ROCK-generated contractility regulates breast epithelial cell differentiation in response to the physical properties of a three-dimensional collagen matrix

Wozniak, Michele A.; Desai, Radhika; Solski, Patricia A.; Der, Channing J.; Keely, Patricia J.

doi:10.1083/jcb.200305010

Cited by 470 publications

(514 citation statements)

References 50 publications

(53 reference statements)

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“…In contrast, little if any effect was seen with PA-1 and COLO 205 cells. These observations were compatible with the suggestion that 3D and 2D substrates differentially regulate integrins and their downstream effectors such as FAK (Paszek et al, 2005;Rhee et al, 2007;Wozniak et al, 2003). However, the fact the set of cells with 3D-regulated changed in FAK phosphorylation was different from those cells with 3D-regulated, integrin-dependent taxol resistance indicated an increased level of FAK activity could not explain this response.…”

Section: Fibroblast 3d Matrix-induced Taxol Responses Depend On β1-insupporting

confidence: 85%

Fibroblast-derived 3D matrix differentially regulates the growth and drug-responsiveness of human cancer cells

et al. 2008

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Recent studies have emphasized the importance of cellular microenvironment in modulating cell growth and signaling. In vitro, collagen matrices, Matrigel, and other synthetic support systems have been used to simulate in vivo microenvironments, and epithelial cells grown in these matrices manifest significant differences in proliferation, differentiation, response to drugs, and other parameters. However, these substrates do not closely resemble the mesenchymal microenvironment that is typically associated with advanced carcinomas in vivo, which is produced to a large extent by fibroblasts. In this study, we have evaluated the ability of a fibroblast-derived three-dimensional matrix to regulate the growth of a panel of 11 human tumor epithelial cell lines. Although proliferative and morphological responses to three-dimensional cues segregated independently, general responsiveness to the matrix correlated with the ability of matrix to influence drug responses. Fibroblast-derived three-dimensional matrix increased β1-integrin-dependent survival of a subset of human cancer cell lines during taxol treatment, while it sensitized or minimally influenced survival of other cells. β1-integrin-dependent changes in cell resistance to taxol did not correlate with degree of modulation of FAK and Akt, implying additional signaling factors are involved. Based on these results, we propose these matrices potentially have value as in vitro drug screening platforms.

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Section: Fibroblast 3d Matrix-induced Taxol Responses Depend On β1-insupporting

confidence: 85%

Fibroblast-derived 3D matrix differentially regulates the growth and drug-responsiveness of human cancer cells

et al. 2008

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“…Dense rigid physical properties suppress tubulogenesis and possibly stimulate invasion of welldifferentiated breast carcinoma cells in collagen gels by stimulating the activity of the small GTPase Rho. 56,57 The cell-derived matrices used in our study are more pliable than the basement membrane or collagen gels commonly used to assess 3D matrix effects on breast carcinoma cell behavior. 58 Therefore, we favor a model in which the fiber topography rather than matrix rigidity governs cell invasion in fibroblast-derived matrices.…”

Section: Discussionmentioning

confidence: 99%

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

Yang

Mosher

Seo

et al. 2011

The American Journal of Pathology

121

126

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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.

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“…This is nicely exemplified by two examples. The first is the differentiation of breast epithelial cells into tubules when cultured in floating 3D collagen gels but not when cultured on gels attached to the culture dish [16] . The second is the recent finding that polyacrylamide (PA) gels of controlled stiffness can direct stem cell lineage specification.…”

Section: Introductionmentioning

confidence: 99%

Polyelectrolyte Multilayer Films of Controlled Stiffness Modulate Myoblast Cell Differentiation

Ren

Crouzier

Roy

et al. 2008

Adv Funct Materials

240

263

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Beside chemical properties and topographical features, mechanical properties of gels have been recently demonstrated to play an important role in various cellular processes, including cell attachment, proliferation, and differentiation. In this work, we used multilayer films made of poly (L-lysine)/Hyaluronan (PLL/HA) of controlled stiffness to investigate the effects of mechanical properties of thin films on skeletal muscle cells (C2C12 cells) differentiation. Prior to differentiation, cells need to adhere and proliferate in growth medium. Stiff films (E 0 > 320 kPa) promoted formation of focal adhesions and organization of the cytoskeleton as well as an enhanced proliferation, whereas soft films were not favorable for cell anchoring, spreading or proliferation. Then C2C12 cells were switched to a low serum containing medium to induce cell differentiation, which was also greatly dependent on film stiffness. Although myogenin and troponin T expressions were only moderately affected by film stiffness, the morphology of the myotubes exhibited striking stiffness-dependent differences. Soft films allowed differentiation only for few days and the myotubes were very short and thick. Cell clumping followed by aggregates detachment could be observed after ~2 to 4 days. On stiffer films, significantly more elongated and thinner myotubes were observed for up to ~ 2 weeks. Myotube striation was also observed but only for the stiffer films. These results demonstrate that film stiffness modulates deeply adhesion, proliferation and differentiation, each of these processes having its own stiffness requirement.

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ROCK-generated contractility regulates breast epithelial cell differentiation in response to the physical properties of a three-dimensional collagen matrix

Cited by 470 publications

References 50 publications

Fibroblast-derived 3D matrix differentially regulates the growth and drug-responsiveness of human cancer cells

Fibroblast-derived 3D matrix differentially regulates the growth and drug-responsiveness of human cancer cells

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

Polyelectrolyte Multilayer Films of Controlled Stiffness Modulate Myoblast Cell Differentiation

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