New York, NY (March 13, 2003) -- The guilty gene responsible for initiating oncogenesis in Kaposi's Sarcoma has been identified -- at last -- by researchers at Weill Cornell Medical College. As reported in the latest issue of Cancer Cell, Kaposi's 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.Ê

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, generally, 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's Sarcoma by blocking the actions of the vGPCR protein itself.

While a very small percentage of people infected with KSHV actually develop Kaposi's Sarcoma (KS), the frequency of KS increases sharply in patients with a compromised immune system, such as organ transplant patients and AIDS patients. Dr. 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's Sarcoma lesions.

"In 1998, we published a paper in the journal Nature showing that a gene (vGPCR) within Kaposi's Sarcoma associated Herpes Virus (KSHV) was able to make normal cells behave like cancer cells, resulting in Kaposi's Sarcoma-like lesions in mice," explains Dr. 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's Sarcoma. The problem, then, becomes that much more complicated for scientists because a lytic gene must be the responsible viral oncogene. So vGPCR could be the culprit, but how, when it is not expressed in all of the cancer cells, and only expressed in those cells fated to die?

Dr. Mesri and colleagues set out to answer this question. Using cultured endothelial cells (cells that line blood vessel walls) that KSHV normally infects, they show that vGPCR expression is capable of converting these normal cells into cancer cells. The mechanism they propose of "autocrine immortalization," where the endothelial cell can preserve itself without any outside help, suggests that vGPCR can exploit an abnormal stage of the herpes viral cycle, an abortive lytic stage. Genes involved early in the lytic stage, like vGPCR, are expressed, but are then shut off before the cell is killed, returning the virus to the latent stage. The criminal is using a "hit and run" tactic; the short expression of vGPCR is enough to change the nature of the endothelial cell, making it capable of preserving itself and initiating the oncogenic process.

Earlier research by Dr. Mesri reveals that cells expressing vGPCR alone undergo an "angiogenic switch," where a cell, such as a tumor cell, is able to recruit new blood vessels. Cells expressing vGPCR produce large amounts of VEGF, or Vascular Endothelial Growth Factor, a molecule critical for the formation of new blood vessels. It is already known that VEGF is capable of prolonging the life of endothelial cells, indicating that an increase in VEGF production, through vGPCR signaling, could begin a positive feedback loop, immortalizing the endothelial cell and driving it towards oncogenesis. VEGF may be vGPCR's accomplice in crime.

The new study in Cancer Cell shows that this is exactly the case. Endothelial cells expressing vGPCR produce more VEGF, causing the cells to increase their expression of the receptor for VEGF--KDR. Signaling from KDR not only tells the cells to make more VEGF, but also sends survival signals, leading to immortalization of the endothelial cells.Ê

New experiments indicate that, at this point, vGPCR is not needed anymore; the external sources of VEGF are enough to continue the cycle. Now that the criminal has completed his "hit," he could "run" and no longer be expressed by the endothelial cell.Ê

The VEGF secreted by the infected endothelial cell does not only affect the one cell that produces it; all surrounding endothelial cells will react to the VEGF. In other infected and immortalized cells, VEGF will compensate for the lack of vGPCR signaling, while in uninfected cells, VEGF will stimulate proliferation, propagating the damage. Therefore, as long as there are infected cells making VEGF, Kaposi's Sarcoma tumor cells can progress without vGPCR expression. The crime continues even after the criminal has left the scene.

"This research points to the effects of vGPCR signaling and VEGF-KDR activation as critical mediators of Kaposi's Sarcoma pathogenesis," states Dr. Mesri, "thus promising new targets for Kaposi's Sarcoma therapy."

Dr. Enrique Mesri is also Director of the Laboratory of Viral Oncogenesis in the Division of Hematology-Oncology at Weill Cornell Medical College. Dr. Roy Silverstein, Dr. Shahin Rafii, and Dr. Sergio Dias from the Division of Hematology-Oncology are collaborators on this research. Co-first author Dr. Carlos Bais, who is presently at the Howard Hughes Medical Institute at Columbia University College of Physicians & Surgeons, is responsible for initiating the project, along with Dr. Albert Van Geelen, currently at the Center for Comparative Medicine at University of California, Davis. Pilar Eroles, Agata Mutlu, and Chiara Chiozzini of Weill Cornell also contributed to this work.

The research was supported by the American Cancer Society, the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, the American Heart Association, the Dorothy Rodbell Cohen Foundation for Sarcoma Research, the New York Community Trust, and the Charles Offin Charitable Trust.