Gene plays 'Jekyll and Hyde' in brain cancer
BOSTON, Mass. (February 6, 2008)—Perhaps the only positive spin one
can put on the brain cancer glioblastoma is that it's relatively
uncommon. Other than that, the news is bad. It is nearly always
fatal, it tends to strike people in the prime of their lives, and the
limited treatment options have changed little over decades. It's no
wonder then that many researchers are determined to find new ways
treat this poorly understood type of cancer.
One approach focuses on a gene called STAT3. In several tumors, STAT3
takes the role of an oncogene, that is, a gene whose normal functions
are derailed and, as a result, becomes a driving force in a tumor's
development. Clearly then, blocking STAT3 would deal a major blow to
such tumors.
But a new study led by a team at Harvard Medical School has found
that STAT3 isn't always the villain. While it does behave as an
oncogene in certain types of glioblastoma, in others it becomes
what's called a "tumor suppressor gene," a type of gene often
responsible for keeping the renegade cancer cells in check.
In other words, the same gene in the same cancer can play a
completely different role from one person to the next, depending on
genetic nuances between individuals. The results appear online
February 6 in Genes and Development.
"This discovery lays the foundation for a more tailored therapeutic
intervention,
at Harvard Medical School, and senior author on this study. "And
that's really important. You can't just go blindly treating people by
inhibiting STAT3."
When most people think of brain cells, they think of neurons, those
cells whose electric signaling gives rise to our consciousness. But
another class of brain cells called astrocytes (named after their
uncanny resemblance to stars) actually outnumber neurons ten to one.
Despite their name, astrocytes play a less glitzy role than neurons
do. Typically, they're support cells, involved with functions such as
providing nutrients to nerve tissue and repairing scars. However,
nearly all brain cancers occur in astrocytes, or in the neural stem
cells that generate astrocytes.
Bonni, a neurologist and neuroscientist by training, decided to
investigate the genetic etiology of glioblastoma by studying whether
certain regulatory genes that control the generation of astrocytes
during normal development also play a role in these tumors. The logic
here is simple: since disease is often the breakdown of a normal
biological process, the more we understand how cells get it right,
the more we understand what can go wrong. And since STAT3 is a key
gene that turns neural stem cells into astrocytes during normal
development, what is its role in glioblastoma"
Bonni and two lead authors, Núria de la Iglesia and Genevieve
Konopka, in collaboration with investigators in the laboratory of
Ronald DePinho at the Dana-Farber Cancer Institute, began by
genetically manipulating mouse astrocytes, then placing them into a
second group of mice whose immune systems had been compromised. The
findings surprised them.
Taking advantage of previously published data, the researchers looked
closely at how two genes, EGFR and PTEN—whose mutated forms are
associated with glioblastoma—
astrocytes. Bonni's group found when EGFR is mutated, STAT3 is an
oncogene; with a PTEN mutation, STAT3 is a tumor suppressor.
"EGFR, in its normal state, is a transmembrane receptor, usually
performing its functions at the cell surface," says Bonni. "However,
when it's mutated, we find it in the cell's nucleus interacting with
STAT3—and turning it into an oncogene. STAT3 itself is not mutated or
damaged. It's the process of regulating STAT3 that gets damaged."
With PTEN, it's a completely different story. PTEN is itself a tumor
suppressor gene. When PTEN becomes disabled in astrocytes, these
potential tumors still have STAT3 standing in their way. This is
because STAT3 acts as a tumor suppressor normally in astrocytes.
However, as more PTEN becomes disabled, a cascade of molecular events
is set in motion with the express purpose of inhibiting STAT3
function and thus turning the tide in the cells toward tumor
formation.
The researchers confirmed these findings in human glioblastoma tumors
as well.
"The belief that STAT3 can only be an oncogene has been a pretty
entrenched dogma in the field," says Bonni, "so we performed many,
many experiments to make sure this was correct. It took some very
persistent investigators in my lab to get the job done. As a result,
we're convinced of our data."
While glioblastoma tends to be uncommon, STAT3 has also been
implicated in prostate and breast cancers, so these results may
translate to other types of tumors as well.
In addition, the findings contribute to the growing body of evidence
for "personalized medicine," showing that many types of cancers
contain subgroups that require different treatments.
###
This research was funded by the Stewart Trust of Washington, D.C.,
the Armenise-Harvard Foundation, and the Carolyn and Peter Lynch
Research Fund.
Full citation:
Genes and Development, Volume 22, Issue 4: February 15, 2008
"Identification of a PTEN-regulated STAT3 brain tumor suppressor
pathway"
Núria de la Iglesia(1), Genevieve Konopka(1,2)
(1,3), Jennifer A. Chan(4), Robert M. Bachoo(5), Mingjian J. You(5),
David E. Levy(6), Ronald A. DePinho(5), and Azad Bonni(1,2,3)
1-Department of Pathology, Harvard Medical School, Boston, MA
2-Program in Neuroscience, Harvard Medical School, Boston, MA
3-Program in Biological and Biomedical Sciences, Harvard Medical
School, Boston, MA
4-Division of Neuropathology, Department of Pathology, Brigham and
Women's Hospital, Boston, MA
5-Department of Medical Oncology, Center for Applied Cancer Science
of the Belfer Institute for Innovative Cancer Science, Dana-Farber
Cancer Institute, and Department of Medicine and Department Genetics,
Harvard Medical School, Boston, MA
6-Department of Pathology and Department of Microbiology, New York
University School of Medicine, New York, NY
Harvard Medical School (www.hms.harvard.
time faculty working in 11 academic departments located at the
School's Boston campus or in one of 47 hospital-based clinical
departments at 17 Harvard-affiliated teaching hospitals and research
institutes. Those affiliates include Beth Israel Deaconess Medical
Center, Brigham and Women's Hospital, Cambridge Health Alliance,
Children's Hospital Boston, Dana-Farber Cancer Institute, Forsyth
Institute, Harvard Pilgrim Health Care, Joslin Diabetes Center, Judge
Baker Children's Center, Immune Disease Institute, Massachusetts Eye
and Ear Infirmary, Massachusetts General Hospital, McLean Hospital,
Mount Auburn Hospital, Schepens Eye Research Institute, Spaulding
Rehabilitation Hospital, and VA Boston Healthcare System.
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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