Abstract
BackgroundThe mechanical properties of the extracellular matrix have an important role in cell growth and differentiation. However, it is unclear as to what extent cancer cells respond to changes in the mechanical properties (rigidity/stiffness) of the microenvironment and how this response varies among cancer cell lines.Methodology/Principal FindingsIn this study we used a recently developed 96-well plate system that arrays extracellular matrix-conjugated polyacrylamide gels that increase in stiffness by at least 50-fold across the plate. This plate was used to determine how changes in the rigidity of the extracellular matrix modulate the biological properties of tumor cells. The cell lines tested fall into one of two categories based on their proliferation on substrates of differing stiffness: “rigidity dependent” (those which show an increase in cell growth as extracellular rigidity is increased), and “rigidity independent” (those which grow equally on both soft and stiff substrates). Cells which grew poorly on soft gels also showed decreased spreading and migration under these conditions. More importantly, seeding the cell lines into the lungs of nude mice revealed that the ability of cells to grow on soft gels in vitro correlated with their ability to grow in a soft tissue environment in vivo. The lung carcinoma line A549 responded to culture on soft gels by expressing the differentiated epithelial marker E-cadherin and decreasing the expression of the mesenchymal transcription factor Slug.Conclusions/SignificanceThese observations suggest that the mechanical properties of the matrix environment play a significant role in regulating the proliferation and the morphological properties of cancer cells. Further, the multiwell format of the soft-plate assay is a useful and effective adjunct to established 3-dimensional cell culture models.
Highlights
The control of epithelial cell (EC) differentiation and proliferation is critical for tissue homeostasis [1,2]
Rigidity-dependent growth of cancer cell lines To measure the growth of cancer cell lines as a function of matrix rigidity we adapted a novel 96-well assay system (‘‘softplate96’’) that uses collagen covalently coupled to polyacrylamide gels as substrates in place of extracellular matrix (ECM)-coated rigid plastic
The studies outlined above underscore the importance of the mechanical properties of the ECM in regulating cancer cell proliferation and survival
Summary
The control of epithelial cell (EC) differentiation and proliferation is critical for tissue homeostasis [1,2]. Nontumorigenic mammary epithelial cells, which normally reside in the soft (E = 150 pascals [Pa] or N/m2) microenvironment of the breast, show increased proliferation when cultured on stiffer matrices (E = 4500 Pa), along with increased migration, augmented ERK signaling, and loss of cellular polarity [16]. These attributes are considered hallmarks of tumor cells and are characterized as being an integral component of a transition from a relatively quiescent to a ‘‘malignant’’ phenotype, driven by a local increase in ECM rigidity [16]. It is unclear as to what extent cancer cells respond to changes in the mechanical properties (rigidity/stiffness) of the microenvironment and how this response varies among cancer cell lines
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