HIF2α cooperates with RAS to promote lung tumorigenesis in mice

The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization

“…Mice conditionally expressing a non-degradable HIF-2α and mutated Kras (Kras G12D ) in the lungs display severe tumor burden and decreased survival, compared to mice expressing Kras G12D only, suggesting that HIF-2α play a pivotal role in lung cancer pathogenesis (Kim et al 2009b). In agreement with a role of HIF-2α in NSCLC tumorigenesis, HIF-2α in clinical material was an independent prognostic marker with high protein expression correlating to poor outcome (Giatromanolaki et al 2001).…”

“…Importantly, and the reason for the focus on HIF-2α in this review, HIF-1α and HIF-2α are differently regulated in tumors such as neuroblastoma, breast cancer, non-small cell lung carcinoma (NSCLC) and glioma and seem to have different impact on tumor behavior and patient outcome in these tumors (Holmquist-Mengelbier et al 2006;Helczynska et al 2008;Heddleston et al 2009;Kim et al 2009b;Li et al 2009;Noguera et al 2009). …”

The Inflammatory Tumor Microenvironment, Epithelial Mesenchymal Transition and Lung Carcinogenesis

“…Although hypoxia has traditionally been viewed as a consequence of malignant tumor growth, it is now widely appreciated to play a critical role in the development and progression of tumors [63,64,67]. Hypoxia is associated with increased resistance to conventional radiation and chemotherapy, and not surprisingly, correlates with poor clinical prognosis in many cancer types, including breast, pancreatic and NSCLC [63,64,67].…”

“…Hypoxia is associated with increased resistance to conventional radiation and chemotherapy, and not surprisingly, correlates with poor clinical prognosis in many cancer types, including breast, pancreatic and NSCLC [63,64,67]. The central mediator of the canonical cellular response to reduced oxygen levels is the basic helix-loop-helix heterodimeric transcription factor hypoxia-inducible factor (HIF)-1, which consists of a constitutively expressed β subunit (also known as aryl hydrocarbon receptor nuclear translocator) and an oxygenregulated α subunit.…”

“…When oxygen is limited, hydroxylation of HIF-1α is inhibited, resulting in stabilization and translocation of HIF-1α into the nucleus, where it heterodimerizes with HIF-1β to form active HIF-1 transcription factor. Following recruitment of numerous coactivators, the HIF complex binds to hypoxia-response elements (HREs) in target genes to regulate a number of pathways including cell survival, proliferation, extracellular matrix remodeling, angiogenesis and apoptosis, consequently promoting tumor invasion and metastasis [63,64,67].…”