TY - JOUR
T1 - Vascularized Hepatocellular Carcinoma on a Chip to Control Chemoresistance through Cirrhosis, Inflammation and Metabolic Activity
AU - Özkan, Alican
AU - Stolley, Danielle L.
AU - Cressman, Erik N.K.
AU - McMillin, Matthew
AU - Yankeelov, Thomas E.
AU - Nichole Rylander, Marissa
N1 - Publisher Copyright:
© 2023 The Authors. Small Structures published by Wiley-VCH GmbH.
PY - 2023/9
Y1 - 2023/9
N2 - 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. Herein, novel 3D vascularized HCC on chips (HCCoCs), composed of HCC, endothelial, stellate, and Kupffer cells tuned to mimic normal or cirrhotic liver stiffness, are created. HCC inflammation is controlled by tuning Kupffer macrophage numbers, and the impact of cytochrome P450-3A4 (CYP3A4) is investigated by culturing HepG2 HCC cells transfected with CYP3A4 to upregulate expression from baseline. This model allows for the simulation of chemotherapeutic delivery methods such as intravenous injection and transcatheter arterial chemoembolization (TACE). It is shown that upregulation of metabolic activity, incorporation of cirrhosis and inflammation, increases vascular permeability due to upregulated inflammatory cytokines leading to significant variability in chemotherapeutic treatment efficacy. Specifically, it is shown 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 are shown to have utility in uncovering the impact of the tumor microenvironment during cancer progression on vascular properties, tumor response to therapeutics, and drug delivery strategies.
AB - 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. Herein, novel 3D vascularized HCC on chips (HCCoCs), composed of HCC, endothelial, stellate, and Kupffer cells tuned to mimic normal or cirrhotic liver stiffness, are created. HCC inflammation is controlled by tuning Kupffer macrophage numbers, and the impact of cytochrome P450-3A4 (CYP3A4) is investigated by culturing HepG2 HCC cells transfected with CYP3A4 to upregulate expression from baseline. This model allows for the simulation of chemotherapeutic delivery methods such as intravenous injection and transcatheter arterial chemoembolization (TACE). It is shown that upregulation of metabolic activity, incorporation of cirrhosis and inflammation, increases vascular permeability due to upregulated inflammatory cytokines leading to significant variability in chemotherapeutic treatment efficacy. Specifically, it is shown 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 are shown to have utility in uncovering the impact of the tumor microenvironment during cancer progression on vascular properties, tumor response to therapeutics, and drug delivery strategies.
KW - chemoresistance
KW - drug metabolism
KW - hepatocellular carcinoma
KW - inflammation
KW - microfluidics
KW - organ on a chip
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U2 - 10.1002/sstr.202200403
DO - 10.1002/sstr.202200403
M3 - Article
C2 - 38073766
AN - SCOPUS:85163796979
SN - 2688-4062
VL - 4
JO - Small Structures
JF - Small Structures
IS - 9
M1 - 2200403
ER -