Structural cues from the tissue microenvironment are essential determinants of the human mammary epithelial cell phenotype (original) (raw)
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Journal of Cell Biology, 1997
In a recently developed human breast cancer model, treatment of tumor cells in a 3-dimensional culture with inhibitory  1-integrin antibody or its Fab fragments led to a striking morphological and functional reversion to a normal phenotype. A stimulatory  1-integrin antibody proved to be ineffective. The newly formed reverted acini re-assembled a basement membrane and re-established E-cadherin-catenin complexes, and re-organized their cytoskeletons. At the same time they downregulated cyclin D1, upregulated p21 cip,waf-1 , and stopped growing. Tumor cells treated with the same antibody and injected into nude mice had significantly reduced number and size of tumors in nude mice. The tissue distribution of other integrins was also normalized, suggesting the existence of inti-mate interactions between the different integrin pathways as well as adherens junctions. On the other hand, nonmalignant cells when treated with either ␣ 6 or  4 function altering antibodies continued to grow, and had disorganized colony morphologies resembling the untreated tumor colonies. This shows a significant role of the ␣ 6/  4 heterodimer in directing polarity and tissue structure. The observed phenotypes were reversible when the cells were disassociated and the antibodies removed. Our results illustrate that the extracellular matrix and its receptors dictate the phenotype of mammary epithelial cells, and thus in this model system the tissue phenotype is dominant over the cellular genotype.
Integrins in Mammary Gland Development and Differentiation of Mammary Epithelium
Journal of Mammary Gland Biology and Neoplasia, 2000
Integrins are major extracellular matrix (ECM) receptors that can also serve for some cellcell interactions. They have been identified as important regulators of mammary epithelial cell growth and differentiation. Their ability to promote cell anchorage, proliferation, survival, migration, and the induction of active ECM-degrading enzymes suggests that they play an essential role in normal mammary morphogenesis, but, on the other hand, reveals their potential to promote tumor progression.
2007
Stromal-epithelial interactions regulate mammary gland development and are critical for the maintenance of tissue homeostasis. The extracellular matrix, which is a proteinaceous component of the stroma, regulates mammary epithelial growth, survival, migration and differentiation through a repertoire of transmembrane receptors, of which integrins are the best characterized. Integrins modulate cell fate by reciprocally transducing biochemical and biophysical cues between the cell and the extracellular matrix, facilitating processes such as embryonic branching morphogenesis and lactation in the mammary gland. During breast development and cancer progression, the extracellular matrix is dynamically altered such that its composition, turnover, processing and orientation change dramatically. These modifications influence mammary epithelial cell shape, and modulate growth factor and hormonal responses to regulate processes including branching morphogenesis and alveolar differentiation. Malignant transformation of the breast is also associated with significant matrix remodeling and a progressive stiffening of the stroma that can enhance mammary epithelial cell growth, perturb breast tissue organization, and promote cell invasion and survival. In this review, we discuss the role of stromal-epithelial interactions in normal and malignant mammary epithelial cell behavior. We specifically focus on how dynamic modulation of the biochemical and biophysical properties of the extracellular matrix elicit a dialogue with the mammary epithelium through transmembrane integrin receptors to influence tissue morphogenesis, homeostasis and malignant transformation.
How integrins control breast biology
Current Opinion in Cell Biology, 2013
This article explores new ideas about how the ECM-integrin axis controls normal and malignant breast biology. We discuss the role of integrins in mammary stem cells, and how cellmatrix interactions regulate ductal and alveolar development and function. We also examine the contribution of integrins to tissue disorganisation and metastasis, and how an altered stromal and ECM tumour microenvironment affects the cancer cell niche both within primary tumours and at distant sites. Finally, we mention novel strategies for integrin-directed breast cancer treatment. Addresses Open access under CC BY license. 38. Wickströ m SA, Lange A, Hess MW, Polleux J, Spatz JP, Krü ger M, Pfaller K, Lambacher A, Bloch W, Mann M et al.: Integrin-linked kinase controls microtubule dynamics required for plasma membrane targeting of caveolae.
