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Title: The mitochondrial translocator protein in human gliomas
Author: Janczar, Karolina
ISNI:       0000 0004 2686 3314
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2010
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The translocator protein (TSPO) is an 18 kDa molecule spanning the outer mitochondrial membrane. Structural predictions, reported physical interactions and experimental data from diverse models suggest that TSPO is involved in apoptosis, proliferation and steroidogenesis. TSPO is up-regulated in several human cancers and its high levels are frequently associated with advanced disease and poor outcome. TSPO was shown to be up-regulated in astrocytomas and this was correlated with high tumour grade and shorter patient survival. Here it is confirmed that TSPO is highly expressed in astrocytomas and this is correlated with tumour grade. TSPO expression is significantly higher in astrocytic tumours than in oligodendrogliomas and this differential expression is epigenetically driven. Low TSPO expression in oligodendrogliomas is associated with frequent promoter methylation, whereas in astrocytomas, where TSPO is expressed at high levels, the promoter typically remains unmethylated. As oligodendrogliomas and astrocytomas have very different biology and prognosis, and several TSPO ligands, including those enabling positron emission tomography (PET) scanning, are in development, we propose pre-operative PET imaging to differentiate these two histotypes. TSPO is not an independent prognostic factor in our patient population. The main cell population expressing TSPO within the tumour bulk are neoplastic cells. Consistent with no evidence for TSPO as a strong prognostic factor in gliomas, no alteration in proliferation, cell cycle progression and baseline or induced apoptosis following TSPO siRNA knock-down in an in vitro astrocytoma model is demonstrated. Furthermore, there was no evidence of cortisol production by several astrocytoma cell lines in vitro despite TSPO protein expression. Out of the examined MPTP-related binding and functional partners of TSPO (VDAC1, ANT, HK I and II) only HKII up-regulation appears be reproducibly related to patient outcome in gliomas. Consistently, targeting hexokinases in vitro in a glioma model inhibited proliferation and increased apoptosis.
Supervisor: Roncaroli, Federico Sponsor: Brain Tumour Research Campaign
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral