Discovery of good -- and bad -- liver stem cells raises possibility
of new treatment
Many scientists believe up to 40 percent of liver cancer is caused by
stem cells gone wild ¡V master cells in the organ that have lost all
growth control. But, despite years spent looking, no one has ever
found these liver ¡§cancer stem cells¡¨ ¡V or even normal stem cells in
the organ. Until now.
In the February 19, 2008 issue of the Proceedings of the National
Academy of Sciences (PNAS), researchers at Georgetown University
Medical Center report discovering both types of stem cells, and by
comparing their genetic ¡§signatures,¡¨ they found evidence to suggest
that a new type of experimental drug now being tested in other
cancers might offer benefit in treating liver cancer.
In fact, preliminary results that have arisen from the current study
indicate that use of the agent, a stat3 inhibitor, dramatically
inhibited liver cancers in human cancer cell lines and mice.
¡§After locating the cancer stem cells that help control development
of these tumors, we were able to find a potential vulnerability that
might form the basis of a new treatment for this disease - which is
greatly needed,¡¨ said the study¡¦s lead author, Lopa Mishra, M.D.,
Director of Cancer Genetics in the Department of Surgery at
Georgetown University and the Department of Veterans Affairs Medical
Center, and the Lombardi Comprehensive Cancer Center.
Liver (hepatocellular) cancer is one of the most lethal and prevalent
cancers in the world, and the number of cases diagnosed in the United
States has risen sharply recently, Mishra said. Five-year survival is
less than five percent because the only treatment that has shown any
benefit is liver transplantation or surgery, but an operation to
remove tumors is only possible when the cancer mass is very small.
Unfortunately, most cancers are diagnosed when tumors are much
larger, she said.
The findings culminate decades of research in Mishra¡¦s laboratory
into the genetic pathways important to development of liver cancer.
An early pivotal discovery was that the transforming growth factor
beta (TGF-ƒÒ) pathway was crucial to the development of the cancer,
because when researchers eliminated the molecular pathway controlled
by TGF-ƒÒ in mice, the animals developed liver cancer. The TGF-ƒÒ
family of proteins helps keep stem cells in an undifferentiated
state, but also, when appropriate, guide development of these cells
into specialized cells. They also are powerful suppressors of cancer
development, she says.
Later work showed that loss of a gene known as ELF, which is common
to stem cells and is found within the TGF-ƒÒ pathway, was sufficient
to induce liver cancer to form. It is now known that ELF is lost in
more than 90 percent of human hepatocellular cancers.
While these studies suggested that stem cells gone wild were key to
liver cancer development, no one could find such cancer stem cells ¡V
or any stem cells - in liver tissue in order to test the theory.
Then, Georgetown transplant surgeon Lynt Johnson, M.D., had an idea
for Mishra and her research team. He suggested they look for stem
cells in donor liver tissue that had been newly transplanted into
patients with a failing organ. Stem cells in this tissue would be
particularly active, Johnson reasoned, because they would be busy
creating new liver cells. (The liver is the only human organ that is
capable of large scale, natural regeneration.
So biopsies taken from six surgery patients of liver tissue up to
four months past transplantation were studied, and it was in this
regenerating tissue that Mishra and her team finally found normal
stem cells. They were rare ¡V two to four cells per 30,000-50,000
cells ¡V but they expressed all the proteins known to be associated
with stem cells, such as Stat3, Oct4, Nanog, ELF, and receptor for
the TGF-ƒÒ protein.
¡§These cells were working really hard, expressing all of these
proteins in abundance,¡¨ Mishra said. ¡§In our staining tests they
looked like stars, surrounded by shells of cells that were also
expressing TGF-ƒÒ in order to make new liver cells.¡¨
Then, in order to find cancer stem cells, the researchers examined
tissue from 10 patients with liver cancer using the same antibody
test that located the stem cells in the regenerating livers. ¡§We
found that all of these stem cells had lost TGF-ƒÒ,¡¨ she
said. ¡§Without the brakes that TGF-ƒÒ puts on cancer, the stem cells
had turned into bad guys.¡¨
The scientists turned to mouse models of liver cancer to see what
would happen if they took out the ¡§stemness¡¨ in the cancer stem cells
and found that only 1 in 40 mice bred without a stat3 gene developed
liver cancer. ¡§But with the stat3 gene intact, 70 percent of mice
developed the cancer,¡¨ Mishra said.
As a final step in the study, Georgetown oncologists are treating
mice with liver cancer that had normal stat3 gene but are missing TGF-
ƒÒ with an experimental stat3 inhibitor drug in development by the
National Cancer Institute ¡V an agent that would shut down stat3. ¡§Now
we have a way to think about treating liver cancer, and this is very
exciting,¡¨ she said. ¡§Besides stat3, there are other proteins that
are activated on cancer stem cells, so they might also offer us
additional drug targets.¡¨
Early studies using stat3 inhibitors in gastrointestinal cancers
indicate that the drug has little toxicity.
###
The study was funded by grants from the National Institutes of
Health, a Veterans Administration Merit Award, and an R. Robert and
Sally D. Funderburg Research Scholar award and a Ben Orr Research
Scholar award. Researchers from The University of Texas M. D.
Anderson Cancer Center, the Department of Veterans Affairs Medical
Center, and Temple University contributed to the study.
About Lombardi Comprehensive Cancer Center
The Lombardi Comprehensive Cancer Center, part of Georgetown
University Medical Center and Georgetown University Hospital, seeks
to improve the diagnosis, treatment, and prevention of cancer through
innovative basic and clinical research, patient care, community
education and outreach, and the training of cancer specialists of the
future. Lombardi is one of only 39 comprehensive cancer centers in
the nation, as designated by the National Cancer Institute, and the
only one in the Washington, DC, area. For more information, go to
http://lombardi.
About Georgetown University Medical Center
Georgetown University Medical Center is an internationally recognized
academic medical center with a three-part mission of research,
teaching and patient care (through our partnership with MedStar
Health). Our mission is carried out with a strong emphasis on public
service and a dedication to the Catholic, Jesuit principle of cura
personalis -- or "care of the whole person." The Medical Center
includes the School of Medicine and the School of Nursing and Health
Studies, both nationally ranked, the world-renowned Lombardi
Comprehensive Cancer Center and the Biomedical Graduate Research
Organization (BGRO), home to 60 percent of the university¡¦s sponsored
research funding.
Public release date: 8-Feb-2008
Contact: Karen Mallet
mallet.karen@
414-312-7085
Georgetown University Medical Center
http://www.eurekale
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StemCells subscribers may also be interested in these sites:
Children's Neurobiological Solutions
http://www.CNSfoundation.org/
Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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