Extracellular Matrix-Induced Gene Expression in Human Breast Cancer Cells

Abstract

Extracellular matrix (ECM) molecules modify gene expression through attachment-dependent (focal adhesion-related) integrin receptor signaling. It was previously unknown whether the same molecules acting as soluble peptides could generate signal cascades without the associated mechanical anchoring, a condition that may be encountered during matrix remodeling and degradation and relevant to invasion and metastatic processes. In the current study, the role of ECM ligand-regulated gene expression through this attachment-independent process was examined. It was observed that fibronectin, laminin, and collagen type I and II induce Smad2 activation in MCF-10A and MCF-7 cells. This activation is not caused by transforming growth factor (TGF)-B ligand contamination or autocrine TGF involvement and is 3-to 5-fold less robust than the TGF-B1 ligand. The resulting nuclear translocation of Smad4 in response to ECM ligand indicates downstream transcriptional responses occurring. Coimmunoprecipitation experiments determined that collagen type II and laminin act through interaction with integrin A 2 B 1 receptor complex. The ECM ligand-induced Smad activation (termed signaling crosstalk) resulted in cell type and ligand-specific transcriptional changes, which are distinct from the TGF-B ligand-induced responses. These findings show that cell-matrix communication is more complex than previously thought. Soluble ECM peptides drive transcriptional regulation through corresponding adhesion and non-attachment-related processes. The resultant gene expressional patterns correlate with pathway activity and not by the extent of Smad activation. These results extend the complexity and the existing paradigms of ECM-cell communication to ECM ligand regulation without the necessity of mechanical coupling.

α2β1 Integrin Promotes Chemoresistance against Doxorubicin in Cancer Cells through Extracellular Signal-regulated Kinase (ERK)

“…Soluble ECM ligands also induce intracellular signaling and modulate cell behavior in solid tumors. Soluble ColI has been shown to influence TGF␤ receptor signaling and gene expression in breast cancer cells (38,39), and soluble integrin ligands such as ColI also rescue neuroblastoma cells from apoptosis under nonadherent conditions (40). ECM remodeling and degradation by metalloproteinases, which is associated with cancer growth and invasion, is likely to lead to the release of ECM components that can act as "soluble" pep- tides within the tumor microenvironment.…”

Important role of integrins in the cancer biology

“…In vivo experiments revealed that collagen 2 interacts with the integrin α2β1 complex [30]. These integrin-type collagen receptors, α1β1, α2β1, α10β1, and α11β1, are involved in cancer progression and invasion.…”

The Biomechanical Properties of 3d Extracellular Matrices and Embedded Cells Regulate the Invasiveness of Cancer Cells

“…Besides the biochemical properties of cells described under invasion modes section, the expression of integrins has long been discussed to play a role in cell invasion. It has been described that the ECM regulates gene expression through focal adhesion-dependent integrin receptor signaling [72]. Several reports show a correlation of integrin expression and cellular invasiveness.…”