An extracellular matrix (ECM) model at high malignant colorectal tumor increases chondroitin sulfate chains to promote epithelial-mesenchymal transition and chemoresistance acquisition

Abstract

Chemoresistance is one of the major barriers for tumor chemotherapy. It is clinically known that chemoresistance increases during tumor progression. Additionally, the extracellular matrix (ECM) is also remodeled during tumor progression. However, it remains unclear how ECM remodeling contributes to chemoresistance acquisition. Recently, it has been reported that epithelial-mesenchymal transition (EMT) contributes to chemoresistance acquisition. Here, how ECM remodeling contributes to 5-fluorouracil (5-FU) resistance acquisition was investigated from the viewpoints of EMT using in vitro ECM models mimicking native ECM in colorectal tumor tissue at three different malignant levels. 5-FU partially induced EMT and increased ABCB1 in colorectal HT-29 cells via TGF-β signaling (an invasive tumor cell model). When HT-29 cells were cultured on an ECM model (high malignant matrices) mimicking native ECM in highly malignant tumor tissues, the cells facilitated TGF-β-induced EMT and increased ABCB1 upregulation compared with that of other ECM models mimicking the low malignant level and normal tissues. High malignant matrices contained more chondroitin sulfate (CS) chains than those of other ECM models. Finally, CS chain-reduced high malignant matrices could not facilitate ABCB1 upregulation and TGF-β-induced EMT. These results demonstrated that ECM remodeling during tumor progression increased CS chains to facilitate EMT and ABCB1 upregulation, contributing to chemoresistance acquisition.