Kaposi's sarcoma virus "reprograms"
blood vessel cells into lymphatic cells
First insight into mechanism of AIDS-associated
BOSTON - 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
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 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.
Media Contact: Sue
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
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