IGF, PI3K and HIF-2 in Normal and Tumor Development

Abstract: Cells adapt to oxygen shortage, hypoxia, by inducing a transcriptional shift governed mainly by Hypoxia Inducible Factor (HIF)-1 and HIF-2. In various cancer forms, including neuroblastoma, high expression of HIF-2α correlates with disseminated disease and poor outcome. It has become evident that HIF-1 and HIF-2 are differentially regulated over time and by oxygen levels. HIF-2α is expressed in a subset of perivascularly located neuroblastoma cells in vivo and appear to be co-expressed with markers of early sympathetic nervous system development, while HIF-1α expression is restricted to necrotic and hypoxic tumor areas. Here, we demonstrate that HIF-2α is regulated at the transcriptional level by the IGF and PI3K signaling pathways, two pathways commonly deregulated in human cancer. In addition, the expression of HIF-2α and IGF-II correlates in neuroblastoma specimens and cell lines, and the finding that HIF-2α and IGF-II are co-expressed in sympathetic neuroblasts during early human development (embryonic week 6.5) suggest that neuroblastoma cells are arrested at a differentiation stage corresponding to when sympathetic chain ganglia begin to coalesce. We further show that the differential regulation of HIF-1α and HIF-2α in neuroblastoma partly can be explained by specific IGF and PI3K-mTOR signaling. While HIF-1α is exclusively regulated at the translational level via mTOR complex 1 (mTORC1) at hypoxia, HIF-2α is regulated at the transcriptional level by mTORC2, providing an opportunity to specifically target the HIF-2α-driven aggressive phenotype in neuroblastoma. At last, PI3K is composed of a regulatory and a catalytic domain, and we highlight the complexity of this signaling pathway by identifying the catalytic subunit, p110δ, responsible for c-Kit mediated cell transformation, and the process of kinase-dependent and –independent activation.