Brain tumors are the second most common tumor type in children after leukemia. The outcome of the patients has become more favorable over the past few decades due to improved treatment modalities. Nowadays, the 5-year prognosis is from less than 60% to 90% depending on the tumor type. Nevertheless, the tumor itself and its treatment reduce quality of life, increase the risk of being handicapped, and raise expenses. Novel treatment modalities are under intense investigation, although a major breakthrough has yet to be discovered.
The aim of this thesis was to find new molecules to be used in the process of diagnosing and evaluating the predictivity, prognosis and follow-up of children with the most common pediatric brain tumors, including pilocytic astrocytomas, ependymomas, medulloblastomas (MBS), and primitive neuroectodermal tumors (PNETs). In this thesis, antioxidative enzymes were investigated in pilocytic astrocytomas and ependymomas, as well as peroxiredoxins in pilocytic astrocytomas. In addition, the role of carbonic anhydrases was studied in medulloblastomas and PNETs. Finally, claudins were analysed in ependymomas.
The first study analysed the antioxidative enzymes (AOEs), including manganese superoxide dismutase (MnSOD), gamma glutamyl cysteinyl synthetase catalytic and regulatory subunits (GLCL-C, GLCL-R), thioredoxin (Trx), thioredoxin reductase (TrxR) and peroxiredoxins (Prx) I-VI in a series of 105 pilocytic astrocytomas. All of them were expressed in pilocytic astrocytomas, suggesting that oxidative damage and consequent defence take place during the progression of the tumors. AOEs correlated with the degenerative features and angiogenesis, possibly associating with reactive oxygen species-derived cellular damage. Moreover, the expression of the AOEs was associated with each other in terms of concurrent activation of the enzymes. With the exception of MnSOD, a strong expression of AOEs was generally associated with higher cell proliferation. Prx VI seemed to have a positive association with a longer recurrence-free interval.
The second study investigated the relationship between AOE (MnSOD, GLCL-C, GLCL-R, Trx, TrxR) expression and clinicopathological features in 67 ependymal tumors. Most of the tumors expressed AOEs. Lower GLCL-C and GLCL-R expression was associated with higher tumor grade. MnSOD, GLCL-C and TrxR expressions were significantly higher in tumors located in the spinal cord compared with those in the brain. Interestingly, decreased expression of Trx predicted worse outcome for the patients. This finding may have clinical relevance when planning treatment modalities and follow-up for patients.
The aim of the third study was to analyse the expression of carbonic anhydrases (CAs) II, IX, and XII in a set of 39 medulloblastomas and PNETs. Interestingly, CA II was expressed in both the neovessel endothelium and tumour cell cytoplasm. CA IX was mainly expressed in the tumor cells located in perinecrotic areas. CA XII showed the most homogenous distribution within the tumors. Importantly, CA IX expression predicted poor prognosis in both univariate and multivariate analyses. CA IX has been previously found to be a promising target molecule for anticancer treatment in other tumors. The results suggest that this could also be the case for medulloblastomas and PNETs.
In the fourth study, expression of claudins (CLDNs) 2-5, 7, and 10 was investigated in a set of 61 ependymomas. According to the results, all CLDNs except for CLDN4 were expressed in these tumors. CLDN5 was related to more aggressive tumors compared with CLDN2 and 10. Tumors expressing these two claudins displayed a better degree of differentiation and a better prognosis. There were also differences in the expression of claudins associated with location of the tumor and between primary and recurrent tumors, CLDNs 3 and 5 were more often found in the cerebrum than in other sites and CLDN7 in primary tumors compared with recurrent ones. Evidently claudins influence the growth and differentiation in ependymomas.
In summary, the studied antioxidative enzymes, peroxiredoxins, carbonic anhydrases, and claudins were expressed in the most common pediatric brain tumors, including pilocytic astrocytomas, ependymomas, medulloblastomas, and PNETs. Prx VI was associated with longer recurrence-free interval in patients with pilocytic astrocytoma, whereas decreased Trx expression predicted worse prognosis of patients with ependymoma. CA IX correlated with worse outcome in patients with medulloblastoma or PNET. Claudins had no significant association with prognosis, nevertheless CLDN5 was related to more aggressive ependymomas.
