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Article

Recellularized Colorectal Cancer Patient-Derived Scaffolds as In Vitro Pre-Clinical 3D Model for Drug Screening

1
Fondazione Istituto di Ricerca Pediatrica Città della Speranza, 35129 Padua, Italy
2
Department of Molecular Sciences and Nanosystems, Ca’ Foscari University of Venice, 30172 Mestre (Venice), Italy
3
First Surgical Clinic, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy
4
LIFELAB Program, Consorzio per la Ricerca Sanitaria-CORIS, Veneto Region, 129 Padua, Italy
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Department of Industrial Engineering, University of Padua, 35131 Padua, Italy
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Department of Pharmaceutical and Pharmacological Sciences, University of Padua, 35131 Padua, Italy
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Institute of Hepatology, Foundation for Liver Research, London SE5 9NT, UK
8
Faculty of Life Sciences & Medicine, King’s College London, London WC2R 2LS, UK
9
Surgical Pathology Unit, Department of Medicine, University of Padua, 35100 Padua, Italy
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(3), 681; https://doi.org/10.3390/cancers12030681
Received: 27 February 2020 / Revised: 4 March 2020 / Accepted: 12 March 2020 / Published: 13 March 2020
(This article belongs to the Special Issue Cancer Organoids in Basic Science and Translational Medicine)
Colorectal cancer (CRC) shows highly ineffective therapeutic management. An urgent unmet need is the random assignment to adjuvant chemotherapy of high-risk stage II and stage III CRC patients without any predictive factor of efficacy. In the field of drug discovery, a critical step is the preclinical evaluation of drug cytotoxicity, efficacy, and efficiency. We proposed a patient-derived 3D preclinical model for drug evaluation that could mimic in vitro the patient’s disease. Surgically resected CRC tissue and adjacent healthy colon mucosa were decellularized by a detergent-enzymatic treatment. Scaffolds were recellularized with HT29 and HCT116 cells. Qualitative and quantitative characterization of matched recellularized samples were evaluated through histology, immunofluorescences, scanning electron microscopy, and DNA amount quantification. A chemosensitivity test was performed using an increasing concentration of 5-fluorouracil (5FU). In vivo studies were carried out using zebrafish (Danio rerio) animal model. Permeability test and drug absorption were also determined. The decellularization protocol allowed the preservation of the original structure and ultrastructure. Five days after recellularization with HT29 and HCT116 cell lines, the 3D CRC model exhibited reduced sensitivity to 5FU treatments compared with conventional 2D cultures. Calculated the half maximal inhibitory concentration (IC50) for HT29 treated with 5FU resulted in 11.5 µM in 3D and 1.3 µM in 2D, and for HCT116, 9.87 µM in 3D and 1.7 µM in 2D. In xenograft experiments, HT29 extravasation was detected after 4 days post-injection, and we obtained a 5FU IC50 fully comparable to that observed in the 3D CRC model. Using confocal microscopy, we demonstrated that the drug diffused through the repopulated 3D CRC scaffolds and co-localized with the cell nuclei. The bioengineered CRC 3D model could be a reliable preclinical patient-specific platform to bridge the gap between in vitro and in vivo drug testing assays and provide effective cancer treatment. View Full-Text
Keywords: 3D culture model; colorectal cancer; extracellular matrix; decellularization; drug test; response to treatment 3D culture model; colorectal cancer; extracellular matrix; decellularization; drug test; response to treatment
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MDPI and ACS Style

Sensi, F.; D’Angelo, E.; Piccoli, M.; Pavan, P.; Mastrotto, F.; Caliceti, P.; Biccari, A.; Corallo, D.; Urbani, L.; Fassan, M.; Spolverato, G.; Riello, P.; Pucciarelli, S.; Agostini, M. Recellularized Colorectal Cancer Patient-Derived Scaffolds as In Vitro Pre-Clinical 3D Model for Drug Screening. Cancers 2020, 12, 681. https://doi.org/10.3390/cancers12030681

AMA Style

Sensi F, D’Angelo E, Piccoli M, Pavan P, Mastrotto F, Caliceti P, Biccari A, Corallo D, Urbani L, Fassan M, Spolverato G, Riello P, Pucciarelli S, Agostini M. Recellularized Colorectal Cancer Patient-Derived Scaffolds as In Vitro Pre-Clinical 3D Model for Drug Screening. Cancers. 2020; 12(3):681. https://doi.org/10.3390/cancers12030681

Chicago/Turabian Style

Sensi, Francesca, Edoardo D’Angelo, Martina Piccoli, Piero Pavan, Francesca Mastrotto, Paolo Caliceti, Andrea Biccari, Diana Corallo, Luca Urbani, Matteo Fassan, Gaya Spolverato, Pietro Riello, Salvatore Pucciarelli, and Marco Agostini. 2020. "Recellularized Colorectal Cancer Patient-Derived Scaffolds as In Vitro Pre-Clinical 3D Model for Drug Screening" Cancers 12, no. 3: 681. https://doi.org/10.3390/cancers12030681

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