Viral gene responsible for oncogenesis identified.

2003 APR 2 - (NewsRx.com & NewsRx.net) -- The guilty gene responsible for initiating oncogenesis in Kaposi sarcoma has been identified - at last - by researchers at Weill Cornell Medical College.

Kaposi sarcoma associated herpes virus (KSHV), which is consistently detected within this highly vascularized cancer, carries the gene, vGPCR. The vGPCR (viral G-protein coupled receptor) gene has been a suspect for a long time. However, scientists have been faced with the conundrum that vGPCR is not expressed either long enough or in enough of the cells within the KS tumor to be "pinned" down.

Now, Dr. Enrique Mesri of Weill Cornell and colleagues propose a new scenario and a new mechanism - namely, a "hit and run" type of crime, where vGPCR is expressed just long enough to cause the initial damage, but then retreats so as not to be caught. These findings, reported in Cancer Cell, reveal a new way to look at the role of viruses in disease and to determine which genes may be important targets for treatments. Specifically, this research offers the promise for alternative treatments of Kaposi sarcoma by blocking the actions of the vGPCR protein itself.

While a very small percentage of people infected with KSHV actually develop Kaposi sarcoma (KS), the frequency of KS increases sharply in patients with a compromised immune system, such as organ transplant patients and AIDS patients. Mesri, in collaboration with Dr. Ethel Cesarman of Weill Cornell, was the first to isolate the KSHV infectious virus, as well as identify the vGPCR gene as a primary suspect in the conversion of normal cells into the cancerous cells of Kaposi sarcoma lesions.

"In 1998, we published a paper in the journal Nature showing that a gene (vGPCR) within KSHV was able to make normal cells behave like cancer cells, resulting in Kaposi's sarcoma-like lesions in mice," explained Mesri, assistant professor of biochemistry in medicine at Weill Cornell and two-time recipient of the Jack Friedman Investigator Award. "However, there were important limitations. The vGPCR gene belongs to the lytic group of viral genes, involved in the massive viral replication that ultimately kills the cell. Classic herpes virology says a viral gene capable of causing a cancerous transformation (i.e., a viral oncogene) must belong to the latent group of viral genes, which allow the cell to stay alive. The viral oncogene must also be present in all of the cancer cells. We were left with a primary suspect with the right weapons, but one that, seemingly, was not and could not be at the scene of the crime."

A normal viral life cycle has two stages, latent and lytic. In the lytic stage, the virus infects the cell and hijacks it, using the cell to produce huge amounts of virus, eventually causing the cell to explode and release new virus into the tissue. In the latent stage, the virus infects the cell, but does not immediately start reproducing. The viral genes involved in the lytic stage are "sleeping" within the cell, waiting to be "woken up" to start making new virus. Latent viral genes are expressed, but they do not normally compromise cell survival. Many times these are the genes responsible for converting normal cells into cancerous cells.

In the case of KSHV, however, other labs have recently shown that the latent genes are not responsible for this transformation in Kaposi sarcoma. The problem, then, becomes that much more complicated for scientists because a lytic gene must be the ...