One WWOX Isn't Enough (To Protect Against Cancer)

COLUMBUS , Ohio – A new study shows that the loss of even one of the two copies of a particular tumor-suppressor gene greatly increases the risk that lung cancer will develop in experimental animals.

The study examined the Wwox gene, a suspected tumor-suppressor gene, and showed that even when mice have one working copy of the gene, they nonetheless develop five times more lung tumors than do mice with both copies of the gene. Tumor-suppressor genes normally keep damaged cells from becoming cancerous.

The findings were published in the Proceedings of the National Academy of Sciences by investigators at the Ohio State University Comprehensive Cancer Center.

“Classic tumor-suppressor genes don't increase cancer risk until cells lose both copies of the gene or when both copies are mutated,” says first author Rami I. Aqeilan, research assistant professor of molecular virology, immunology and medical genetics at Ohio State.

“These findings suggest that losing one copy of Wwox can predispose normal cells to become cancerous. This emphasizes the importance that Wwox may have in initiating the disease.”

Surprisingly, the research also links loss of the gene and a form of bone cancer called chondroid osteosarcoma. The research may offer the first animal model for the study of this human disease.

Osteosarcoma is rare in humans, but it is the most common form of bone tumor and the second highest cause of cancer-related death in children, after leukemia, he says.

“These findings suggest that losing one copy of Wwox can predispose normal cells to become cancerous. This emphasizes the importance that Wwox may have in initiating the disease.”

“Osteosarcoma forms at an early age due to the rapid growth of the bones and skeleton,” says Aqeilan, who is also a researcher with the Ohio State human cancer genetics program.

“These mice have given us a very interesting clue that loss of both copies of Wwox gene may initiate tumors in the bone.”

This study initially set out to prove that Wwox is a bona fide tumor suppressor gene. The gene is missing or altered in 85 percent of lung cancers, 65 percent of breast cancers, and in a high proportion of cancers of the stomach, colon and prostate and some lymphomas.

Wwox is located on chromosome 16, spanning a region called a fragile site, a place where the chromosome often breaks during environmental stress. Breakage at fragile sites results in the loss of pieces of chromosomes and in chromosomal abnormalities. Both can lead to cancer.

“The location of this gene in a fragile site is important,” Aqeilan says. “Our findings suggest that if an environmental stress, such as tobacco smoke, causes the loss of one copy of the gene, it might predispose a person to lung cancer.”

For this study, Aqeilan and colleagues at Ohio State and the University of Massachusetts Medical School developed strains of mice that were missing one copy of the Wwox gene. The mice were bred to produce animals lacking both Wwox genes and mice having both copies of the gene. Mice with both copies served as controls.

Mice born with no copies of Wwox died by four weeks of age. Thirteen of those animals were studied closely, and four of them (31 percent) showed evidence of early osteosarcoma.

Of 58 animals with only one copy of the gene, 16 percent – or nearly one in six – developed lung cancer compared with only 3 percent of the control mice, a five-fold increase.

The researchers also exposed animals with one copy of the gene to a carcinogen, ethyl nitrosourea, to learn about the kinds of tumors that Wwox might help suppress.

Of 46 animals exposed to the chemical, 80 percent developed tumors vs. just under half of control animals that had both copies of the gene. Most of the animals developed lung cancer or lymphoma. Liver cancer, squamous cell carcinoma and malignant B-cell infiltration into the liver and lungs developed in small numbers.

The researchers are now looking for the loss of Wwox in human osteosarcomas and are generating a mouse model that will allow them to study the ability of the gene to reverse tumor growth after it is restored in adult animals with cancer.

“Wwox-mutant mice are useful in understanding the role of this gene in human cancer, and they provide models for studying the carcinogenecity of compounds, and the development, prevention and treatment of common cancers,” Aqeilan says.

A Kimmel Scholar Award and funding from the National Cancer Institute supported this research.

Other OSU researchers involved in this study were Francesco Trapasso, Stefan Costinean, Dean Marshall, Yuri Pekarsky, John P. Hagan, Nicola Zanesi, Mohamed Kaou and Carlo M. Croce.

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Contact: Darrell E. Ward, Medical Center Communications, 614-293-3737, or Darrell.Ward@osumc.edu