Recreating the tumor microenvironment in a bilayer, hyaluronic acid hydrogel construct for the growth of prostate cancer spheroids

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dc.citation.firstpage9049en_US
dc.citation.issueNumber35en_US
dc.citation.journalTitleBiomaterialsen_US
dc.citation.lastpage9060en_US
dc.citation.volumeNumber33en_US
dc.contributor.authorXu, Xianen_US
dc.contributor.authorGurski, Lisa A.en_US
dc.contributor.authorZhang, Chuen_US
dc.contributor.authorHarrington, Daniel Antonen_US
dc.contributor.authorFarach-Carson, Mary C.en_US
dc.contributor.authorJia, Xinqiaoen_US
dc.date.accessioned2017-08-01T16:30:11Zen_US
dc.date.available2017-08-01T16:30:11Zen_US
dc.date.issued2012en_US
dc.description.abstractCancer cells cultured in physiologically relevant, three-dimensional (3D) matrices can recapture many essential features of native tumor tissues. In this study, a hyaluronic acid (HA)-based bilayer hydrogel system that not only supports the tumoroid formation from LNCaP prostate cancer (PCa) cells, but also simulates their reciprocal interactions with the tumor-associated stroma was developed and characterized. HA hydrogels were prepared by mixing solutions of HA precursors functionalized with acrylate groups (HA-AC) and reactive thiols (HA-SH) under physiological conditions. The resultant viscoelastic gels have an average elastic modulus of 234 ± 30 Pa and can be degraded readily by hyaluronidase. The orthogonal and cytocompatible nature of the crosslinking chemistry permits facile incorporation of cytokine-releasing particles and PCa cells. In our bilayer hydrogel construct, the top layer contains heparin (HP)-decorated, HA-based hydrogel particles (HGPs) capable of releasing heparin-binding epidermal growth factor-like growth factor (HB-EGF) in a sustained manner at a rate of 2.5 wt%/day cumulatively. LNCaP cells embedded in the bottom layer receive the growth factor signals from the top, and in response form enlarging tumoroids with an average diameter of 85 μm by day 7. Cells in 3D hydrogels assemble into spherical tumoroids, form close cellular contacts through E-cadherin, and show cortical organization of F-actin, whereas those plated as 2D monolayers adopt a spread-out morphology. Compared to cells cultured on 2D, the engineered tumoroids significantly increased the expression of two pro-angiogenic factors, vascular endothelial growth factor-165 (VEGF(165)) and interleukin-8 (IL-8), both at mRNA and protein levels. Overall, the HA model system provides a useful platform for the study of tumor cell responses to growth factors and for screening of anticancer drugs targeting these pathways.en_US
dc.identifier.citationXu, Xian, Gurski, Lisa A., Zhang, Chu, et al.. "Recreating the tumor microenvironment in a bilayer, hyaluronic acid hydrogel construct for the growth of prostate cancer spheroids." <i>Biomaterials,</i> 33, no. 35 (2012) Elsevier: 9049-9060. https://doi.org/10.1016/j.biomaterials.2012.08.061.en_US
dc.identifier.digitalRecreating_tumor_microenvironmenten_US
dc.identifier.doihttps://doi.org/10.1016/j.biomaterials.2012.08.061en_US
dc.identifier.urihttps://hdl.handle.net/1911/96012en_US
dc.language.isoengen_US
dc.publisherElsevieren_US
dc.rightsThis is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by Elsevier.en_US
dc.titleRecreating the tumor microenvironment in a bilayer, hyaluronic acid hydrogel construct for the growth of prostate cancer spheroidsen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpost-printen_US
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