Glioblastoma-induced attraction of endogenous neural precursor cells is associated with improved survival

Neural precursor cells contribute to adult neurogenesis and to limited attempts of brain repair after injury. Here we report that in a murine experimental glioblastoma model, endogenous neural precursors migrate from the subventricular zone toward the tumor and surround it. The association of endogenous precursors with syngenic tumor grafts was observed, after injecting red fluorescent protein-labeled G261 cells into the caudate-putamen of transgenic mice, which express green fluorescent protein under a promoter for nestin (nestin-GFP). Fourteen days after inoculation, the nestin-GFP cells surrounded the tumors in several cell layers and expressed markers of early noncommitted and committed precursors. Nestin-GFP cells were further identified by a characteristic membrane current pattern as recorded in acute brain slices. 5-bromo-2-deoxyuridine labeling and dye tracing experiments revealed that the tumor-associated precursors originated from the subventricular zone. Moreover, in cultured explants from the subventricular zone, the neural precursors showed extensive tropism for glioblastomas. Tumor-induced endogenous precursor cell accumulation decreased with age of the recipient; this correlated with increased tumor size and shorter survival times in aged mice. Coinjection of glioblastoma cells with neural precursors improved the survival time of old mice to a level similar to that in young mice. Coculture experiments showed that neural precursors suppressed the rapid increase in tumor cell number, which is characteristic of glioblastoma, and induced glioblastoma cell apoptosis. Our results indicate that tumor cells attract endogenous precursor cells; the presence of precursor cells is antitumorigenic; and this cellular interaction decreases with aging

Simulations of dose enhancement for heavy atom nanoparticles irradiated by protons

A possible dose enhancement effect by proton or electron irradiation in the vicinity of nanoparticles consisting of different high Z atomic materials has been investigated using the track structure Monte Carlo code TRAX. In the simulations, Fe, Ag, Gd, Pt and Au nanoparticles (r = 22 and 2 nm) were irradiated with monoenergetic proton beams at energies of therapeutic interest (2, 80 and 300 MeV) and 44 keV electrons. Due to the large number of electrons in atoms with high atomic numbers, many electrons can be released in Auger cascades in addition to the primary ionization process. The potential additional nanoscopic radial dose contributions in the presence of metallic nanoparticles are assessed by comparison with liquid water and water simulated with the same density as the metallic materials. We find a noticeable impact of Auger electrons emitted from the nanoparticles. Special focus has been given to the assessment of complete sets of low-energy electron cross sections for the nanoparticle materials. © 2014 Institute of Physics and Engineering in Medicine

Advancing the modeling in particle therapy: From track structure to treatment planning

We present a series of implementations on Monte Carlo track structure level which might have an impact on treatment planning for particle therapy. We evaluated the effect of multiple ion scattering and radical diffusion on the nanoscopic radial dose. Our cross section database for electron interactions was extended to be able to predict the sensitizing effect of gold nanoparticles in particle therapy. We also implemented LiF as a possible target for efficiency calculations of thermoluminescent detectors (TLDs). © 2013 Elsevier Ltd

Low-energy electron transport in non-uniform media

We simulated the transport of low and medium energy electrons with energies between 1.26 eV and 10 keV in non-uniform carbon targets using the track structure Monte Carlo code TRAX which has several applications in biophysics and radiation physics. Cross sections for electrons incident on carbon have been critically assessed. Furthermore the code has been extended to handle non-uniform targets allowing a complex geometry description. Solid state targets, which are commonly used as targets in electron spectrometers and other devices can be non-uniform, e.g. have highly irregular surfaces or pinholes. The resulting electron spectra can be significantly affected by these non-uniformities. We reproduce experimental data obtained by GSI's Toroid electron spectrometer using thin solid state foils as targets. This unique experiment was designed to gain further insight in the emission and transport of low energy electrons in solids to improve the description of microscopic energy deposition. The realistic implementation of non-uniform targets in TRAX was verified by comparison with available experimental data. The increased backscattering due to the roughness of an unpolished target in comparison with polished ones could be reproduced as well as secondary electron spectra from the Toroid. © 2013 Elsevier B.V. All rights reserved

The antitumorigenic response of neural precursors depends on subventricular proliferation and age

Glioblastomas, the most aggressive primary brain tumors, occur almost exclusively in adult patients. Neural precursor cells (NPCs) are anti-tumorigenic in mice, as they can migrate to glioblastomas and induce tumor cell death. Here, we show that the anti-tumor effect of NPCs is age-dependently controlled by cell proliferation in the subventricular zone (SVZ) and that NPCs accumulating at a glioblastoma are diverted from their normal migratory path to the olfactory bulb. Experimentally induced cortical glioblastomas resulted in decreased subventricular proliferation in adult (postnatal day 90), but not in young (postnatal day 30) mice. Adult mice supplied less NPCs to glioblastomas and had larger tumors than young mice. Apart from the difference in proliferation, there was neither a change in cell number and death-rate in the SVZ nor in angiogenesis and immune cell-density in the tumors. The ability to kill glioblastomas was similar in NPCs isolated from young and adult mice. The proliferative response of NPCs to glioblastomas depended on the expression of D-type cyclins. In young mice, NPCs express the cyclins D1 and D2, but the expression of cyclin D1 is lost during aging and in adult NPCs only cyclin D2 remains. In young and adult cyclin D2-deficient mice we observed a reduced supply of NPCs to glioblastomas and the generation of larger tumors, as compared to wild-type mice. We conclude that cyclin D1 and D2 are non-redundant for the antitumor response of subventricular NPCs. Loss of a single D-type cyclin results in a smaller pool of proliferating NPCs, lower number of NPCs migrating to the tumor and reduced anti-tumor activity

Bone morphogenetic protein-7 release from endogenous neural precursor cells suppresses the tumourigenicity of stem-like glioblastoma cells

Glioblastoma cells with stem-like properties control brain tumour growth and recurrence. Here, we show that endogenous neural precursor cells perform an anti-tumour response by specifically targeting stem-like brain tumour cells. In vitro, neural precursor cells predominantly express bone morphogenetic protein-7; bone morphogenetic protein-7 is constitutively released from neurospheres and induces canonical bone morphogenetic protein signalling in stem-like glioblastoma cells. Exposure of human and murine stem-like brain tumour cells to neurosphere-derived bone morphogenetic protein-7 induces tumour stem cell differentiation, attenuates stem-like marker expression and reduces self-renewal and the ability for tumour initiation. Neurosphere-derived or recombinant bone morphogenetic protein-7 reduces glioblastoma expansion from stem-like cells by down-regulating the transcription factor Olig2. In vivo, large numbers of bone morphogenetic protein-7-expressing neural precursors encircle brain tumours in young mice, induce canonical bone morphogenetic protein signalling in stem-like glioblastoma cells and can thereby attenuate tumour formation. This anti-tumour response is strongly reduced in older mice. Our results indicate that endogenous neural precursor cells protect the young brain from glioblastoma by releasing bone morphogenetic protein-7, which acts as a paracrine tumour suppressor that represses proliferation, self-renewal and tumour-initiation of stem-like glioblastoma cells