Disruption of hypoxia-inducible factor-2 in neutrophils decreases colitis-associated colon cancer

Neutrophils are abundant immune cells in the colon tumor microenvironment. Studies have shown that neutrophils are recruited into hypoxic foci in colon cancer. However, the impact of hypoxia signaling on neutrophil function and its involvement in colon tumorigenesis remain unclear. To address this, we generated mice with a deletion of hypoxia-inducible factor (HIF)-1 alpha or HIF-2 alpha in neutrophils driven by the MRP8Cre (HIF-1 alpha(Delta Neu)) or (HIF-2 alpha(Delta Neu)) and littermate controls. In an azoxymethane (AOM)/dextran sulfate sodium (DSS) model of colon cancer, the disruption of neutrophils-HIF-1 alpha did not result in any significant changes in body weight, colon length, tumor size, proliferation, or burden. However, the disruption of HIF-2 alpha in neutrophils led to a slight increase in body weight, a significant decrease in the number of tumors, and a reduction in tumor size and volume compared with their littermate controls. Histological analysis of colon tissue from mice with HIF-2 alpha-deficient neutrophils revealed notable reductions in proliferation as compared with control mice. In addition, we observed reduced levels of proinflammatory cytokines, such as TNF-alpha and IL-1 beta, in neutrophil-specific HIF-2 alpha-deficient mice in both the tumor tissue as well as the neutrophils. Importantly, it is worth noting that the reduced tumorigenesis associated with HIF-2 alpha deficiency in neutrophils was not evident in already established syngeneic tumors or a DSS-induced inflammation model, indicating a potential role of HIF-2 alpha specifically in colon tumorigenesis. In conclusion, we found that the loss of neutrophil-specific HIF-2 alpha slows colon tumor growth and progression by reducing the levels of inflammatory mediators.NEW & NOTEWORTHY Despite the importance of hypoxia and neutrophils in colorectal cancer (CRC), the contribution of neutrophil-specific HIFs to colon tumorigenesis is not known. We describe that neutrophil HIF-1 alpha has no impact on colon cancer, whereas neutrophil HIF-2 alpha loss reduces CRC growth by decreasing proinflammatory and immunosuppressive cytokines. Furthermore, neutrophil HIF-2 alpha does not reduce preestablished tumor growth or inflammation-induced colitis. The present study offers novel potential of neutrophil HIF-2 alpha as a therapeutic target in CRC.