A cytokine called TRAIL binds to TRAIL receptors and kills cancer cells, but not normal cells. Therefore, various anticancer drugs targeting TRAIL receptors have been developed and have attracted wide attention as promising cancer therapeutics, but a certain population of cancer patients does not respond to the therapy. Therefore, many researchers have attempted to identify a key molecule that determines the sensitivity of cancer cells to TRAIL therapy.
The surface of every cell in our body is decorated with sugar chains called glycans, which determine the character of cells and allow cells to talk to each other. Glycan structures on the surface of cells change dramatically when cells become cancerous. In this multi-institutional study led by Associate Professor Moriwaki of Toho University and Professor Miyoshi of Osaka University, identified the glycan structure that makes cancer cells vulnerable to the death-inducing cytokine, TRAIL , and paved the way for the development of a predictive biomarker for TRAIL Therapy.
Previously, Drs. Moriwaki and Miyoshi found that fucose, which is one of the building blocks of glycans, is an important sugar affecting the sensitivity of cancer cells to TRAIL. This time, they looked closely at the structures of fucose-carrying glycans and found that cancer cells that strongly expressed the specific glycan structure called Lewis glycans on the surface were more vulnerable to TRAIL-induced cell death. They also found that although Lewis glycans are attached to proteins and lipids on the surface, Lewis glycans on lipids, but not on proteins, improve sensitivity to TRAIL. Moreover, they could predict the susceptibility of cancer cells derived from colon cancer patients to TRAIL-induced cell death by testing the expression level of Lewis glycans. Therefore, this specific glycan structure should be a valuable biomarker to predict the effectiveness of TRAIL therapy.
These findings shed light on the regulatory mechanism of TRAIL-induced cell death and encourage the development of a novel therapeutic strategy targeting TRAIL signaling. Moreover, resistance to TRAIL is a vital intrinsic mechanism that renders cancer cells insensitive to certain types of cancer immunotherapy. These findings therefore also have an important impact on the development of a predictive biomarker for cancer immunotherapy.
Dr. Tomoya Fukuoka, lead author of the study
These results were published in Oncogene, in August 2022. This research was conducted in collaboration with Drs. Keiichi Ozono from Osaka University, Masahiro Inoue from Kyoto University, Yasuhide Miyamoto from the Osaka International Cancer Institute, and Hiroyuki Kaji from the National Institute of Advanced Industrial Science and Technology.
Fukuoka, T. et al. (2022) Lewis glycosphingolipids as critical determinants of TRAIL sensitivity in cancer cells. Oncogene. doi.org/10.1038/s41388-022-02434-3.