AbstractIntermittent hypoxia (IH), evidenced in solid tumours, positively influences the tumour growth by modulating the behaviour of cancer cells, but also of the endothelial cells (EC) from the tumour vasculature. The formation of the new tumour vasculature plays a critical role in tumour development and metastasis dissemination. However, the molecular mechanisms regulated by IH in these tumours, and more particularly in EC, remain still largely undetermined. In order to better understand the molecular mechanisms regulated by IH, we studied, during this thesis, the modifications of transcriptomic and proteomic expression in EC exposed to IH cycles in comparison to EC incubated under normoxia or continuous hypoxia. We showed that IH induces, in EC, the stabilization of HIF-1 alpha subunit as well as its phosphorylation, which is probably due, at least in part, to the Protein Kinase A (PKA) specifically activated by IH. The activity of the HIF-1 transcription factor is also increased under IH. This activity depends on the phosphorylation of HIF-1 alpha subunit by the PKA. We next evidenced, by a transcriptomic study, variations of the expression of gene known to favour angiogenic processes. This pro-angiogenic effect of IH was confirmed by the increase in EC migration. By the use of siRNA, we demonstrated the involvement of HIF-1 in the IH-induced increase in endothelial migration. Finally, we studied the changes induced by IH in the EC proteome. We identified some proteins, the expression of which varied under IH. Amongst these ones, we showed that NDRG1 and CRK-I/II are regulators of EC migration under IH. All these results show that IH favours angiogenic processes promoting EC activation and hence, the tumour vasculature and the tumour growth.
|Date of Award||30 Oct 2009|
|Supervisor||Carine Michiels (Supervisor), Martine Raes (President), Jean-Yves Matroule (Jury), Jean-Michel Dogne (Jury) & Olivier Feron (Jury)|
Effet de l'hypoxie intermittente sur l'expression génique et le phénotype angiogénique de cellules endothéliales
Toffoli, S. (Author). 30 Oct 2009
Student thesis: Doc types › Doctor of Sciences