5-Fluorouracil resistant CRC cells derived exosomes promote cancer-associated fibroblasts secreting more CXCL12

• Published in: Journal of Cancer Vol. 15; no. 11; pp. 3441 - 3451
• Main Authors: Zhang, Tongxin, He, Zilong, Qi, Xiaowei, Zhang, Yu, Liu, Yankui, Jin, Linfang, Wang, Teng
• Format: Journal Article
• Language: English
• Published: Australia Ivyspring International Publisher 01.01.2024
• Subjects: Research Paper; Cancer-associated fibroblast; Transient receptor potential canonical 5; CXCL12; Chemoresistance; Colorectal cancer
• ISSN: 1837-9664; 1837-9664
• DOI: 10.7150/jca.95248

Chemoresistance is a key reason for treatment failure in colorectal cancer (CRC) patients. The tumor microenvironment of chemoresistant CRC is distinctly immunosuppressive, although the underlying mechanisms are unclear. The CRC data sets GSE69657 and GSE62080 were downloaded from the GEO database, and the correlation between TRPC5 and FAP expression was analyzed by Pearson method. The in-situ expression of transient receptor potential channel 5 (TRPC5) and fibroblast activation protein (FAP) in the CRC tissues was examined by immunohistochemistry. TRPC5 expression levels in the HCT8 and HCT116 cell lines and the corresponding 5-fluorouracil (5-FU)-resistant cell lines (HCT8R and HCT116R) were analyzed by western blotting and RT-PCR. Exosomes were isolated from the HCT8R and HCT116R cells and incubated with colorectal normal fibroblasts (NFs), and cancer-associated fibroblasts (CAFs)markers were detected. NFs were also incubated with exosomes isolated from TRPC5-knockdown HCT8R cells, and the changes in intracellular Ca levels and C-X-C motif chemokine ligand 12 (CXCL12) secretion were analyzed. TRPC5 and FAP expression showed positive correlation in the datasets. Immunostaining of CRC tissue specimens further revealed that high TRPC5 and FAP expressions were significantly associated with worse tumor regression. Furthermore, chemoresistant CRC cells expressed higher levels of TRPC5 compared to the chemosensitive cells, and knocking down TRPC5 reversed chemoresistance. Exosomes derived from CRC cells induced the transformation of NFs to CAFs. However, TRPC5-exosomes derived from chemoresistant CRC cells can promote CAFs to secrete more CXCL12. Chemoresistant CRC cells can induce CAFs activation and promote CXCL12 secretion through exosomal TRPC5.