Researchers Discover Gene That Regulates Cancer Growth

"Cancer cells express sugar or carbohydrate structures that enable the cancer to grow rapidly," says Dr. Jim Dennis, holder of the Ontario Research and Development Challenge Fund Industrial Chair in Glycobiology, a Senior Scientist at the Samuel Lunenfeld Research Institute at Mount Sinai Hospital, and Professor in the Department of Molecular and Medical Genetics at the University of Toronto.

"What we have done is look at how those sugars on the cell surface affect the growth and spread of cancer," said Dennis. "We found that the synthesis of sugar chains, called Mgat5, are elevated in human malignancies of breast, colon and skin cancers. By knocking out the Mgat5 gene in mice, we found that this suppressed cancerous tumour growth and the spread of tumour cells to the lung."

The researchers created mutant mice deficient in Mgat5 by a method known as gene targeting. These mice appear normal in every way, however, they react differently from other mice when exposed to a powerful gene that causes cancer. The Mgat5 deficient mice had an 80 to 95 per cent reduction in breast cancer growth and metastasis to the lungs compared to other mice, indicating that these sugar structures play a role in promoting the growth and spread of cancer.

"Our study suggests that the Mgat5 gene in cancers promote cell movement, which drives growth-signaling pathways inside the cells," says Dennis. "This is the first time that we have been able to show a direct involvement of carbohydrate chains in cancer growth. This study and ongoing investigations in the signaling pathways affected by Mgat5 will direct us to new approaches to control the spread of tumours."

In addition, the researchers found that mice missing Mgat5 had a stronger immune response, which may contribute to its role in suppressing tumour growth. While further research is required, this finding raises the intriguing possibility that inhibitors of Mgat5 may augment the immune response in cancer patients following chemotherapy.

GlycoDesign Inc. of Toronto, a biotechnology company, is engaged in research to discover inhibitors of Mgat5 and related enzymes building on the progress being made at the Samuel Lunenfeld Research Institute.

Co-authors of the study with Dennis include Maria Granovsky and Judy Pawling, Samuel Lunenfeld Research Institute at Mount Sinai Hospital; Jimmie Fata and Dr. Rama Khokha, Department of Medical Biophysics at the University of Toronto, the Ontario Cancer Institute, and Princess Margaret Hospital; and Dr. William J. Muller, Institute for Molecular Biology and Biotechnology, McMaster University in Hamilton.

This research was supported by grants from the National Cancer Institute of Canada, the Mizutani Foundation, the National Sciences and Engineering Council of Canada, the Ontario Research and Development Challenge Fund, GlycoDesign Inc. of Toronto, and the Medical Research Council of Canada.