|Researchers Uncover an Error in Immature Brain
Cells in Lab and Animal Studies that May Promote the Growth of
Some Brain Tumors
In experiments done in lab and animal studies, a breakdown in
proper cell development has been shown to cause brain-specific
stem cells to become starter seeds for aggressive brain tumors
called glioblastoma multiforme, according to research from a team
of researchers at the National Cancer Institute (NCI) and the National
Institute of Neurological Disease and Stroke (NINDS), parts of
the National Institutes of Health (NIH).
This developmental breakdown is caused by an error in methylation,
one of the cell's primary methods of controlling the extent to
which genes are expressed. In laboratory studies and animal models
of brain cancer, reversing this error repaired the breakdown, restoring
the normal neural cell development pathway. The findings, which
appear in the January 2008, issue of Cancer Cell, could
increase basic understanding of brain tumor biology and lead to
the development of targeted therapies for brain cancer.
"The discovery of a link between tumor stem-like cells and
expression control is both novel and exciting," said NCI Director
John Niederhuber, M.D. "These results bring new clarity to
how all aspects of the genome's function, regulation, and structure
can be perturbed in the development of cancer."
Many researchers have come to believe that the activity of a small
group of stem-like tumor starter cells, or tumor-initiating cells
with stem-like properties (TICs) may be one of the main reasons
that cancer develops. Like normal stem cells, TICs are able to
self-renew; unlike stem cells , TICs give rise to cells that develop
into tumors, instead of differentiating into normal tissue. TICs
have been reportedly found in tumors in a number of organs, including
the breast, colon, lung, and brain.
Because normal stem cells and TICs are similar in some ways and
dissimilar in others, a research team led by Howard Fine, M.D.,
chief of the Neuro-Oncology Branch at NCI's Center for Cancer Research,
set out to identify what biological pathways are altered in these
starter cells that enable them to give rise to tumor cells. Harvesting
TICs from glioblastoma multiforme patients, the Fine team developed
a human cell called 0308 that did not respond normally to environmental
cues — specifically, exposure to two proteins, called bone
morphogenetic protein-2 (BMP2) and ciliary neurotrophic factor
(CNTF) — that cause normal neuronal stem cells to begin differentiating.
Rather, they responded to these cues much like very immature neuronal
stem cells in that they grew in response to BMP2 and were unresponsive
to CNTF, suggesting that the 0308 starter cells were somehow locked
in a very early stage of development.
Because the response to BMP2 in normal stem cells is linked to
the presence of particular BMP receptors, which are present during
specific developmental stages, Fine and his colleagues compared
the expression of genes for BMP receptors in 0308 with what occurs
in normal neuronal stem cells. The researchers found that the gene
for one receptor, BMPR1B, was almost completely silent in 0308
cells. Experimentally reactivating this gene in the 0308 line caused
the cells to respond more normally to environmental cues and reduced
their potential for tumor development.
Subsequently, the Fine group determined that BMPR1B expression
in 0308 cells was blocked via methylation, a chemical modification
used by the cell to control gene expression. A methylated gene
cannot be expressed and is rendered silent. Methylation-associated
silencing of tumor suppressor genes has been found in several cancers.
Interestingly, methylation has also been identified as a key mechanism
for the control of proper cellular development in the early brain,
and particularly for the differentiation of neuronal stem cells.
Again, experimentally demethylating 0308 cells caused them to behave
more normally. The results mimicked those seen when early normal
embryonic neuronal stem cells are demethylated, adding further
weight to the argument that the 0308 cells were locked in a developmentally
To put these findings into clinical context, Fine and his group
then examined a set of 54 glioblastoma multiforme tumors, finding
that in about 20 percent of tumors, BMPR1B expression was greatly
reduced; in the majority of these tumors the gene for BMPR1B was
heavily methylated. These tumors also displayed the same markers
of stalled differentiation found in 0308 cells.
"This research highlights an example of a stem cell whose
normal development has been blocked in such a way as to both prevent
it from differentiating and force it to contribute to the development
of an aggressive tumor," said Fine. "The results we have
generated can help us better understand the biology of neuronal
stem-like starter cells in glioblastoma multiforme and other cancers,
and give us a strong rationale for investigating BMPR1B as a potential
target for therapeutic development."
For patients and health professionals with specific clinical or
scientific questions regarding brain tumors, please visit the NCI's
Neuro-Oncology branch Web site at http://home.ccr.cancer.gov/nob/ or
call the Neuro-Oncology Branch at (301) 402-6383.
For more information on Dr. Fine's laboratory, please go to http://ccr.cancer.gov/staff/staff.asp?profileid=5635.
For more information about cancer, please visit the NCI Web site
or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
For clinical trials and other information about brain tumors,
please visit the NINDS Web site at http://www.ninds.nih.gov.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.
Lee J, Son MJ, Woolard K, Donin NM, Li A, Cheng CH, Kotliarova S,
Kotliarov Y, Walling J, Ahn S, Kim M, Totnchy M, Cusack T, Ene C,
Ma H, Su Q, Zenklusen JC, Zhang W, Maric D, and Fine HA. Epigenetic-mediated
dysfunction of the bone morphogenetic protein pathway inhibits differentiation
of glioblastoma-initiating cells. Cancer Cell, January 8,
2008, Vol. 13, No. 1.