Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells

被引:921
作者
Piccirillo, S. G. M.
Reynolds, B. A.
Zanetti, N.
Lamorte, G.
Binda, E.
Broggi, G.
Brem, H.
Olivi, A.
Dimeco, F.
Vescovi, A. L. [1 ]
机构
[1] Univ Milano Bicocca, Dept Biosci & Biotechnol, I-20126 Milan, Italy
[2] Univ Milano Bicocca, StemGen Spa, Unit Canc Stem Cell Biol, I-20126 Milan, Italy
[3] Univ Queensland, Queensland Brain Inst, Lab Neural Stem Cell Biol, Brisbane, Qld, Australia
[4] Hosp San Raffaele, Stem Cell Res Inst, I-20132 Milan, Italy
[5] Natl Neurol Inst C Besta, I-20133 Milan, Italy
[6] Johns Hopkins Univ, Dept Neurosurg, Baltimore, MD 21287 USA
关键词
D O I
10.1038/nature05349
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Transformed, oncogenic precursors, possessing both defining neural-stem-cell properties and the ability to initiate intracerebral tumours, have been identified in human brain cancers(1). 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 cells(2,3) - 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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页码:761 / 765
页数:5
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