HIF2α reduces growth rate but promotes angiogenesis in a mouse model of neuroblastoma

Background: HIF2 alpha/EPASI is a hypoxia-inducible transcription factor involved in catecholamine homeostasis, vascular remodelling, physiological angiogenesis and adipogenesis. It is overexpressed in many cancerous tissues, but its exact role in tumour progression remains to be clarified. Methods: In order to better establish its function in tumourigenesis and tumour angiogenesis, we have stably transfected mouse neuroblastoma NIE-115 cells with the native form of HIF2 alpha or with its dominant negative mutant, HIF2a (1 - 485) and studied their phenotype in vitro and in vivo. Results: In vitro studies reveal that HIF2a induces neuroblastoma cells hypertrophy and decreases their proliferation rate, while its inactivation by the HIF2a (1 - 485) mutant leads to a reduced cell size, associated with an accelerated proliferation. However, our in vivo experiments show that subcutaneous injection of cells overexpressing HIF2a into syngenic mice, leads to the formation of tumour nodules that grow slower than controls, but that are well structured and highly vascularized. In contrast, HIF2a (1 - 485)- expressing neuroblastomas grow fast, but are poorly vascularized and quickly tend to extended necrosis. Conclusion: Together, our data reveal an unexpected combination between an antiproliferative and a pro-angiogenic function of HIF2a that actually seems to be favourable to the establishment of neuroblastomas in vivo.