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Bone morphogenetic proteins inhibit the
tumorigenic potential of human brain tumour-initiating cells
S. G. M. Piccirillo1,2,
B. A. Reynolds3, N. Zanetti2,
G. Lamorte2, E. Binda4,
G. Broggi5, H. Brem6,
A. Olivi6, F. Dimeco5,6
and A. L. Vescovi1,2,4
1Department
of Biotechnology and Biosciences, University of Milan–Bicocca, 20126
Milan, Italy. 2Unit of Cancer Stem Cell
Biology, StemGen Spa, University of Milan–Bicocca, 20126 Milan,
Italy. 3Laboratory for Neural Stem Cell
Biology, Queensland Brain Institute, University of Queensland, 4072
Brisbane, Queensland, Australia. 4Stem
Cell Research Institute, H. S. Raffaele, 20132 Milan, Italy. 5National
Neurological Institute 'C. Besta', 20133 Milan, Italy. 6Department
of Neurosurgery, John Hopkins University, Baltimore, 21287 Maryland,
USA. -- Correspondence to: A. L. Vescovi. Correspondence and requests
for materials should be addressed to A.L.V. (Email: vescovi@tin.it).
-- Received 6 April 2006; Accepted 12 October 2006.
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Transformed, oncogenic precursors,
possessing both defining neural-stem-cell properties and the ability
to initiate intracerebral tumours, have been identified in human brain
cancers1.
Here we report that bone morphogenetic
proteins (BMPs), amongst which BMP4 elicits the strongest effect,
trigger a significant reduction in the stem-like, tumour-initiating
precursors of human glioblastomas (GBMs).
Transient in vitro
exposure to BMP4 abolishes the capacity of transplanted GBM cells to
establish intracerebral GBMs.
Most importantly, in
vivo delivery of BMP4 effectively blocks the tumour growth and
associated mortality that occur in 100% of mice after intracerebral
grafting of human GBM cells.
We demonstrate that BMPs activate their
cognate receptors (BMPRs) and trigger the Smad signalling cascade in
cells isolated from human glioblastomas (GBMs).
This is followed by a reduction in
proliferation, and increased expression of markers of neural
differentiation, with no effect on cell viability.
The concomitant reduction in clonogenic
ability, in the size of the CD133+
population and in the growth kinetics of GBM cells indicates that BMP4
reduces the tumour-initiating cell pool of GBMs.
These findings show that the BMP–BMPR
signalling system—which controls the activity of normal brain stem
cells2, 3—may also act as a key
inhibitory regulator of tumour-initiating, stem-like cells from GBMs
and the results also identify BMP4 as a novel, non-cytotoxic
therapeutic effector, which may be used to prevent growth and
recurrence of GBMs in humans.
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