OTTAWA, Ontario - Researchers at Mount Sinai Hospital's Samuel Lunenfeld Research Institute, Toronto, have identified a key gene that slows cancer growth. This discovery opens the door to new approaches for effective cancer treatments.
The work revolves around the discovery that malignant transformation is accompanied by an increase in cell surface carbohydrates. This research was published in Nature Medicine (Vol. 6, No.3).
According to one of the authors of the paper, Dr. Jim Dennis, a senior scientist at the Lunenfeld Institute and professor in the department of molecular and medical genetics at the University of Toronto, "Our research investigated how these cancer cells express carbohydrate structures on the cell surface and the mechanisms that enable the cancer to grow rapidly and spread.
"We found that the synthesis of carbohydrate chains, called Mgat5 (a Golgi carbohydrate processing enzyme, alternatively termed GlcNAc-TV), 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 tumor growth and the spread of tumor cells to the lung."
The researchers created mutant mice deficient in Mgat5 through 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 percent to 95 percent reduction in breast cancer growth and metastasis to the lungs compared to other mice, indicating that these carbohydrate structures play a role in promoting the growth and spread of cancer.
"Our study suggests that the Mgat5 gene in cancers promotes 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 signalling pathways affected by Mgat5 will direct us to new approaches to control the spread of tumors."
In addition, the researchers found that mice missing Mgat5 had a stronger immune response, which may contribute to its role in suppressing tumor 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.
The research was supported in part by private biotechnology company GlycoDesign Inc. of Toronto. Company spokesperson Julie Dzerowicz told BioWorld International that the research conducted by Denis and his colleagues validates Mgat as a cancer target. The company is engaged in research to discover inhibitors of Mgat5 and related enzymes, building on the progress being made at the Lunenfeld Institute, Dzerowicz added.
The discovery of the cell surface carbohydrate structures responsible for tumor growth and spread, and the identification of intracellular enzymes responsible for making these structures led GlycoDesign scientists to the idea of creating inhibitors of carbohydrate processing enzymes (CPIs) as therapeutics to attack diseases. CPIs block the action of enzymes involved in the intra-cellular processing of carbohydrate structures, preventing the synthesis of "disease-related" cell-surface carbohydrates, and returning the cell surface carbohydrates closer to normal.
The results from the present study are consistent with those found from clinical trials of GlycoDesign's lead compound, GD0039, an orally-administered inhibitor of the enzyme Golgi a-mannosidase II, currently in Phase II cancer trials and Phase I/II trials as a chemoprotective agent.