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Hakanson M , Kobel S , Lutolf MP , Textor M , Cukierman E , Charnley M
Controlled Breast Cancer Microarrays for the Deconvolution of Cellular Multilayering and Density Effects upon Drug Responses
Plos One. 2012 Jun;7(6) :e40141
PMID: WOS:000305892100215    PMCID: PMC3387021    URL: http://www.ncbi.nlm.nih.gov/pubmed/22792141
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Abstract
Background: Increasing evidence shows that the cancer microenvironment affects both tumorigenesis and the response of cancer to drug treatment. Therefore in vitro models that selectively reflect characteristics of the in vivo environment are greatly needed. Current methods allow us to screen the effect of extrinsic parameters such as matrix composition and to model the complex and three-dimensional (3D) cancer environment. However, 3D models that reflect characteristics of the in vivo environment are typically too complex and do not allow the separation of discrete extrinsic parameters. Methodology/Principal Findings: In this study we used a poly(ethylene glycol) (PEG) hydrogel-based microwell array to model breast cancer cell behavior in multilayer cell clusters that allows a rigorous control of the environment. The innovative array fabrication enables different matrix proteins to be integrated into the bottom surface of microwells. Thereby, extrinsic parameters including dimensionality, type of matrix coating and the extent of cell-cell adhesion could be independently studied. Our results suggest that cell to matrix interactions and increased cell-cell adhesion, at high cell density, induce independent effects on the response to Taxol in multilayer breast cancer cell clusters. In addition, comparing the levels of apoptosis and proliferation revealed that drug resistance mediated by cell-cell adhesion can be related to altered cell cycle regulation. Conversely, the matrix-dependent response to Taxol did not correlate with proliferation changes suggesting that cell death inhibition may be responsible for this effect. Conclusions/Significance: The application of the PEG hydrogel platform provided novel insight into the independent role of extrinsic parameters controlling drug response. The presented platform may not only become a useful tool for basic research related to the role of the cancer microenvironment but could also serve as a complementary platform for in vitro drug development.
Notes
Hakanson, Maria Kobel, Stefan Lutolf, Matthias P. Textor, Marcus Cukierman, Edna Charnley, Mirren Competence Centre for Materials Science and Technoloy (CCMX); Swiss National Science Foundation (SNSF)[CR23I2_125290/1]; National Centers for Competence in Research (NCCR); National Institutes of Health/National Cancer Institute[CA113451] The authors thank the Competence Centre for Materials Science and Technoloy (CCMX; www.ccmx.ch), the Swiss National Science Foundation (SNSF; www.snf.ch; grant number CR23I2_125290/1) and the National Centers for Competence in Research (NCCR; www.nccr.ch; Nano-P5, project 03) for their financial support of this work. The authors also acknowledge funds from National Institutes of Health/National Cancer Institute grant CA113451 (to EC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 59 Public library science San francisco 967fo