Mechanism of inflammatory cancer-associated fibroblast-mediated drug resistance in colorectal cancer cells / 中国癌症杂志

ABSTRACT

Background and purpose:Colorectal cancer(CRC)is one of the common malignancies,but the mechanism by which it develops resistance to drug remains unclear.The tumor microenvironment(TME),especially cancer-associated fibroblast(CAF),plays an important role in the occurrence,development and drug resistance of tumors.This study aimed to investigate the effect of inflammatory cancer-associated fibroblasts(iCAF)on drug resistance in CRC cells and its possible mechanism.Methods:The primary CAFs were collected from CRC patients underwent surgery in Putuo Hospital,Shanghai University of Traditional Chinese Medicine from Aug.2022 to Sep.2022,and the primary cells were sorted according to the surface marker of CAF[approved by the Ethics Committee of Putuo Hospital Affiliated to Shanghai University of Traditional Chinese Medicine:PTEC-A-2023-5(S)-1],platelet derived growth factor receptor alpha(PDGFRA),to screen iCAF.Human intestinal fibroblast(HIF)and iCAF cells were cultured using serum-free medium to obtain conditioned medium.According to the treatment method,colon cancer cells were divided into control group(no treatment),experimental group 1(treated with HIF-CM)and experimental group 2(treated with iCAF-CM).We observed the changes in the survival rate and apoptotic rate of CRC cells,the changes in protein and mRNA levels and the effect on the Wnt/β-catenin signaling pathway after stimulation with HIF-CM or iCAF-CM.Results:After iCAFs stimulation,the half inhibition concentration(IC50)of CRC cells was higher compared with the control group and HIF-CM group(P＜0.05).Compared with the control group and HIF-CM group,the apoptotic rate of tumor cells in iCAF-CM group decreased significantly,the expression of caspase-3 was decreased,and the expressions of Bcl-2,Bcl-xL and survivin were increased(P＜0.05).The Wnt/β-catenin signaling pathway was activated in the iCAF-CM group.Conclusion:iCAFs can mediate drug resistance in CRC cells,and the mechanism is related to the activation of Wnt/β-catenin signaling pathway.