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Cancer biologists are turning their attention to the normal
cells that give rise to cancers, to learn more about how tumor
growth

"Identifying the specific, normal cells that cancers come
from can provide critical insight into how cancers develop,"
said Robert Wechsler-Reya, an associate professor of
Pharmacology and Cancer Biology at Duke University Medical
Center. "This may help us develop more rational and effective
approaches to treatment."

Every cancer comes from a normal cell. The hard part is
finding the cell at the root of each particular subtype of
cancer. For the first time, the Duke team has identified two
types of cells in the brain that can give rise to the malignant
brain tumor medulloblastoma.

This dangerous cancer, which occurs most commonly in
children, is currently treated with a combination of surgery,
chemotherapy and radiation, which have extremely severe side
effects, said Wechsler-Reya, who is a member of the Preston
Robert Tisch Brain Tumor Center at Duke.

To find the normal cells at the root of medulloblastoma,
Wechsler-Reya's laboratory, in collaboration with Brandon
Wainwright's laboratory at the University of Queensland in
Australia, created mouse models of medulloblastoma by turning
off the patched gene, a key regulator of cell growth in the
developing brain cerebellum. In particular, they tested the
effects of shutting off patched in granule neuron precursors
(GNPs), which can only make one particular type of nerve cell
(neuron), or in stem cells, which can make all the different
cell types in the cerebellum.

When they deleted patched in the neuron precursors, 100
percent of the mice developed medulloblastoma. Deleting patched
from stem cells initially led to the formation of many more
stem cells. However, most of these stem cells went on to form
normal cell types within the cerebellum. Only the patched-less
stem cells that gave rise to GNPs went on to form
medulloblastoma tumors.

According to Wechsler-Reya, these studies provide the first
definitive proof that medulloblastoma can be triggered in a
granule neuron precursor or a stem cell. But even more
importantly, they suggest that when it comes to cancer
formation, the cell type in which a mutation happens is as
important as the mutation itself. Although stem cells that lack
patched also gave rise to other forms of brain cells, those
cells did not form the tumors.

"Simply mutating a gene is not enough to cause cancer,"
Wechsler-Reya said. "The mutation has to happen in the right
cell type at the right time. In the case of patched, GNPs
provide the critical context for tumor formation."

Wechsler-Reya said that cancer biologists need to learn more
about the genes that regulate proliferation (cell division),
differentiation, survival, and programmed cell death in normal
cells. A mutation in a proliferation gene, for example, can
send the cell on a path of exaggerated division of cells --
becoming a fast-growing tumor. Understanding the way these
genes are controlled during normal development can shed light
on how they go awry in human cancers.

This work, published in the August issue of Cancer Cell, was
funded by the Hope Street Kids Foundation, the Kislak-Sussman
Fund, the Children's Brain Tumor Foundation, the Pediatric
Brain Tumor Foundation, the McDonnell Foundation, and a grant
from the National Institute of Neurological Disorders and
Stroke. The collaborative work in Dr. Wainwright's lab was
supported by the National Health and Medical Research Council
of Australia, the ARC Special Research Centre for Functional
and Applied Genomics, the Queensland Cancer Fund.

Other authors on the paper include Zeng-Jie Yang, Shirley
Markant, Tracy-Ann Read and Jessica Kessler of the Duke
Department of Pharmacology and Cancer Biology; Tammy Ellis, and
Melissa Bourboulas of the Institute for Molecular Bioscience at
the University of Queensland in St. Lucia, Australia; Ulrich
Schuller of the Center for Neuropathology at
Ludwig-Maximilians-Universitat in Munich; Robert Machold and
Gord Fishell of the Smilow Neuroscience Program and Department
of Cell Biology at New York University School of Medicine; and
David H. Rowitch of the Institute for Regeneration Medicine and
Division of Neonatology at the University of California – San
Francisco.