June 27, 2004 -- Blood-vessel-lining cells that are infected with the virus that causes the skin tumor Kaposi's sarcoma (KS) appear to transform into the type of cells that usually line lymphatic vessels. The report from researchers at the Cutaneous Biology Research Center (CBRC) at Massachusetts General Hospital (MGH) will appear in an upcoming issue of Nature Genetics and is being released online today.
"Our study suggests, for the first time, that Kaposi's sarcoma tumors are derived from blood vessel endothelial [lining] cells that have been reprogrammed by infection with the Kaposi's sarcoma herpes virus," says Michael Detmar, MD, of the MGH CBRC, who led the research team. "This infection 'turns on' genes associated with lymphatic vessel development and 'switches off' blood vessel genes."
The most common malignant tumor seen in patients with AIDS, KS also develops in other patients in whom the immune system is suppressed. Characterized by lesions that may look red or purple on the skin or tissues lining areas like the nose and mouth, KS can seriously affect quality of life, with specific effects depending on the location of lesions. For HIV-infected individuals, the best treatment has been combination antiretroviral therapy, although there are other treatments directed specifically at the lesions.
Because of the way cells in KS lesions appear and the fact that they express genes usually associated with lymphatic system cells, it had been believed that the tumor originated in the cells lining lymphatic vessels. Recent studies have identified a gene called Prox1 as playing a major role in controlling the development and differentiation of lymphatic vessels and found that aberrant expression of Prox1 in mature blood-vessel-lining cells can reprogram them to develop into lymphatic-lining cells. Because the KS virus can infect blood vessel lining, the research team decided to investigate whether it might similarly reprogram infected cells.
The researchers first analyzed normal gene expression in both lymphatic system and blood vessel cells and identified several genes, including Prox1, that usually were expressed only in lymphatic cells. They then infected blood-vessel-lining cells from human skin with the KS virus. A week later, they found that the viral infection had caused a significant increase in the expression of Prox1 and other genes normally active only in lymphatic cells. A second experiment in which cells from umbilical veins were infected with the virus led to similar lymphatic gene expression.
"As far as I know, this is the first report of a switch from one differentiated cell type to another," says Detmar. "Although clinical applications are difficult to predict, some of the genes we identified as associated with KS growth may be targets for potential new therapies." He noted that the study's first author – Young-Kwon Hong, PhD, a member of Detmar's research team at the CBRC – is studying how Prox1 is activated and looking for additional factors involved in the "lymphatic switch" produced by KS virus infection. Detmar is an associate professor and Hong an instructor in Dermatology at Harvard Medical School.
Other authors of the Nature Genetics report are Jay Shin, MD, PhD, and Satoshi Hirakawa, MD, PhD, of the MGH CBRC, Kimberly Foreman, PhD, and Christine Curry of Loyola University Medical Center in Illinois; and David Sage, Towie Libermann, PhD, Joyce Fingeroth, MD, and Bruce Dezube, MD, of Beth Israel Deaconess Medical Center. The study was supported by grants from the National Institutes of Health, the American Cancer Society, the American Heart Association, and the CBRC.
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $400 million and major research centers in AIDS, cardiovascular research, cancer, cutaneous biology, medical imaging, neurodegenerative disorders, transplantation biology and photomedicine. In 1994, MGH and Brigham and Women's Hospital joined to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups, and nonacute and home health services. Additional information can be found at http://www.massgeneral.org.
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