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Bioreactor-engineered cancer tissue-like structures mimic phenotypes, gene expression profiles and drug resistance patterns observed "in vivo"

Hirt, Christian and Papadimitropoulos, Adam and Muraro, Manuele G. and Mele, Valentina and Panopoulos, Evangelos and Cremonesi, Eleonora and Ivanek, Robert and Schultz-Thater, Elke and Droeser, Raoul A. and Mengus, Chantal and Heberer, Michael and Oertli, Daniel and Iezzi, Giandomenica and Zajac, Paul and Eppenberger-Castori, Serenella and Tornillo, Luigi and Terracciano, Luigi and Martin, Ivan and Spagnoli, Giulio C.. (2015) Bioreactor-engineered cancer tissue-like structures mimic phenotypes, gene expression profiles and drug resistance patterns observed "in vivo". Biomaterials, 62. pp. 138-146.

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Official URL: https://edoc.unibas.ch/61812/

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Abstract

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 TLS, 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.
Faculties and Departments:03 Faculty of Medicine > Bereich Operative Fächer (Klinik) > Querschnittsbereich Forschung > Tissue Engineering (Martin)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Operative Fächer (Klinik) > Querschnittsbereich Forschung > Tissue Engineering (Martin)
03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Cancer Immunotherapy (Iezzi)
03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Tissue Engineering (Martin)
UniBasel Contributors:Martin, Ivan and Iezzi, Giandomenica
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Elsevier
ISSN:0142-9612
e-ISSN:1878-5905
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:06 Nov 2018 18:11
Deposited On:30 Oct 2018 17:59

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