Scientist in the Spotlight:
Finding Zinc's Link to Cancer Risk

When Louise Fong, PhD, first began identifying how zinc deficiency affects esophageal cancer risk more than 30 years ago, the study of diet and cancer was only just beginning. Then at Massachusetts Institute of Technology, at the time it was unknown whether zinc deficiency could increase or decrease cancer risk.

What she saw in her lab research set Fong upon a path she would follow for the next several decades.

"I was amazed by the way zinc deficiency affected the esophagus," said Fong, now an associate professor at Thomas Jefferson University. "When the rats were on a zinc-deficient diet, the esophagus become very, very thick; the cells were multiplying, which is one of the hallmarks of cancer."

Like many nutrients, too much zinc or too little can cause health problems. The bluish-white metallic element is essential to a host of body processes, ranging from cell communication to maintaining our immune system. Zinc also appears to play a key role in the normal functioning of squamous cells, flat cells that line the esophagus, mouth and pharynx. The most common type of esophageal cancer develops in the squamous cells.

AICR gave Fong her first grant on the topic in the early 1990s and continues to support her work. In a series of lab studies over the years, Fong and her colleagues have built up a body of evidence showing that zinc deficiency increases risk for esophageal and oral cancers, and that zinc supplementation may help prevent these cancers.

"In my previous work we could not really pinpoint a mechanism, now we can see the mechanism is chronic inflammation," notes Fong, referring to one of her recent studies published in Oncogene.

One big difference in this study, she says, is the amount of the carcinogen. In all her previous research, animals were exposed to a single low dose of a carcinogen. But Fong wanted to better mirror what humans experience: repeated low-doses of carcinogens, such as from smoking.

After giving rats three low doses of a carcinogen, about two-thirds of the animals eating a diet deficient in zinc developed esophageal squamous cell carcinoma. None of the animals eating a zinc-sufficient diet developed cancer. And compared to the cancer-free animals, Fong found high levels of activity in numerous cancer-related inflammation genes.

In many types of cancer, including esophageal and oral cancers, tumor cells exhibt abnormally high levels of COX-2, an enzyme linked to inflammation. Fong's studies have shown that in rats fed a zinc-deficient diet, high levels of COX-2 are accompanied by rapid cell division. When the rats were then fed a zinc-enriched diet, COX-2 levels dropped and cells stopped dividing rapidly. Exposure to a cancer-causing chemical caused tumors in the zinc-deficient rats but not in the rats with adequate zinc levels.

Fong and her coworkers have identified several genes that promote inflammation and are overproduced in zinc-deficient rats.

We have shown that zinc deficiency causes unrestrained cell division in the esophagus and also that it increases inflammation," explains Dr. Fong. "Unrestrained cell division and inflammation create a precancerous condition that rapidly progresses to cancer when the animals are exposed to low doses of a cancer-causing chemical.

In other work focusing on oral cancer, Fong's research suggests that zinc supplements may also reduce cell proliferation and inflammation

"Animals receiving zinc supplementation developed fewer tumors and when tumors do occur they were smaller and less aggressive," she said

In the United States, zinc deficiency is uncommon overall, according to the Office of Dietary Supplements. Fong's research on zinc and cancer risk is promising but more research is needed to understand how zinc plays a role in cancer risk for humans.

"I want to understand the basis of zinc deficiency in cancer and this is not the entire story," says Fong. She is currently investigating the role of microRNA, a form of RNA that regulates gene expression. "This adds another layer of mechanisms."

Dietary zinc deficiency fuels esophageal cancer development by inducing a distinct inflammatory signature Oncogene. 2011 Dec 19. doi: 10.1038/onc.2011.592.

http://preventcancer.aicr.org/site/News2?page=NewsArticle&id=21483&news_iv_ctrl=2302