The Interaction between Cancer-associated Fibroblasts and Cancer Cells Enhances Bcl-xL and Mcl-1 in Colorectal Cancer

概要

The acquisition of resistance to apoptosis is one of the biggest problems in colorectal cancer (CRC) treatment. The purpose of this study was to elucidate the mechanism of the resistance to apoptosis in CRC with a focus on interleukin (IL)-6 produced by the interaction between colon cancer cells and cancer-associated fibroblasts (CAFs) in the tumor microenvironment. The results showed that IL-6 clearly enhanced the expression of Bcl-xL and Mcl-1, which are anti-apoptotic members of the Bcl-2 family of proteins, as well as the phosphorylation of STAT3 in a dose-dependent manner. Co-culturing of colon cancer cells and CAFs enhanced the expression of Bcl-xL and Mcl-1, and this enhancement was clearly attenuated by anti-human IL-6 receptor antibody. Moreover, the co-culturing of colon cancer cells and CAFs led to the production of more IL-6 than the culturing of colon cancer cells or CAFs alone. Immunohistochemistry of resected CRC specimens also clearly showed a positive correlation between CAF invasion and BclxL/Mcl-1 expression. These results showed that the interaction between CAFs and cancer cells enhances Bcl-xL and Mcl-1 expression through the IL-6/STAT3 signaling pathway in CRC. Our findings may provide new potential therapeutic targets and a new strategy for CRC treatment.