Abstract IA5-3: HIFs, hypoxia, and tumor progression

Abstract

Abstract Hypoxia-inducible factor (HIF)-1α and −2α display unique and sometimes opposing activities in regulating cellular energy homeostasis, cell fate decisions, and oncogenesis. To fully characterize hypoxic adaptations, distinct functions of HIF-1α versus HIF-2α must be elucidated. Macrophages accumulate both HIF-αS under hypoxia, but HIF-2α overexpression in tumor-associated macrophages (TAMs) is specifically correlated with high-grade human tumors and poor prognosis. HIF-1α regulates myeloid-mediated inflammatory and antibacterial activities, in part through control of glycolysis and ATP production. However, the precise role of HIF-2α during macrophage-mediated inflammatory responses remained unclear. We demonstrate here that mice lacking myeloid HIF-2α are resistant to lipopolysaccharide-induced endotoxemia and display a marked inability to mount inflammatory responses to cutaneous and peritoneal irritants. Furthermore, HIF-2α directly regulates pro-inflammatory cytokine/chemokine expression in macrophages activated in vitro. Using independent murine hepatocellular and colitis-associated colon carcinoma models, we show that HIF-2α -deficient macrophages exhibit migratory defects associated with reduced tumor cell proliferation and progression. Of note, HIF-2α modulates macrophage migration by regulating the expression of cytokine receptor M-CSFR and chemokine receptor CXCR4, without altering intracellular ATP levels. Collectively, our data identify HIF-2α as an important regulator of innate immunity, suggesting it may be a useful therapeutic target for treating inflammatory disorders and cancer. Citation Information: Clin Cancer Res 2010;16(14 Suppl):IA5-3.