Vascularized Hepatocellular Carcinoma on a Chip to Control Chemoresistance through Cirrhosis, Inflammation and Metabolic Activity
Understanding the effects of inflammation and cirrhosis on the regulation of drug metabolism during the progression of hepatocellular carcinoma (HCC) is critical for developing patient-specific treatment strategies. In this work, we created novel three-dimensional vascularized HCC-on-a-chips (HCCoC)...
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Published in | Small structures Vol. 4; no. 9 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
Germany
John Wiley & Sons, Inc
01.09.2023
Wiley-VCH |
Subjects | |
Online Access | Get full text |
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Summary: | Understanding the effects of inflammation and cirrhosis on the regulation of drug metabolism during the progression of hepatocellular carcinoma (HCC) is critical for developing patient-specific treatment strategies. In this work, we created novel three-dimensional vascularized HCC-on-a-chips (HCCoC), composed of HCC, endothelial, stellate, and Kupffer cells tuned to mimic normal or cirrhotic liver stiffness. HCC inflammation was controlled by tuning Kupffer macrophage numbers, and the impact of cytochrome P450-3A4 (CYP3A4) was investigated by culturing HepG2 HCC cells transfected with CYP3A4 to upregulate expression from baseline. This model allowed for the simulation of chemotherapeutic delivery methods such as intravenous injection and transcatheter arterial chemoembolization (TACE). We showed that upregulation of metabolic activity, incorporation of cirrhosis and inflammation, increase vascular permeability due to upregulated inflammatory cytokines leading to significant variability in chemotherapeutic treatment efficacy. Specifically, we show that further modulation of CYP3A4 activity of HCC cells by TACE delivery of doxorubicin provides an additional improvement to treatment response and reduces chemotherapy-associated endothelial porosity increase. The HCCoCs were shown to have utility in uncovering the impact of the tumor microenvironment (TME) during cancer progression on vascular properties, tumor response to therapeutics, and drug delivery strategies. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Conceptualization: A.Ö. conceived of the idea for the study. Supervision: E.N.K.C, T.E.Y. and M.N.R. supervised the project. E.N.K.C., M.M., T.E.Y. and M.N.R provided feedback and assistance with manuscript preparation. Investigation: A.Ö., D.L.S., and M.N.R were responsible for performing the studies and analyzing the experimental data. Writing: A.Ö. wrote the initial draft of the paper. All authors discussed the results and revised the manuscript. Author contributions |
ISSN: | 2688-4062 2688-4062 |
DOI: | 10.1002/sstr.202200403 |