Pushing the envelope on lung-cancer research

New center research has revealed a surprising explanation for how a cancer-causing animal virus spurs the growth of lung tumors.

The work, published in the April 14 issue of Nature, focused on the jaagsiekte sheep retrovirus (JSRV), which causes a contagious lung cancer in sheep and goats. Most cancer viruses similar to JSRV cause tumors when their genetic material lodges near and disrupts the normal function of genes in the infected cell. But the researchers found that JSRV owes its cancerous nature to a single protein that coats the virus. Such viral "structural" proteins have not been known before to cause cancer.

Since humans can develop a type of lung cancer, unrelated to smoking, that is similar to the sheep disease, the findings may lead to new insights into the cause of the disease in men and women — and ultimately, to improved treatments.

"This is a very novel mechanism for a retrovirus — and for viruses in general — to use to cause cancer," said Dr. Sarah Wootton, a postdoctoral fellow in Dr. Dusty Miller's lab who co-authored the study. "We'd like to understand how this protein causes cancer — and the system we've developed may prove to be a good model for understanding human lung cancer."

Staff scientist Dr. Christine Halbert, also of Miller's laboratory in the Human Biology and Basic Sciences divisions, co-authored the study.

Miller's group originally began studying JSRV for its potential applications for gene therapy for lung diseases including cystic fibrosis. Gene therapy is a technique that attempts to introduce healthy versions of genes into cells that lack them. Viruses are typically engineered to serve as harmless delivery systems for the therapeutic genes.

Earlier work in Miller's lab did not identify any parts of the virus that looked similar to other cancer-causing viral or host proteins. But certain experiments caused them to look more carefully at a viral protein called Env, short for envelope. Env forms the outer covering of the virus that interacts with a target receptor on the surface of lung cells. They suspected that the attachment of Env caused the receptor to stimulate the cell to divide uncontrollably, the first step toward cancer.

In the new study, Wootton and Halbert examined whether Env alone could cause lung tumors in a situation where no receptor existed. To do this, they turned to mice, since mouse cells do not contain a receptor for JSRV infection. In order to deliver the Env protein into mouse cells they used another virus that does not cause cancer, called adeno-associated virus (AAV serotype 6), and engineered it to carry the Env gene.

Immune-system response

Using this system, the researchers found that the Env protein delivered by AAV6 was able to cause lethal tumors in mice that lacked a functional immune system. The tumors formed in the exact same lung tissue in which the disease occurs in sheep. In contrast, tumors rarely formed in normal mice, demonstrating that they can mount an immune response against Env that protects them from cancer.

Wootton said that sheep are susceptible to lung tumors caused by JSRV because their immune systems are naturally tolerant to the virus, which allows JSRV to infect lung cells, multiply and cause cancer. The reason is because their immune systems already have been exposed to innate sheep proteins that look similar to those of JSRV.

Humans can develop a type of lung cancer analogous to the sheep disease that accounts for about 25 percent of all lung-cancer cases and can occur in those without a prior history of smoking.

Miller said the cause of many lung cancers is unknown, but human cells do contain receptors that are virtually identical to the sheep JSRV receptor. In 2002, his group discovered the human version of the JSRV receptor. When they engineered hamster cells to contain the human receptor, the hamster cells became susceptible to JSRV infection.

"No one has discovered a human virus analogous to JSRV," he said. "But this is an idea that we are exploring."

Interestingly, antibodies that react against JSRV proteins react against about 30 percent of human bronchiolo-alveolar cancers, which suggests that these human tumors contain JSRV-like proteins of unknown origin.

Wootton said the AAV6-delivery system they have developed may prove to be a superior model for studying lung-cancer development in mice than currently available approaches.

Gene therapy

"Typically, scientists must create and breed genetically engineered mice, which can take months," she said. "By using the AAV6-delivery system, we can analyze the effects of specific proteins on lung-cancer development much more rapidly. We're very interested in using our system to study the mechanism by which Env causes tumors."

Wootton said that the AAV6 system also may prove to be a useful delivery system for gene therapy, which is still the primary research focus of Miller's lab. Because the virus specifically infects lung cells and does not cause cancer in its natural form, it may serve as an effective way to deliver therapeutic genes for lung diseases such as cystic fibrosis.