Journal
BIOMATERIALS
Volume 62, Issue -, Pages 138-146Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2015.05.037
Keywords
Bioreactors; Tri-dimensional cultures; Tumor tissue-like structures; Colorectal cancer; Drug resistance
Funding
- Lichtenstein-Stiftung of the University of Basel [DMS2209]
- Kommission fur Technologie und Innovation (KTI, Bern, Switzerland)
- Department of Surgery of the University Hospital Basel
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Anticancer compound screening on 2D cell cultures poorly predicts in vivo performance, while conventional 3D culture systems are usually characterized by limited cell proliferation, failing to produce tissue-like-structures (TLS) suitable for drug testing. We addressed engineering of TLS by culturing cancer cells in porous scaffolds under perfusion flow. Colorectal cancer (CRC) HT-29 cells were cultured in 2D, on collagen sponges in static conditions or in perfused bioreactors, or injected subcutaneously in immunodeficient mice. Perfused 3D (p3D) cultures resulted in significantly higher (p < 0.0001) cell proliferation than static 3D (s3D) cultures and yielded more homogeneous TB, with morphology and phenotypes similar to xenografts. Transcriptome analysis revealed a high correlation between xenografts and p3D cultures, particularly for gene clusters regulating apoptotic processes and response to hypoxia. Treatment with 5-Fluorouracil (5-FU), a frequently used but often clinically ineffective chemotherapy drug, induced apoptosis, down-regulation of anti-apoptotic genes (BCL-2, TRAF1, and c-FLIP) and decreased cell numbers in 2D, but only nucleolar stress in p3D and xenografts. Conversely, BCL-2 inhibitor ABT-199 induced cytotoxic effects in p3D but not in 2D cultures. Our findings advocate the importance of perfusion flow in 3D cultures of tumor cells to efficiently mimic functional features observed in vivo and to test anticancer compounds. (c) 2015 Elsevier Ltd. All rights reserved.
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