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Angiogenesis factor may help tumors
prepare the way for spread to lymph nodes
Tumor cells use VEGF-A to stimulate
lymphatic vessel growth beyond primary site
BOSTON - April 4, 2005 - Production of the protein VEGF-A,
already known to stimulate the growth of blood vessels associated
with tumors, also contributes in unexpected ways to the spread of
cancer. In the April Journal of Experimental Medicine, researchers
from Massachusetts General Hospital (MGH) and the Swiss
Federal Institute of Technology describe finding that VEGF-A
promotes the development of lymphatic vessels that can carry cancer
cells to lymph nodes and may actually prepare the way for tumor
metastasis by inducing new lymphatic vessels to grow within the
nodes even before a secondary tumor has developed.
"This observation is our most surprising and exciting finding,"
says Michael Detmar, MD, of the MGH Cutaneous
Biology Research Center, the study's senior author. "It's
a new twist to the 'seed and soil' hypothesis, which postulates
that distinct cancer types preferentially metastasize to organs
that are optimally suited for them. Our results indicate that the
'seeds' can actively modify the 'soil' and prepare it for later
metastatic arrival."
While it is now accepted that tumors can stimulate development of
their own blood supply, a process called angiogenesis, similar growth
of new lymphatic vessels was not suspected until 2001. At that time
Detmar and his colleagues showed that human breast tumors implanted
into mice induce the growth of lymphatic vessels and that lymphangiogenesis
plays a key role in tumors' spread to lymph nodes. It had previously
been believed that tumors had no functioning lymphatic vessels.
The 2001
study focused on VEGF-C, the first factor identified to promote
lymphatic vessel growth, and subsequent research has identified
another lymphatic factor called VEGF-D, which also is active in
the spread of cancer.
While VEGF-A had been believed to promote the development of new
blood vessels only, recent research at the MGH and elsewhere found
that it also induced proliferation of lymphatic tissue and vessels
in laboratory and animal models. As a result, the MGH team decided
to investigate its possible role in tumor-associated lymphangiogenesis.
Research fellow Satoshi Hirakawa, MD, PhD, the study's first author
developed a strain of transgenic mice in which skin cells express
a green fluorescent protein and also produce elevated levels of
VEGF-A. The reseachers then induced the development of benign and
malignant skin tumors in both the transgenic mice and normal mice
in order to identify differences that could be attributed to elevated
levels of VEGF-A.
The transgenic mice were found to develop both benign papillomas
and malignant squamous cell carcinomas more rapidly and more extensively
than did mice with normal VEGF-A expression. Both strains of mice
had increased levels of angiogenesis associated with benign and
malignant tumors, but the transgenic mice also had more and larger
lymphatic vessels than did the normal mice. In addition, the new
lymphatic vessels were shown to carry the receptor molecule known
to interact with VEGF-A.
Examination of sentinel lymph nodes - those most adjacent to the
tumors - showed increased spread of malignant cells to the nodes
of transgenic mice. Those cells expressed the green fluorescent
protein, confirming they originated in the skin tumors. The transgenic
mice were also twice as likely to develop metastases in more distant
lymph nodes. Detailed analysis of the nodes themselves found greater
numbers of both blood vessels and lymphatic vessels in metastatic
nodes of the transgenic mice, compared with cancer-containing nodes
in normal mice. In addition, the transgenic mice also had increased
lymphatic development in nodes that were cancer-free, suggesting
that VEGF-A-induced lymphangiogenesis takes place in lymph nodes
even before a metastatic tumor develops.
Another unexpected finding was that the metastatic lymph nodes of
transgenic mice, which continued to overexpress VEGF-A, actively
promote further lymphatic development, a newly discovered phenomenon
the researchers called lymph node lymphangiogenesis. Detmar explains
that the transportation of tumor cells by the lymphatic system previously
had been considered a passive process. "Our findings reveal
that tumor cells, even after they have metastasized to the lymph
nodes, can very actively induce the growth of the very channels
that will enable transport to other nodes and the organs."
Detmar notes that this newly identified process could be a promising
target for therapies designed to prevent the further spread of metastatic
cancer, which has been a major challenge in cancer treatment. He
is an associate professor of Dermatology at Harvard Medical School
and is also a professor of Pharmacogenomics at the Swiss Federal
Institute of Technology.
Additional co-authors of the study are Shohta Kodama, MD, PhD, Rainer
Kunstfeld, MD, and Kentaro Kajiya, MSc, of the MGH and Lawrence
Brown, MD, of Beth Israel Deaconess Medical Center. The research
was supported by grants from the National Institutes of Health,
the American Cancer Society Research Project and the MGH Cutaneous
Biology Research Center.
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 $450 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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