Immunotherapy and chemotherapy are major strategies in current cancer treatments. In the first half of this thesis, a new way of antigen cross-presentation from apoptotic cells to APCs, mediated by... Show moreImmunotherapy and chemotherapy are major strategies in current cancer treatments. In the first half of this thesis, a new way of antigen cross-presentation from apoptotic cells to APCs, mediated by gap junctions, is described. And potential anti-tumor applications of gap junction mediated antigen cross-presentation are discussed in the context of the current knowledge. In the second half of this thesis, an unexpected novel mechanism of action__selective induction of histone eviction__is described, which could explain the long standing clinical observation that anthracycline members, like doxorubicin, daunorubicin and aclarubicin, are efficient but with long term side-effects such as cardiotoxicity Show less
There is an urgent need for a better and more effective therapy for neuroblastoma, a pediatric tumor of the sympathetic nervous system. Despite intensive treatment, less than 50 % of the patients... Show moreThere is an urgent need for a better and more effective therapy for neuroblastoma, a pediatric tumor of the sympathetic nervous system. Despite intensive treatment, less than 50 % of the patients with high-risk neuroblastoma survive. Therefore we have investigated if doublecortin-like kinase is a potential therapeutic target for neuroblastoma. Doublecortin-like kinase (DCLK1) gene encodes doublecortin-like (DCL) and DCLK-long that are crucial for correct proliferation and differentiation of neuroblasts. We found that these proteins are overexpressed in human neuroblastomas and gliomas but not in other tumors or normal tissue. DCL/DCLK-long knockdown in mouse and human neuroblastoma cells resulted in apoptotic cell death. We also found that DCL is involved in the control of mitochondrial activity, energy production and neuroblastoma cell proliferation. In vivo, we observed delayed tumor growth in neuroblastoma tumor xenografts with inducible DCL knockdown. Moreover, we showed that combining DCL/DCLK-long knockdown with low doses of vinca alkaloids results in a synergistic apoptotic effect, confirming that this is a potential approach to consider for neuroblastoma therapy. In conclusion, the data presented in this thesis provide new insights in the biological function of the DCLK1 gene and indicate that DCL and DCLK-long are potential therapeutic targets for neuroblastoma. Show less
Cells in the human body have to deal with DNA damage daily, either caused by external or internal sources. The DDR is particularly strong in stem cells. Since these cells have a long life span and... Show moreCells in the human body have to deal with DNA damage daily, either caused by external or internal sources. The DDR is particularly strong in stem cells. Since these cells have a long life span and are essential for tissue homeostasis, tolerance to damaged DNA would lead to accumulation of mutations and malignant transformation. In addition, accumulation of damaged DNA would lead to loss of the stem cell pool and contribute to aging. In this thesis I investigated the role of the DNA damage response in the context of stem cells as well as cancer cells, from the response to different DNA damaging agents, to the importance of the interaction with the extracellular matrix in combination with the presence of oncogenes. In order to acquire a complete picture of the DNA damage response in mES cells, and therefore elucidate novel pathways involved in this particular response, we combined OMICS techniques such as Functional Genomics, Transcriptomics and Phosphoprotoemics, that once overlapped, allowed us to find novel pathways that where not previously described to be involved in the DNA damage response. Show less
In 1997, Danen-Van Oorschot et al. described for the first time that apoptin, a protein encoded by an avian virus, induces p53-independent apoptosis in a tumor-specific way. Various pre-clinical... Show moreIn 1997, Danen-Van Oorschot et al. described for the first time that apoptin, a protein encoded by an avian virus, induces p53-independent apoptosis in a tumor-specific way. Various pre-clinical studies in animal tumor models have demonstrated apoptin as a safe and efficient anti-tumor agent. In tumor cells, apoptin is imported into the nucleus prior to the induction of apoptosis and regulated by a kinase activity specifically present in cancer cells. In this thesis, several studies have been carried out to reveal the novel aspects of the molecular pathways underlying the transformation-related apoptosis induction by the viral protein apoptin. Show less
