Swales, A.G.; (2011) The role of neural stem cells in tumourigenesis of the central nervous system. Doctoral thesis , UCL (University College London).

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Abstract

To develop targeted brain tumour therapies that carry fewer side effects it is essential to understand brain tumour histogeneiss and identify the cell of origin. It has been suggested that neoplastic transformation of neural stem/progenitor cells in the adult brain can result in the development of intrinsic brain tumours. Using the Cre-LoxP system we have developed a model that allows us to inactivate tumour suppressor genes Rb, p53 and PTEN in neural stem/progenitor cells both in vivo and in vitro. In vivo recombination of these tumour suppressor genes in neural stem/progenitor cells resulted in the formation of intrinsic brain tumours, with the phenotype depending on the combination of recombined genes. Intracerebral engraftment of in vitro recombined neural stem/progenitor cells produced a similar tumour phenotype pattern. However, while in vivo recombination of Rb and p53 frequently caused brain tumours, in vitro recombined and engrafted Rb-/-; p53-/- neurospheres rarely generated tumours. The converse was true following in vivo recombination of Rb and PTEN. These results suggest that microenvironment influences tumour formation. An increased number of tumourigenic neural stem/progenitor cells expressed the cancer stem cell marker CD133 when compared to control cells. In vivo engraftment of purified CD133+ Rb-/-; p53-/-; PTEN-/- neural stem/progenitor cells resulted in the preferential development of gliomas. We also showed that astrocytes are not capable of forming tumours following either orthotopic recombination or in vitro recombination and engraftment. In conclusion, we found that (i) certain phenotypes of brain tumours develop from neural stem/progenitor cells in the subventricular zone, (ii) the combination of inactivated tumour suppressor genes is the most significant but not sole determinant of in vitro functional profile and behaviour in vivo, (iii) the cellular microenvironment of neural stem/progenitor cells influences their tumourigenic profile, and (iv) terminally differentiated astrocytes do not contribute to tumour development in this model.

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