Abstract
Variations in tumor biology from patient to patient combined with the low overall survival rate of hepatocellular carcinoma (HCC) present significant clinical challenges. During the progression of chronic liver diseases from inflammation to the development of HCC, microenvironmental properties, including tissue stiffness and oxygen concentration, change over time. This can potentially impact drug metabolism and subsequent therapy response to commonly utilized therapeutics, such as doxorubicin, multi-kinase inhibitors (e.g., sorafenib), and other drugs, including immunotherapies. In this study, we utilized four common HCC cell lines embedded in 3D collagen type-I gels of varying stiffnesses to mimic normal and cirrhotic livers with environmental oxygen regulation to quantify the impact of these microenvironmental factors on HCC chemoresistance. In general, we found that HCC cells with higher baseline levels of cytochrome p450-3A4 (CYP3A4) enzyme expression, HepG2 and C3Asub28, exhibited a cirrhosis-dependent increase in doxorubicin chemoresistance. Under the same conditions, HCC cell lines with lower CYP3A4 expression, HuH-7 and Hep3B2, showed a decrease in doxorubicin chemoresistance in response to an increase in microenvironmental stiffness. This differential therapeutic response was correlated with the regulation of CYP3A4 expression levels under the influence of stiffness and oxygen variation. In all tested HCC cell lines, the addition of sorafenib lowered the required doxorubicin dose to induce significant levels of cell death, demonstrating its potential to help reduce systemic doxorubicin toxicity when used in combination. These results suggest that patient-specific tumor microenvironmental factors, including tissue stiffness, hypoxia, and CYP3A4 activity levels, may need to be considered for more effective use of chemotherapeutics in HCC patients.
Highlights
Cancer is the second-highest cause of mortality in the United States, lagging just slightly behind cardiovascular disease in 2020 [1]
We establish that chemoresistance can be regulated by hypoxic and cirrhotic conditions in the tumor microenvironment (TME) through direct modulation of CYP3A4 expression
This regulation can differentially alter the efficacy of chemotherapeutic drugs in hepatocellular carcinoma (HCC) cell lines, which potentially has clinical translation to patient-specific HCC treatments
Summary
Cancer is the second-highest cause of mortality in the United States, lagging just slightly behind cardiovascular disease in 2020 [1]. Despite screening efforts for at-risk patients, most are not surgical candidates for partial resection, and the availability of full liver transplantation is very low relative to the need [5] These issues mean that systemic and localized drug-based therapies play a significant role in current standard therapy for HCC. TACE blocks the arterial blood supply of a tumor through particulate or viscous liquid agents such as degradable starch microspheres, drug-eluting beads, or ethiodized oil This is a well-established technique that allows a high local dose while simultaneously increasing the residence of chemotherapeutic drugs in the target area, cutting off the supply of nutrients, and limiting exposure and toxicity for the rest of the body [11]. While a substantial survival benefit can be realized, there is still much room for improvement and understanding of the changes that occur in the tumor cells during embolization [6,7,8]
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