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New tumor suppressor may play important
role in deadly brain tumors
Level of gene activity corresponds
with tumor growth, angiogenesis
BOSTON - March 17, 2004 - Researchers from Massachusetts
General Hospital (MGH) have identified a new tumor suppressor gene
that appears to be inactivated in gliomas, a deadly form of brain
tumor. Levels of the protein coded by the gene, called ING4, appear
to correspond with tumor aggressiveness, with the lowest levels
seen in the highly malignant glioblastomas. In their report in the
March 18 issue of Nature, the researchers also describe how
ING4 appears to suppress the growth of new blood vessels to feed
the tumor, a process called angiogenesis.
ING (for INhibitor of tumor Growth) is a family of proteins known
to be essential to the activity of the powerful tumor suppressor
p53. The research team, led by Igor Garkavtsev, MD, PhD, of the
Steele
Laboratory in the MGH Department of Radiation Oncology, searched
a gene database to identify genes with a similar structure to the
previously identified ING1.
"The ING4 gene had been cloned simultaneously in both laboratories
at the MGH and at the National Institutes of Health," says
Garkavtsev. "Its functional role in the prevention of tumor
progression had not been investigated. Finding that malignant gliomas
have strikingly lower levels of ING4 and knowing that ING4 regulates
angiogenesis sparked interest toward potential targets that were
independent of p53."
The research team first tested samples from 50 tumors of various
malignancy grades for evidence of ING4 gene expression. They found
that gene expression was two to three times lower than normal in
lower-grade tumors and up to six times lower in the high-grade glioblastomas.
Similarly another test that compared tissue from brain tumors with
samples of nearby normal tissue found abundant ING4 levels in the
normal tissue but significantly less in the tumors.
To investigate the protein's effect on angiogenesis, the researchers
created lines of tumor cells that were manipulated to express levels
of ING4 higher and lower than found in control tumors. Cells from
each of these lines and from unaltered tumors were implanted into
cranial windows, transparent compartments placed on the brains of
mice to allow observation of blood vessel growth.
Implants of cells with suppressed ING4 expression grew much faster
and developed more complex blood vessel networks than did the controls.
The implants that overexpressed ING4 grew much more slowly and showed
significantly less blood vessel growth. Further examination with
an advanced imaging technology confirmed that suppression of ING4
was associated with more mature and complex vascular networks, while
overexpression kept vessels from significant development.
Another set of experiments indicated that ING4 acts to suppress
the activity of a protein called NF-kappa B, which is known to stimulate
genes that are overactive in many forms of cancer. Loss of the ING4
suppressor causes overproduction of the NF-kappa-B-responsive gene
for interleukin 8 (Il-8), which is known to stimulate angiogenesis.
Knowing the mechanism by which gliomas are able to support their
growth offers some possible drug targets - including restoration
of ING4 function, inactivation of Il-8 production through NF-kappa
B, or blocking the Il-8 sensitivity of tumor cells.
Additional authors of the Nature paper are senior author
Rakesh Jain, PhD, director of the Steele Laboratory; Sergey Kozin,
DSc; Lei Xu, MD, PhD; Frank Winkler, MD, PhD; and Edward Brown,
PhD, all of the Steele Lab; and Olga Chernova, PhD, and Gene Barnett,
MD, of the Cleveland Clinic. The research was supported by grants
from the National Cancer Institute.
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.
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Media Contact: Julie
Bergan , MGH Public Affairs
Physician Referral Service: 1-800-388-4644
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