Findings could lead to improvements in cancer diagnostics. Cancer researchers led by Antonio Giordano, M.D., Ph.D., associate professor of pathology, anatomy and cell biology at Jefferson Medical College, have for the first time found direct evidence of a potential mechanism of a monkey virus in the development of mesothelioma, a rare connective-tissue cancer commonly associated with asbestos exposure.
In research reported in the August 3 issue of Nature Medicine, Dr. Giordano's team found that simian virus 40 (SV40), a DNA tumor virus from monkeys, targets key proteins that normally prevent tumors from forming, rendering them ineffective. These proteins, made by so-called tumor-suppressor genes, are in the retinoblastoma family (pRb, pRb2/p130, and p107). A viral protein called SV40 T-ag (T-antigen) binds to and inactivates the tumor-halting proteins, causing them to lose their natural ability to regulate cell growth and prevent cancer. The discovery underscores the important role that Rb family proteins play in controlling cell growth.
"We are not saying that the virus is the only factor, but clearly there is more than one factor involved in the onset of mesothelioma," said Dr. Giordano, who is also president of the Sbarro Institute for Cancer Research and Molecular Medicine, which is affiliated with the college. "It is a complex mechanism."
According to Dr. Giordano, the finding could have important implications for developing cancer diagnostics, even a "potential test for the early development of cancer. There are implications that the pRb2/p130 gene could also be involved in the development of other cancers, such as ovarian and breast."
Previous studies by other researchers had shown the presence of SV40 in animals and in some cases, human. But no one knew if the virus played a direct role in causing disease. Giordano’s team’s discovery of a potential mechanism for some cases of disease development strengthens the argument for the virus.
"Although mesothelioma is one of the most aggressive human cancers, no one had reported alterations of important cell cycle controllers, such as Rb family genes," said Dr. Giordano. "When we studied Rb family genes in mesothelioma, we were surprised to find that the genes were present in normal levels. This led us to study why the genes are present, but not working."
Mesothelioma is diagnosed in 2,000 to 3,000 patients in the United States each year. Incidence of this disease is increasing among non-asbestos exposed individuals, and there are currently no effective treatments. Until the discovery of SV40 in mesothelioma patients in 1994 by Drs. Michele Carbone, Harvey Pass, and Antonio Procopio, asbestos was the only known agent associated with the disease.
Armed with new information about SV40’s interaction with Rb family proteins, Dr. Giordano’s team is pursuing research that may lead to new treatments for mesothelioma and lung cancer. The team hopes to identify the source of SV40 infections in humans and understand how the virus is transmitted. They are also working to develop a gene therapy approach to restore
growth-suppressor function of the pRb2/p130 gene. To date, the treatment has shown success in animal studies and is about to enter phase 1 clinical trials in humans.
Dr. Giordano was the first to identify and clone the pRb-2/p130 gene and demonstrate that it could halt the growth of tumors. He has been studying the family of tumor-suppressor genes for nine years.
"The findings of Dr. Giordano's team will point the way to future developments in gene therapy," said Dr. Emanuel Rubin, M.D., chairman of the Department of Pathology, Anatomy, and Cell Biology at Jefferson Medical College. "By identifying the virus that causes tumor-suppressor genes to stop working, his research may lead to the development of tests to determine mesothelioma in early stages, and treatments that will allow the genes to restore normal function."
The SV40 findings are the latest step in a series of important research on Rb family genes and their involvement in cancer. In May 1996, Dr. Giordano's team identified the gene pRb-2/p130 and showed that it makes a protein that plays a vital role in controlling cell cycle in all human and mammalian cells. When pRb-2/p130 is altered and cannot produce its protein, the cell may not reach its natural stage of programmed cell death. Instead, the cell continues to live and grow out of control - possibly leading to tumor formation and cancer.
In the July 1996 issue of Clinical Cancer Research, Dr. Giordano's team reported that damage to pRb-2/p130 may lead to lung cancer. Cigarette smoke, air pollution, some toxins breathed by workers and other environmental carcinogens may inhibit the body's ability to make the pRb-2/p130 protein.
Other collaborating institutions include Loyola University, Chicago, the University of Naples, Italy, and the Karmanos Cancer Institute, Detroit.
Journal
Nature Medicine