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)-1α or HIF-2α in neutrophils driven by the MRP8Cre (HIF-1αΔNeu) or (HIF-2αΔNeu) and littermate controls. In an
azoxymethane (AOM)/
dextran sulfate sodium (DSS) model of
colon cancer, the disruption of neutrophils-HIF-1α did not result in any significant changes in
body weight, colon length,
tumor size, proliferation, or burden. However, the disruption of HIF-2α 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-2α-deficient neutrophils revealed notable reductions in proliferation as compared with control mice. In addition, we observed reduced levels of proinflammatory
cytokines, such as TNF-α and IL-1β, in neutrophil-specific HIF-2α-deficient mice in both the
tumor tissue as well as the neutrophils. Importantly, it is worth noting that the reduced
tumorigenesis associated with HIF-2α deficiency in neutrophils was not evident in already established syngeneic
tumors or a DSS-induced
inflammation model, indicating a potential role of HIF-2α specifically in colon
tumorigenesis. In conclusion, we found that the loss of neutrophil-specific HIF-2α 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-1α has no impact on
colon cancer, whereas neutrophil HIF-2α loss reduces CRC growth by decreasing proinflammatory and immunosuppressive
cytokines. Furthermore, neutrophil HIF-2α does not reduce preestablished
tumor growth or
inflammation-induced
colitis. The present study offers novel potential of neutrophil HIF-2α as a therapeutic target in CRC.