Insight into lung cancer

Sheep virus supplies clues in Dusty Miller laboratory
Dr. Dusty Miller and Vladimir Vigdorovich
Dr. Dusty Miller looks on as graduate student Vladimir Vigdorovich looks through a microscope at viral-infected cells. Photo by Theresa Naujack

A cancer-causing virus in sheep may shed light on a disease whose incidence is increasing and accounts for about 25 percent of all lung cancer cases.

The finding, by scientists in the Hutch Human Biology Division, pertains to human bronchiolo-alveolar carcinoma.

A study from Dr. Dusty Miller's laboratory indicates that Jaagsiekte sheep retrovirus (JSRV) infects both sheep and human cells cultured outside the body and does so by attaching to a receptor on the surface of lung cells.

Miller's group, including postdoctoral fellow Dr. Sharath Rai, graduate student Vladimir Vigdorovich and collaborators at the National Cancer Institute, identified the human version of the viral receptor, a cell-surface protein called HYAL2 that has been implicated in lung cancer.

Lung-disease tools

Their findings, published last week in the Proceedings of the National Academy of Sciences, may provide clues for understanding how some forms of human lung cancer initiate and may also aid in the development of tools for successful gene therapy of lung diseases such as cystic fibrosis.

JSRV causes a contagious form of lung cancer in sheep that results in excessive production of virus-filled lung fluid. The virus can induce formation of tumors in as little as 10 days. Causes of human bronchiolo-alveolar carcinoma are unknown.

Cancer-causing viruses typically contain oncogenes, genes that induce the formation of tumors. JSRV is unusual in that it is a simple virus with few genes, none of which resemble previously discovered oncogenes.

One of the viral genes, env, specifies a protein that forms the viral envelope, the outer covering of the virus that interacts with a target receptor on the surface of lung cells.

To identify the JSRV receptor in lung cells, Miller developed a system using cultured hamster cells that contain small pieces of human DNA. Hamster cells are unable to be infected by JSRV, but if the cells harbor a piece of human DNA that contains the viral receptor, the cells become susceptible to the virus.

Pinpointed gene

Using this method, the team identified a portion of human DNA that enabled JSRV to infect hamster cells and subsequently pinpointed the gene responsible for viral infection.

Miller said that the viral receptor gene, HYAL2, was located on a region of human chromosome 3 that is frequently altered in lung cancers.

"In 100 percent of small-cell lung cancers, there is a deletion in this region of chromosome 3, very often including the HYAL2 gene," he said.

HYAL2 codes for a protein that is anchored to the cell surface of lung cells. Miller said that other proteins anchored to the cell surface in a similar fashion are known to play roles in cell proliferation, suggesting a possible mechanism for how HYAL2 might be involved in tumor formation.

"There are other membrane-bound proteins that transmit mitogenic (proliferation) signals in cells," he said. "For example, cell surface proteins that respond to growth factors can be deregulated in some cancers."

Binding of JSRV sheep lung cells might interfere with the receptor's normal role in regulating cell proliferation, causing unregulated growth. While no human virus analogous to JSRV is known, Miller speculates that there may be viruses that interact with the HYAL2 in human cells.

Human virus identification

"Part of our effort is to identify viruses in humans that may be involved in lung cancer," he said.

His group began studying JSRV for it's potential applications for gene therapy for lung diseases including cystic fibrosis, provided the oncogenic potential of the virus can be controlled, Miller said.

"Since JSRV replicates well in the lung, it could be used to develop viral vectors for gene therapy," he said. "Viruses for gene transfer to the lung could be engineered to contain JSRV envelope proteins, allowing them to specifically target lung cells."

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