No reason to reconsider HIF-2 as an oncogene in neuroblastoma and other cancer forms

Westerlund et al. (1) conclude that HIF-2α is linked to neuroblastoma suppression, contradicting several previous observations and current views of the role of HIF-2 in tumorigenesis. We believe that their conclusions are based on flawed cellular models and inappropriate interpretations of their own and public neuroblastoma expression data, as detailed below. First, HIF proteins are continuously translated but instantly degraded at oxygenated conditions, leading to weak correlation between mRNA and protein levels (2, 3). Given this general mechanism of HIF activation, it is surprising that Westerlund et al. challenge existing models of HIF-2 without examining tumor specimens at the cellular level or HIF-2α expression at the protein level. By analyzing total tumor EPAS1 mRNA, the authors fail to address the fact that most EPAS1/HIF-2α is likely derived from nontumorous cells such as tumor-associated macrophages (4). Supporting this notion and likely explaining the …