Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States.
Cellular and Molecular Biology and Medical Scientist Training Program, University of Michigan, Ann Arbor, Michigan, United States.
Am J Physiol Gastrointest Liver Physiol. 2024 Jan 1;326(1):G53-G66. doi: 10.1152/ajpgi.00182.2023. Epub 2023 Nov 7.
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 () or () 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. 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.
中性粒细胞是结肠肿瘤微环境中丰富的免疫细胞。研究表明，中性粒细胞被募集到结肠癌的缺氧焦点中。然而，缺氧信号对中性粒细胞功能的影响及其在结肠肿瘤发生中的作用仍不清楚。为了解决这个问题，我们生成了由 MRP8Cre 驱动的中性粒细胞中缺失缺氧诱导因子 (HIF)-1α 或 HIF-2α 的小鼠（）或（）及其同窝对照小鼠。在结直肠肿瘤的氧化偶氮甲烷 (AOM)/葡聚糖硫酸钠 (DSS) 模型中，中性粒细胞-HIF-1α 的缺失并没有导致体重、结肠长度、肿瘤大小、增殖或负担的任何显著变化。然而，与同窝对照相比，中性粒细胞中 HIF-2α 的缺失导致体重略有增加，肿瘤数量显著减少，肿瘤大小和体积减小。与对照小鼠相比，HIF-2α 缺陷中性粒细胞的结肠组织的组织学分析显示增殖明显减少。此外，我们观察到在肿瘤组织和中性粒细胞中，缺失中性粒细胞特异性 HIF-2α 的小鼠促炎细胞因子（如 TNF-α 和 IL-1β）的水平降低。重要的是，值得注意的是，与中性粒细胞中 HIF-2α 缺失相关的肿瘤发生减少在已建立的同基因肿瘤或 DSS 诱导的炎症模型中并不明显，表明 HIF-2α 可能在结肠肿瘤发生中具有特定作用。总之，我们发现缺失中性粒细胞特异性 HIF-2α 通过降低炎症介质的水平来减缓结肠肿瘤的生长和进展。尽管缺氧和中性粒细胞在结直肠癌 (CRC) 中很重要，但中性粒细胞特异性 HIFs 对结肠癌发生的贡献尚不清楚。我们描述了中性粒细胞 HIF-1α 对结肠癌没有影响，而中性粒细胞 HIF-2α 的缺失通过减少促炎和免疫抑制细胞因子来减少 CRC 的生长。此外，中性粒细胞 HIF-2α 不会减少已建立的肿瘤生长或炎症诱导的结肠炎。本研究为中性粒细胞 HIF-2α 作为 CRC 的治疗靶点提供了新的潜力。
