“In a collaborative investigation, we found that arsenic, at environmentally relevant levels, is capable of activating the Hedgehog pathway and may represent a novel pathway of arsenic-associated diseases, such as bladder cancer,” says epidemiologist and coauthor Margaret R. Karagas, Ph.D., a professor in the Department of Community and Family Medicine at Dartmouth Medical School (DMS) and codirector of the Cancer Epidemiology and Chemoprevention Research Program at Dartmouth’s Norris Cotton Cancer Center (NCCC). “We provide important insight into the etiology of arsenic-induced disease, potentially relevant to the millions of people worldwide who are exposed to arsenic.”
Studies to date show that residents of areas prone to arsenic contamination tend to contract cancer at an elevated rate. Particularly in Taiwan, Bangladesh, and Argentina, high levels of arsenic occur naturally in drinking water. In the United States, Karagas adds, arsenic concentrations of more than 10 grams per liter often contaminate wells and other private, unregulated drinking-water systems.
While scientists have long since established the correlation between exposure to arsenic and development of tumors in humans – particularly those derived from bladder, lung, and skin – the molecular mechanisms driving this connection remain subjects of intense research. Karagas and colleagues, including principal investigator David Robbins, Ph.D., examined the hypothesis that arsenic might activate a secreted protein called Hedgehog (Hh), a key oncogenic signaling pathway.
Robbins is a former DMS associate professor of pharmacology and toxicology and former member of NCCC’s Molecular Therapeutics Research Program. During his tenure at DMS, he led a lab dedicated to studying the Hedgehog pathway. Robbins lab researchers who contributed to the new study include first author Dennis Liang Fei, a DMS doctoral student; research assistant Kendall Black; and postdoctoral fellow Samer Singh, Ph.D.
Using experimental data from cell cultures and results of epidemiologic studies, the researchers found that arsenic activates the Hedgehog signaling by decreasing the stability of the repressor form of GLI3 – one of the transcription factors that regulate Hedgehog activity. Also, Karagas and her colleagues found high levels of arsenic exposure associated with high levels of Hedgehog activity.
“Constitutive Hedgehog signaling has been implicated in a wide spectrum of solid tumors,” says Anthony Capobianco, Ph.D., a member of the editorial board of Cancer Research. “This report is the first to link arsenic exposure to activation of the signaling pathway and its potential mediator of arsenic-driven tumors.”
Other Dartmouth researchers contributing to the study were James DiRenzo, Ph.D., an associate professor of pharmacology and toxicology at DMS and scientific codirector of NCCC’s breast clinical oncology program; Kathleen A. Martin, an assistant professor of surgery and of pharmacology and toxicology at DMS and a member of the NCCC molecular-therapeutics program; Hua Li, Ph.D., a research associate in the department of pharmacology and toxicology at DMS; Courtney Kozul Horvath, Ph.D., an environmental toxicologist in the department of pharmacology and toxicology and a member of the Dartmouth Toxic Metals Research Program; and postdoc Julie A. Gosse, Ph.D., of the toxic-metals group.
Also collaborating in the arsenic research were former DMS faculty member and former toxic-metals group researcher Joshua Hamilton, now the chief academic and scientific officer at the Marine Biological Laboratory in Woods Hole, Mass.; and Baolin Wang, Ph.D., an associate professor of cell and development biology and of genetic medicine at Weill Cornell Medical College, where he researches Hedgehog signaling.