration directionality. Conversely, an elevated fibronectin level in ECM-Sdc1 was responsible for the enhanced attachment of the breast carcinoma cells. These observations suggest that Sdc1 expression in breast carcinoma stromal fibroblasts promotes the assembly of an architecturally abnormal ECM that is permissive to breast carcinoma directional migration and invasion. Epithelial-stromal interactions play crucial roles in directing mammary gland development and in maintaining normal tissue homeostasis. Conversely, during tumorigenesis, the stroma accelerates carcinoma growth and progression. The predominant cell type within the stromal compartment is the fibroblast, which synthesizes, organizes, and maintains a three-dimensional (3D) network of glycoproteins and proteoglycans known as the extracellular matrix (ECM). Normal stromal fibroblasts and their ECM are believed to exert an inhibitory constraint on tumor growth and progression. 1,2 Major alterations occur in the stromal fibroblasts and ECM during neoplastic transformation, giving rise to a permissive and supportive microenvironment for carcinomas. Compared with their quiescent normal counterpart, carcinoma-associated fibroblasts display an activated phenotype, which is characterized by the expression of smooth muscle markers, an enhanced proliferative and migratory potential, and altered gene expression profiles. Carcinoma-associated fibroblasts produce and deposit elevated amounts and abnormal varieties of ECM components. 3-5 Recent evidence 6,7 indicates that not only ECM composition but also ECM architecture are altered in carcinomas and that these changes may promote tumor progression. However, the contribution of these stromal modifications to tumor development and the molecular mechanisms and signaling events underlying these alterations are incompletely understood.

Syndecan-1 is a potential biomarker for triple-positive breast carcinomas in Asian women with correlation to survival

“…However, the mechanism in which syndecan-1 is implicated in breast cancer is still unclear, although studies have shown that induction of syndecan-1 in stromal fibroblasts stimulates breast cancer cell growth, (20) regulates extracellular matrix fibre organisation and malignant cell motility, (21) as well as enhances tumour angiogenesis. (22) Syndecan-1 has also been reported to have more intense staining of the stromal component of breast cancer tissue compared to normal breast tissue, (23) in keeping with our study findings.…”

Extracellular matrix and cell signalling: the dynamic cooperation of integrin, proteoglycan and growth factor receptor

“…For example, removal of 6-O sulphates can reduce tumour growth in vivo (Narita et al 2006), and HSPGs from normal versus malignant epithelial cells show differences in their ability to support FGF-2/FGFR complex formation (Mundhenke et al 2002). Stromal fibroblasts expressing high levels of syndecan-1, a HSPG core protein, enhanced the attachment of breast carcinoma cells and the establishment of cancer microenvironment permissive to the cancer cell migration and invasion (Yang et al 2011). Basement membranes of renal cell carcinomas show altered ability to bind to members of the FGF family in an HS-dependent manner (Friedl et al 1997).…”

Human Breast Cancer Histoid

“…In contrast, the previously reported in vitro breast cancer models were not evaluated for their batch-to-batch reproducibility. The use of rotary bioreactors to carry out co-cultures of breast cancer cells and fibroblasts under defined and stringent culture conditions offered several distinct advantages over the traditional 3-D co-cultures on xenogenically derived gel matrix, which were used in the previously reported studies (Gudjonsson et al 2002(Gudjonsson et al , 2003Sung et al 2009;Bauer et al 2010;Han et al 2010;Inman and Bissell 2010;Beliveau et al 2011;Yang et al 2011;Sung et al 2011).…”

“…Such a model, representing major cellular components of the breast tumor microenvironment, may serve as a basis Gudjonsson et al 2002;Seidl et al 2002;Sung et al 2008;Hsaio et al 2009;Han et al 2010;Beliveau et al 2011;Sung et al 2011;Yang et al 2011. for the study of molecular mediators of cancer progression, which promote malignant growth, angiogenesis, metastasis, and reduced apoptosis.…”