Glioma-Research

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Neural stem cells - glioma interaction

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Figure 1
The recruitment of NPCs to gliomas in a mouse model.

The response of endogenous NPCs (green) to experimental glioblastomas (red) was observed in nestin-GFP mice at 14 days after tumor inoculation. NPCs were efficiently recruited to tumors in young (postnatal day 30) mice


Scientific focus
Gliomas are the most frequent primary tumours of the central nervous system (CNS). The majority of glioma patients suffers from glioblastoma multiforme, which is the most aggressive form of a glioma, consituting an average survival of only 14 months after diagnosis. We have established previously, that endogenous neural precursor cells (NPCs) are attracted to experimental brain tumors (gliomas) and induce tumour cell death. Our current data show that NPCs exert an even more far-reaching anti-tumorigenic effect: NPCs migrate to murine and primary human CD133-positive glioma stem cells and may suppress glioma stem cells via release of bone morphogenetic protein-7 (BMP7).

Current state of the field
Neural stem and precursor cells in the adult brain are restricted to stem cell niches like the subventricular zone (SVZ)(2). In addition to their role in brain plasticity, NPCs contribute to brain repair after injury (3). However, genetic mutations can transform NPCs into extremely aggressive primary brain tumors, such as glioma (4, 5). Glioblastoma (GBM) patients have an average survival time of about one year after diagnosis. Current treatment strategies are designed to target the bulk tumour mass and potentially fail to suppress an aggressive sub-population in gliomas, the so called glioma stem cells (6). These glioma stem cells can be identified, since they express the cell surface
glycoprotein CD133. It is now well accepted that a successful glioma therapy should target these CD133-positive glioma stem cells. Recently it was disovered that recombinant BMP4 can suppress gliomas by specifically targeting glioma stem cells (7), which was confirmed by an independent study (8).

Own contributions
We have recently discovered that endogenous NPCs are recruited to experimental glioma and that NPCs exhibit anti-tumorigenic actions against GBM; i.e. NPCs induce glioma cell death (9, 10). In our current experiments, we investigated BMP expression in samples of experimental murine brain tumors by immunohistochemistry and detected BMP7 in the tumormargin, where it was located in NPCs. Glioma associated, BMP7 expressing NPCs are PSA-NCAM positive (not shown). Real-time PCR (not shown) and ELISA of cultured cells revealed that BMP7 is most abundantly expressed in PSA-NCAM positive NPCs. BMP7 release from cultivated NPCs was identified by Western blotting and ELISA. In vitro, NPC-conditioned medium reduced the number of murine glioma stem cells by about 40%. This effect was seen in bulk glioma cultures and in GSC-enriched cultures. Addition of recombinant BMP7 (rBMP7) to bulk gliomas cultures and to GSCs fully mimicked the effect of NPC conditioned medium, whereas a specific BMP receptor antagonist (dorsomorphin) (11) fully blocked the effect of the NPC-conditioned medium. Importantly, we found that BMP7 release from NPCs suppresses the brain tumour initiating function of glioma stem cells: Pre-treatment of glioma stem cells with rBMP7 prior to brain-injection into mice strongly enhanced survival, as compared to controls receiving untreated glioma stem cells. Overall, our findings suggest that NPCs are attracted to glioma and that BMP7 release from NPCs suppresses CD133+ glioma stem cells.

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Figure 2
BMP7 expression in glioma associated NPCs in vivo.

14 days after glioma inoculation into nestin-GFP mice (P30), BMP7 was detected in NPCs accumulating at a glioma (upper panel). The boxed area in the upper panel was magnified (left panel), showing that BMP7 is expressd in the NPCs (note colocalisation in the 3D view). Scale: 100μm

References
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stem cells Nature 414, 105-11.
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brain Neuron 41, 683-6.
3. Hallbergson, A. F., Gnatenco, C. & Peterson, D. A. (2003) Neurogenesis and brain injury: managing a renewable resource for repair J Clin Invest 112, 1128-33.
4. Holland, E. C. (2000) Glioblastoma multiforme: the terminator PNAS 97, 6242-4.
5. Holland, E. C. (2001) Progenitor cells and glioma formation Curr Opin Neurol 14, 683-8.
6. Singh, S. K., Hawkins, C., Clarke, I. D., Squire, J. A., Bayani, J., Hide, T., Henkelman, R. M.,
Cusimano, M. D. & Dirks, P. B. (2004) Identification of human brain tumour initiating cells Nature
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A., Dimeco, F. & Vescovi, A. L. (2006) Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells Nature 444, 761-5.
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Walling, J., Ahn, S., Kim, M., Totonchy, M., Cusack, T., Ene, C., Ma, H., Su, Q., Zenklusen, J. C.,
Zhang, W., Maric, D. & Fine, H. A. (2008) Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells Cancer Cell 13, 69-80.
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Kiwit, J., Kempermann, G. & Kettenmann, H. (2005) Glioblastoma-induced attraction of endogenous neural precursor cells is associated with improved survival J Neurosci 25, 2637-46.
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Kaminska B, Kempermann G, Uckert W, Kaczmarek L, Kettenmann H, Glass R (2008) The antitumorigenic response of neural precursors depends on subventricular proliferation and age Stem
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11. Yu, P. B., Hong, C. C., Sachidanandan, C., Babitt, J. L., Deng, D. Y., Hoyng, S. A., Lin, H. Y.,
Bloch, K. D. & Peterson, R. T. (2008) Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism Nat Chem Biol 4, 33-41.
12. Chirasani S.R., Sternjak A., Wend P., Momma S., Campos B., Herrmann I. M., Graf D., Mitsiadis T., Herold-Mende Ch., Besser D., Synowitz M., Kettenmann H., Glass R.
Bone morphogenetic protein-7 release from endogenous neural precursor cells suppresses the tumourigenicity of stem-like glioblastoma cells. Brain (2010) vol. 133 (Pt 7) pp. 1961-72.