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Cancer cells can compress blood vessels,
block entry of drugs
MGH studies add to understanding
of tumor physiology, suggest treatment strategies
BOSTON - February 18, 2004 - A growing tumor needs an increased
blood supply for its proliferating cells. But the implications of
tumor-related angiogenesis - the growth of new blood vessels - are
much more complex than many investigators have realized. Although
these new vessels are required to nourish the tumor itself, they
are disorganized and abnormal and can actually block therapeutic
agents from reaching malignant cells.
In the Feb. 19 issue of Nature, researchers from Massachusetts
General Hospital (MGH) describe how proliferating cancer cells compress
both blood and lymphatic vessels within tumors. The findings suggest
new strategies for improving the success of cancer treatment. Related
studies in the February issue of Nature Medicine provide
more information about improving the delivery of anticancer drugs
to tumor cells.
"We've known for several years that internal pressure can make
it difficult for many drugs to penetrate into a tumor," says
Rakesh Jain, PhD, director of the Edwin
Steele Laboratory in the MGH Department of Radiation Therapy,
senior author of the Nature and Nature Medicine papers.
"Much of our work has focused on fluid pressure within tumors,
but this was the first look at solid pressure."
As described in the Nature study, fluid pressure had been
assumed to be the force compressing vessels within tumors, but actual
fluid pressures inside both tumors and their blood vessels are almost
equal. The MGH team investigated whether solid pressure exerted
by proliferating cancer cells could compromise blood supply in the
same way that stepping on a hose cuts off the flow of water. Using
human tumors implanted in mice, the researchers administered diphtheria
toxin, which kills tissue from humans but not from mice, to selectively
destroy cancer cells.
Analysis of the toxin-treated tumors found that both blood vessels
and lymphatic vessels looked much more open than did vessels from
untreated tumors, which were largely collapsed. However, although
the treated blood vessels appeared to be functioning nearly normally,
treated lymphatic vessels were not functional. "Some of the
new questions we need to investigate are why decompressed lymphatics
do not function, what role vessel decompression may play in tumor
growth and metastasis, and how we can use vessel decompression to
improve cancer treatment," say Jain, who is Cook Professor
of Tumor Biology at Harvard Medical School.
One of the Nature Medicine papers may explain the mechanism
of action behind the anti-angiogenesis drug Avastin (bevacizumab),
which is currently in clinical trails for FDA approval. In a small
group of patients with rectal cancer, the MGH researchers found
that Avastin treatment reduces both the number and density of blood
vessels within tumors, as well as reducing fluid pressures. Taken
with the positive early results of the Avastin trials, this finding
is the first clinical confirmation that normalizing the distorted
blood supply within tumors could improve the results of therapy.
The second Nature Medicine report uses an advanced imaging
technique to examine the structure of the tumor extracellular matrix,
composed of connective tissues which block anticancer drugs from
reaching tumor cells. The new imaging tool - two-photon fluorescence
correlation microscopy - is a significantly better method of measuring
the passage of molecules within the matrix. The MGH study revealed
that the matrix actually has two components, one that is nearly
liquid and a more viscous component that appears to be the most
significant barrier to drug delivery. Targeting the viscous matrix
component may also improve treatment results.
The Nature study was led by Timothy Padera of the Steele
Laboratory. The Nature Medicine Avastin study was led by
Christopher Willett, MD, of MGH Radiation Oncology, and the extracellular
matrix study was led by George Alexandrakis, PhD, of the Steele
Laboratory. All three studies were supported by 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 $350 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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