Minoru Fukuda, Ph.D.
Professor, Tumor Microenvironment
Many studies have focused on carbohydrates that increase in cancer cells, but only a few have looked at carbohydrates that appear in normal cells but decrease or disappear in cancer cells. A specific mucin-type O-glycans (core 3 O-glycans) is one such carbohydrate, and Dr. Minoru Fukuda’s laboratory has examined its roles in tumor formation and metastasis.
When core 3 O-glycans were forced to express on human prostate cancer cell lines, those cancer cells produced much smaller tumors and almost no metastasis. By contrast, the parent cancer cells, which did not express core 3 O-glycans, produced robust primary and metastatic tumors. The Fukuda laboratory showed that the expression of core 3 O-glycans decreases a formation of the a2ß1-integrin complex, receptors that mediate cell adhesion, diminishing cancer cell migration.
The Fukuda laboratory also revealed a tumor suppressor function in unique laminin-binding glycans on dystrophin-glycoprotein complex—carbohydrates located on a-dystroglycan, which is also associated with cell adhesion. The Fukuda team found that these unique glycans play a critical role in epithelial-basement membrane interaction in normal cells, and the decrease or loss of the glycans lead to increased cell migration by invasive carcinoma cells. The laboratory demonstrated that interaction of laminin with the unique glycans on a-dystroglycan attenuates the cell migration signals that are mediated by integrin binding to its ligands. The down-regulation of specific glycosyltransferases, which control the synthesis of these carbohydrates, results in a dramatic decrease in the laminin-binding glycans, leading to higher locomotion by invasive cancer cells.
These results indicate that certain carbohydrates present on normal cells function as tumor suppressors and upregulation of those key glycosyltransferases can be a novel therapeutic approach against cancer.