Fibronectin Expression Modulates Mammary Epithelial Cell Proliferation during Acinar Differentiation

Abstract

The mammary gland consists of a polarized epithelium surrounded by a basement membrane matrix that forms a series of branching ducts ending in hollow, sphere-like acini. Essential roles for the epithelial basement membrane during acinar differentiation, in particular laminin and its integrin receptors, have been identified using mammary epithelial cells cultured on a reconstituted basement membrane. Contributions from fibronectin, which is abundant in the mammary gland during development and tumorigenesis, have not been fully examined. Here, we show that fibronectin expression by mammary epithelial cells is dynamically regulated during the morphogenic process. Experiments with synthetic polyacrylamide gel substrates implicate both specific extracellular matrix components, including fibronectin itself, and matrix rigidity in this regulation. Alterations in fibronectin levels perturbed acinar organization. During acinar development, increased fibronectin levels resulted in overproliferation of mammary epithelial cells and increased acinar size. Addition of fibronectin to differentiated acini stimulated proliferation and reversed growth arrest of mammary epithelial cells negatively affecting maintenance of proper acinar morphology. These results show that expression of fibronectin creates a permissive environment for cell growth that antagonizes the differentiation signals from the basement membrane. These effects suggest a link between fibronectin expression and epithelial cell growth during development and oncogenesis in the mammary gland. [Cancer Res 2008;68(9):3185-92]

TiO2nanotube stimulate chondrogenic differentiation of limb mesenchymal cells by modulating focal activity

“…Several recent studies showed that a nanotubebearing surface allows dynamic and coordinated changes in cytoskeletal organization, locomotion, and cell-to-cell communication in a great variety of cell systems, including dendritic cells, monocytes, human embryonic kidney 293T cells, normal rat kidney cells, primary macrophages, T cells, activated B cells, and human glioblastoma cells (Ryu et al, 2005;Dumortier et al, 2006;Brammer et al, 2008;Gurke et al, 2008;Kaiser et al, 2008;Williams et al, 2008;Park et al, 2009). Since morphological transition via reorganization of the actin cytoskeleton is essential for chondrocytic differentiation, we hypothesized that a nanotubebearing surface could be a useful culture substrate for maintaining chondrocytic phenotypes and allowing chondrocytes to differentiate.…”

Regulation of Matrix Assembly through Rigidity-dependent Fibronectin Conformational Changes

“…For example, stiff ECM has been shown to promote tumor progression by breast cancer cells (10,68), and FN contributes to development of a tumorigenic phenotype by mammary epithelial cells (30). In addition, progression of liver fibrosis has been found to correlate with a progressive increase in liver stiffness (11,69), and interestingly, an increase in liver stiffness has been shown to precede the pathological deposition of ECM proteins (70).…”

“…These results show that cells assemble FN matrix relative to the stiffness of their substrate. Substrate stiffness might affect gene expression or protein secretion (30), which could contribute to differences in assembly; therefore, FN levels in the medium were normalized by addition of exogenous rat FN at 10 g/ml. Assembly was analyzed at 6 and 12 h after plating.…”

Levels of serum fibronectin as a biomarker in gastric cancer patients: Correlation with clinical diagnosis and outcome

“…Fibronectin serves a prominent role in cell adhesion, growth, migration and differentiation, and it is important for processes, including wound healing and embryonic development via integrins and other cell surface receptors (1)(2)(3)(4)(5)(6)(7)(8). Altered expression of fibronectin, degradation and organization have been associated with a number of pathologies, including cancer (1)(2)(3)(4)(5)(6)(7)(8).…”

“…Fibronectin serves a prominent role in cell adhesion, growth, migration and differentiation, and it is important for processes, including wound healing and embryonic development via integrins and other cell surface receptors (1)(2)(3)(4)(5)(6)(7)(8). Altered expression of fibronectin, degradation and organization have been associated with a number of pathologies, including cancer (1)(2)(3)(4)(5)(6)(7)(8). Several of the morphological changes observed in tumor types and tumor-derived cell lines have been attributed to decreased expression of fibronectin, increased fibronectin degradation, and/or decreased expression of fibronectin-binding receptors, including α5β1 integrins (1)(2)(3)(4)(5)(6)(7)(8).…”