Abstract C67: Hypoxia-inducible factor-2α regulates macrophage functions in both acute and tumor inflammation

Abstract

Abstract Hypoxia and inflammation in the tumor microenvironment profoundly influence carcinogenesis and tumor progression. In order to connect hypoxic signaling to inflammatory responses and their roles in oncogenesis, we investigated how one of the master regulators of hypoxic hypoxia-inducible factor (HIF)-2α, adaptations, regulates macrophage functions in both acute inflammatory diseases and cancer (a disease involving various inflammatory components). Myeloid-specific deletion of HIF-2α results in defective expression of a panel of proinflammatory cytokines in macrophages responding to innate stimuli. Also, mice lacking myeloid HIF-2α are resistant to lipopolysaccharide-induced endotoxemia and display a marked inability to mount inflammation in response to several other acute irritants, revealing that this transcription factor is essential for macrophage inflammatory responses. Tumor-associated macrophages (TAMs) represent the major inflammatory cell type within tumors and HIF-2α is robustly expressed in these cells. Clinically, increased TAM HIF-2α level correlates with high tumor grade and poor prognosis in breast and uterine cervical cancer, respectively. To characterize roles of HIF-2α in TAMs, we induced hepatocellular carcinoma (HCC) and colitis-associated cancer (CAC), two established inflammation-associated tumor models, in mice lacking myeloid HIF-2α expression. Interestingly, we found that HIF-2α -deficient TAMs migrate less efficiently into tumors, leading to reduced tumor cell proliferation and decreased malignancy in mutant mice. Further studies revealed that the deficient macrophages were attributable to compromised migration capacity of HIF-2α to insufficient expression of M-CSF receptor, CXCR4 and extracellular fibronectin-1. Therefore, our study demonstrated HIF-2α as an important regulator in both acute inflammation and cancer, suggesting that the myeloid HIF-2α pathway could be exploited as therapeutic targets for treating these diseases. Citation Information: Cancer Res 2009;69(23 Suppl):C67.