Integrin signaling in mammary epithelial cells and breast cancer
2012
Cells sense and respond to the extracellular matrix (ECM) by way of integrin receptors, which facilitate cell adhesion and intracellular signaling. Advances in understanding the mammary epithelial cell hierarchy are converging with new developments that reveal how integrins regulate the normal mammary gland. But in breast cancer, integrin signaling contributes to the development and progression of tumors. This paper highlights recent studies which examine the role of integrin signaling in mammary epithelial cells and their malignant counterparts.
Bi-Directional Signaling: Extracellular Matrix and Integrin Regulation of Breast Tumor Progression
Critical Reviews in Eukaryotic Gene Expression, 2013
Cell transformation and tumor progression involves a common set of acquired capabilities, including increased proliferation, failure of cell death, self-sufficiency in growth, angiogenesis, and tumor cell invasion and metastasis (1). The stromal environment consists of many cell types, including fibroblasts, macrophages, and endothelial cells, in addition to various extracellular matrix (ECM) proteins that function to support normal tissue maintenance, but have also been implicated in tumor progression (2). Both the chemical and mechanical properties of the ECM have been shown to influence normal and malignant cell behavior. For instance, mesenchymal stem cells differentiate into specific lineages that are dependent on matrix stiffness (3) , while tumor cells undergo changes in cell behavior and gene expression in response to matrix stiffness (4). ECM remodeling is implicated in tumor progression and includes changes in both the chemical and mechanical properties of the ECM (5) that can be a result of 1.) increased deposition of stromal ECM, 2.) enhanced contraction of ECM fibrils, and 3.) altered collagen alignment and ECM stiffness. In addition, remodeling of the ECM may alter whether tumor cells employ proteolytic degradation mechanisms during invasion and metastasis. Tumor cells respond to such changes in ECM remodeling through altered intracellular signaling and cell cycle control that lead to enhanced proliferation, loss of normal tissue architecture, and local tumor cell migration and invasion into the surrounding stromal tissue (6). This review will focus on the bi-directional interplay between the mechanical properties of the ECM and changes in integrin-mediated signal transduction events in an effort to elucidate cell behaviors during tumor progression.
Journal of Biological Chemistry, 2012
Background: Integrin-mediated ECM adhesion is required for mammary epithelial proliferation, but the mechanism is not known. Results: Gene deletion studies show that 1-integrin-null mammary epithelial cells retain 3-integrins and the ability to undergo two-dimensional migration, and Rac1 rescues their proliferation defect. Conclusion: 1-Integrins uniquely control proliferation in mammary cells via Rac1, whereas 3-integrins support two-dimensional migration. Significance: Specific -integrin-containing adhesions determine different cell-fate responses.
Methods, 2003
The normal human breast comprises an inner layer of luminal epithelial cells and an outer layer of myoepithelial cells separated from the connective tissue stroma by an intact basement membrane. In breast cancer, tumor cells are in direct contact with the surrounding highly activated collagenous stroma, with little or no discernible myoepithelial fence from the original double-layered structure. To understand the evolution of these two scenarios, we took advantage of a three-dimensional hydrated collagen gel approach. The contribution of myoepithelial cells to normal morphogenesis was studied by ablation and rescue experiments, and genes regulated on tumor cell-fibroblast interaction were identified in a tumor environment assay. In normal breast morphogenesis, the ability to correctly polarize sialomucin to the luminal membrane of emerging acini was used as a criterion for apical polarity and functional differentiation. In the assay of breast neoplasia, the consequence of reciprocal tumor cell-fibroblast interaction was addressed morphologically as well as by a differential display approach. Normal breast epithelial cells were purified immunomagnetically and an established cell line, MCF-7, was used as a surrogate tumor cell. With regard to the importance of myoepithelial cells in normal breast epithelial morphogenesis, the collagen gel assay elucidated the following subtleties: In contrast to culturing in basement membrane gels, luminal epithelial cells when cultured alone made structures that were all inversely polarized. This aberrant polarity could be rescued by co-culture with myoepithelial cells. The molecular activity of myoepithelial cells responsible for correct morphogenesis was narrowed down to the laminin-1 component of the basement membrane. As for the consequence of interaction of tumor cells with connective tissue fibroblasts, the assay allowed us to identify a hitherto undescribed gene referred to as EPSTI1. The relevance of the assay-based identification of regulated genes was confirmed in a series of breast carcinomas in which EPSTI1 was highly upregulated compared with normal breast. Few if any of these observations would have been possible on two-dimensional tissue culture plastic.