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OHSU-led team discovers link between cancer, neurodegenerative diseases

Findings come after almost a decade of work, study of a disease centered on the island populations of Guam, Japan, New Guinea

A research team led by Oregon Health & Science University scientists has added important new evidence to a growing belief that was unheard of just a few years ago — that there may be a molecular link between certain types of neurodegenerative disease and cancer.

The new findings were published online this month in the Public Library of Science's PLoS One journal.

OHSU researchers Glen Kisby, Ph.D., and Peter Spencer, Ph.D., designed the experiment to test the action of a DNA-damaging cancer agent on mature nerve cells. The agent — called methylazoxymethanol, or MAM — is a genotoxin found in cycads, ancient plants that have been used for medicine and food among the indigenous people of the islands of Guam (Chamorro), Honshu (Japanese) and New Guinea (Papuan). All three island populations have suffered from a disappearing, cycad-associated neurodegenerative disease that in one patient combines elements of amyotrophic lateral sclerosis (Lou Gehrig’s disease), parkinsonism and Alzheimer’s-like dementia.

“We knew that MAM disrupts brain development in rodents, causes neuromuscular disease in large animals, and is strongly correlated with risk for ALS and parkinsonism-dementia among Guam Chamorros. But the brains of young adult mice seemed to be insensitive to MAM-induced DNA damage,” said Spencer, a professor of neurology in the OHSU School of Medicine, senior scientist in the OHSU Center for Research on Occupational & Environmental Toxicology (CROET) and director of OHSU’s Global Health Center. “However, this protection disappeared in young adult animals that lacked machinery to repair brain DNA damage. In these animals, MAM-activated pathways linked to human neurological disease, which provides significant support for the cycad hypothesis.”

Kisby, the study’s lead author, is a former CROET scientist and is now an associate professor of pharmacology at the College of Osteopathic Medicine of the Pacific Northwest. He explained the action of the cycad genotoxin on cells in the body.

“While MAM-induced DNA damage in the mouse brain activated molecular pathways that cause nerve cells to die in humans, the same DNA lesions and molecular pathways trigger malignant tumors in organs like the gut,” Kisby said. “In essence, MAM can act as both a neurotoxin and a carcinogen.” The outcome depends, Kisby said, on whether the cell that is damaged by MAM can divide (gut cell) or not (nerve cell).

The new findings complement recent studies suggesting a link between cancer and neurodegenerative diseases. Recent epidemiological studies, for instance, have suggested that individuals with Parkinson's disease are less likely to develop non-melanoma cancers and vice versa. In contrast, the co-occurrence of Parkinson’s and melanoma often has been noted.

Additionally, half of the cases of early-onset Parkinson’s involve changes in the gene that is abnormally low in several tumor types. “Our new findings suggest that certain genotoxic chemicals can trigger molecular pathways leading to cancer and neurodegeneration,” Kisby said. “The overlap of molecular pathways implicated in cancer and neurodegeneration may indicate the possibility of developing novel therapeutic approaches for both groups of disorders.”

The newly published study consumed almost a decade of research collaboration among researchers at OHSU (Kisby, Michael Lasarev, M.S., Valerie Palmer, B.S., and Spencer), the Fred Hutchinson Cancer Research Center, the Massachusetts Institute of Technology, the National Center for Toxicological Research, the University of North Carolina at Chapel Hill, and the University of Washington. Much of the OHSU-based research was conducted in the CROET.

The study was funded by the National Institute of Environmental Health Sciences.

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