UM/Sylvester Scientists Develop a Key Research Tool That will Help Yield Treatments
New research from the University of Miami Sylvester Comprehensive Cancer Center has clearly identified the role of a single gene in the development of a cancer that is prevalent in people with HIV/AIDS, and has created a valuable research model to confirm it. Enrique A. Mesri, Ph.D., member of the UM/Sylvester Viral Oncology Research Program and associate professor of microbiology and immunology at the UM Leonard M. Miller School of Medicine, and his colleagues are the first to conclusively link this gene with its ability to fuel Kaposi’s sarcoma, a cancer common to people with compromised immune systems such as HIV/AIDS and organ transplant patients. They isolated the role of the gene through the creation of a novel animal model that realistically creates an environment close to how Kaposi’s sarcoma develops in humans. The work is published in the March 12 issue of the journal Cancer Cell.
The viral G protein coupled receptor gene (vGPCR) exists in the Kaposi’s sarcoma herpesvirus (KSHV) and it has long been suspected of playing a role in “switching on” Kaposi’s sarcoma. A healthy immune system can suppress the virus so Kaposi’s sarcoma is rare in the general population. Although KSHV infects more than five percent of the general population, Kaposi’s sarcoma affects only about one in 100,000 people. In those with compromised immunity, like transplant patients and those with HIV/AIDS, Kaposi’s sarcoma is much more common. As many as one in 20 HIV-positive Americans will be afflicted with this KSHV-induced cancer.
Previous research on the role of the virus and its genes in Kaposi’s sarcoma was done in isolated cell lines in the lab, but the environment in humans with Kaposi’s is much more complex. Patients are immunocompromised and the virus is a biological entity, able to adapt. So, for the first time, Mesri and his colleagues were able to create an animal model in which to test the role of the virus in Kaposi’s sarcoma, which allowed them to clearly study how responsible the suspect gene, vGPCR, is in fueling the cancer.
They set up a series of experiments to isolate the gene and clearly show its role in both activating cancer in certain cells and also encouraging the growth of new blood vessels to feed the fledgling tumor. “Our most important finding was showing that the virus encoded genes with the potential for causing the disease,” said Mesri, who came to UM from Cornell University in 2005. He has studied KSHV since 1996 and published data in the prestigious journal Nature in 1998 linking vGPCR with new blood vessel growth.
In most cancers, different processes activate the two stages which are critical to the development of tumors: the oncogenic activation of a cell, which is cell mutations that allow cancer cells to grow uncontrolled and resist cell death; and angiogenesis, which allows cancer cells to induce the growth of new blood vessels to feed the growing tumor.
“In our case, we found that cell transformation and angiogenesis activation happen together because this virus infects and transforms the endothelial cells,” explained Mesri. “Endothelial cells cover the inner part of our blood vessels and are the type that the herpesvirus infects.” Left unchecked, this leads to Kaposi’s sarcoma, a vascular cancer which causes angioproliferative tumors on the skin and mucous membranes in the nose and mouth.
Previous studies have examined KSHV in tightly controlled laboratory settings, but Mesri and his colleagues from UM/Sylvester, the Weill Medical College of Cornell University, the University of North Carolina Chapel Hill, and the University of Texas Health Science Center in San Antonio wanted to create a more realistic setting. That led to this novel animal model, in which they used normal bone marrow cells from mice. When they used genetic methods to transfer KSHV to the normal cells, the virus quickly activated both cancer potential and new blood vessel growth. When they removed the virus, the cancerous properties went away.
Next, they isolated the role of vGPCR, the gene they suspected of being a key to the activation of Kaposi’s sarcoma. When their normal cells were harboring the virus, oncogenesis and angiogenesis – malignant cell proliferation and new blood vessel growth – were switched on. If they left the virus but removed the vGPCR gene, the cancer didn’t die but it also didn’t proliferate. Knocking out the vGPCR gene froze the tumors at a small size, unable to attract a blood supply. This result demonstrated that vGPCR was critical for providing blood supply to infected tumors and thus for Kaposi’s sarcoma tumor development.
Mesri is actively working to exploit this knowledge with UM Miller School colleagues including William Harrington, Jr., M.D., and Glen N. Barber, Ph.D., co-leaders of the Viral Oncology Program at UM/Sylvester.
Because of the ability of viruses to quickly adapt to change in the body, and because of the compromised immune systems in Kaposi’s patients, attacking the virus is difficult. For example, chemotherapy suppresses the immune system, complicating treatment for HIV-positive patients who are receiving anti-retroviral therapy. That is why it is so important to be able to test a gene target like vGPCR in a model that is similar to an infected patient. A therapy that shows potential in this new model is much more likely to be successful in humans. One fairly new immunosuppressant drug, sirolimus (Rapamune), seems to also suppress Kaposi’s sarcoma. There is also new research showing that cyclooxygenase inhibitors, or Cox-2 inhibitors, like celecoxib and rofecoxib (Celebrex and Vioxx) may block the blood vessel-inducing effects of vGPCR.
“We are working with a human pathogen,” said Mesri. “So, while I am interested in what I can learn from this puzzling disease, I want to see what I can learn that will improve care for the patients and make life easier for the patients and the physicians. That’s always the primary goal.”
The study will be available March 12 at http://www.cancercell.org/.
UM/Sylvester opened in 1992 to provide comprehensive cancer services and today serves as the hub for cancer-related research, diagnosis, and treatment at the University of Miami Leonard M. Miller School of Medicine. UM/Sylvester handles nearly 1,600 inpatient admissions annually, performs 3,000 surgical procedures, and treats 3,000 new cancer patients. All UM/Sylvester physicians are on the faculty of the Miller School of Medicine, South Florida’s only academic medical center. In addition, UM/Sylvester physicians and scientists are engaged in more than 250 clinical trials and receive more than $30 million annually in research grants. UM/Sylvester at Deerfield Beach opened in 2003 to better meet the needs of residents of Broward and Palm Beach counties. This 10,000 square-foot facility at I-95 and S.W. 10th Street offers appointments with physicians from six cancer specialties, complementary therapies from the Courtelis Center, and education and outreach events.