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Senior Citizen Health & Medicine
Shutting Down Genetic ‘Gang of 4’ Slows Spread of
Breast Cancer Almost to Halt
Silencing quartet nearly completely
stopped
tumor growth, spread
April 11, 2007 - Studies of human tumor cells
implanted in mice have shown that the abnormal activation of four genes
drives the spread of breast cancer to the lungs. Although shutting off
these genes individually can slow cancer growth and metastasis, researchers found that turning off all four together had a far more
dramatic effect on halting cancer growth and metastasis.
The new studies by Howard Hughes Medical Institute
researchers reveal that the aberrant genes work together to promote the
growth of primary breast tumors. Cooperation among the four genes also
enables cancerous cells to escape into the bloodstream and penetrate
through blood vessels into lung tissues.
Metastasis occurs when cells from a primary tumor
break off and invade another organ. It is the deadliest transformation
that a cancer can undergo, and therefore researchers have been looking
for specific genes that propel metastasis.
In the newly published experiments, the researchers
also found that they could reduce the growth and spread of human breast
tumors in mice by simultaneously targeting two of the proteins produced
by these genes, using drugs already on the market.
The researchers are
exploring clinical testing of combination therapy with the drugs—cetuximab
(trade name Erbitux) and celecoxib (Celebrex)—to treat breast cancer
metastasis.
The research team, led by Howard Hughes Medical
Institute investigator Joan Massagué at the Memorial Sloan-Kettering
Cancer Center, published its findings in articles in the April 12, 2007,
issue of the journal Nature and in the online early edition of the
Proceedings of the National Academy of Sciences on April 9, 2007.
In an earlier study, Massagué and his colleagues
had identified 18 genes whose abnormal activity is associated with
breast cancer’s ability to spread to the lungs. In the new study
published in Nature, Massagué and his colleagues at Sloan-Kettering,
along with researchers from Hospital Clinic de Barcelona and the
Institute for Research in Biomedecine in Spain, focused on four of these
genes.
These genes, which code for proteins called
epiregulin, COX2, and matrix metalloproteinases 1 and 2, were already
known to help regulate growth and remodeling of blood vessels, said
Massagué.
"Our understanding of the genes for these four
proteins and their behavior in metastasis led us to hypothesize that
they might be cooperating with each other in a way that would give an
advantage to cells in the primary tumor," said Massagué. "These same
genes, we believed, might also be used for some related purpose in the
target organ, the lung."
To test this idea, the researchers silenced various
combinations of the four genes in human breast cancer cells that had
metastasized to the lung, and then tested these cells in mice. To
silence the four genes, the scientists used a technique called RNA
interference, in which RNA molecules are tailored to suppress expression
of target genes.
"We found that depriving aggressive metastatic
tumor cells of these genes decreased both their ability to grow large
aggressive tumors in the mouse mammary gland and also the ability to
release cells from these tumors into the circulation," said Massagué.
"The remarkable thing was that while silencing these genes individually
was effective, silencing the quartet nearly completely eliminated tumor
growth and spread."
Microscopic analysis of blood vessel structure in
the tumors revealed that knocking down all four genes greatly reduced
growth of the tangle of blood vessels typically seen in tumors. Further
experiments revealed that the tumor blood vessels that did form allowed
fewer cancer cells to escape into circulation.
The researchers next explored how loss of the four
abnormal genes affected the metastatic capability of the cells in the
lung. They injected cells deficient in the four genes directly into the
circulatory system of mice. "When these cells reached the lung
capillaries, they just got stuck there," said Massagué. "We concluded
that metastatic cells use these same genes to loosen up cells in
capillaries, so that the cells can penetrate the lung tissue to grow
there.
"These findings provide a beautiful explanation for
how the genes that we identified in breast cancer patients as being
associated with lung metastasis manipulate blood vessels to give them an
advantage both in the primary tumors and in the lung," he said.
Two drugs already on the market act directly on
proteins produced by the genes Massagué’s group had been studying.
Cetuximab is an antibody that blocks the action of epiregulin and is
used to treat advanced colorectal cancer. Celecoxib is an inhibitor of
COX2 that is used as an anti-inflammatory, and is being tested in
clinical trials against many types of cancer. The researchers also
tested whether cetuximab and celecoxib would work effectively in concert
to reduce metastasis in mice.
"We found that the combination of these two
inhibitory drugs was effective, even though the drugs individually were
not very effective," said Massagué. "This really nailed the case that if
we can inactivate these genes in concert, it will affect metastasis," he
said.
Massagué said that while clinical trials of the
drug combination are being discussed, "there are already treatments to
diminish the chance of metastasis in breast cancer, so such trials would
have to be designed very carefully to understand how and whether the new
drug combination would be of additional benefit."
In the article published in the Proceedings of the
National Academy of Sciences, Massagué and his colleagues explored how
the entire group of 18 genes, called the ‘lung metastasis
gene-expression signature’ (LMS) influenced both breast tumor growth and
spread to the lungs. Co-authors on the paper were from the University of
Chicago, The Netherlands Cancer Institute, Veridex L.L.C., The Cleveland
Clinic and the Erasmus Medical Center in The Netherlands.
"There has been an undeniable link between tumor
size and growth and metastatic risk, but the molecules and mechanisms
underlying this link have remained unresolved," said Massagué. "The
hypothesis we wanted to test was that these signature genes play a role
in both primary tumor growth and metastasis to the lung."
After analyzing 738 human breast cancer tumors, the
researchers concluded that those in which the LMS genes were abnormally
active were, indeed, more likely to develop lung metastases. They also
found that the activity of these LMS genes gave cancer cells a growth
advantage by allowing tumors to develop a rich network of blood vessels
to deliver oxygen and nutrients, said Massagué.
Although large tumors are more likely to
metastasize, Massagué said his group’s findings indicated that the
activity of the LMS genes was also critical to the metastasis process.
"As the tumors grow and become enriched with LMS-positive cells, because
the genes give them an advantage, they reach a point where the tumor
becomes richly vascularized," said Massagué. "Then, they can massively
execute the advantage the LMS genes provide them to metastasize to the
lung."
Massagué said he and his colleagues will explore in
more detail the function of other LMS genes, in addition to the four
reported in the Nature paper. They plan to investigate whether shutting
down other LMS genes will affect metastasis of breast cancer to the
lung, and whether the LMS genes influence breast cancer metastasis to
other sites, such as the bone and brain. Finally, they will explore
whether the LMS genes play a corresponding role in metastasis of other
cancers -- such as sarcoma, melanoma and colon cancer -- to the lung,
said Massagué.
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