Petruzzelli Michele, Ferrer Miriam, Schuijs Martijn J, Kleeman Sam O, Mourikis Nicholas, Hall Zoe, Perera David, Raghunathan Shwethaa, Vacca Michele, Gaude Edoardo, Lukey Michael J, Jodrell Duncan I, Frezza Christian, Wagner Erwin F, Venkitaraman Ashok R, Halim Timotheus Y F, Janowitz Tobias
Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK.
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Cancers (Basel). 2022 Feb 15;14(4):963. doi: 10.3390/cancers14040963.
An elevated neutrophil-lymphocyte ratio negatively predicts the outcome of patients with cancer and is associated with cachexia, the terminal wasting syndrome. Here, using murine model systems of colorectal and pancreatic cancer we show that neutrophilia in the circulation and multiple organs, accompanied by extramedullary hematopoiesis, is an early event during cancer progression. Transcriptomic and metabolic assessment reveals that neutrophils in tumor-bearing animals utilize aerobic glycolysis, similar to cancer cells. Although pharmacological inhibition of aerobic glycolysis slows down tumor growth in C26 tumor-bearing mice, it precipitates cachexia, thereby shortening the overall survival. This negative effect may be explained by our observation that acute depletion of neutrophils in pre-cachectic mice impairs systemic glucose homeostasis secondary to altered hepatic lipid processing. Thus, changes in neutrophil number, distribution, and metabolism play an adaptive role in host metabolic homeostasis during cancer progression. Our findings provide insight into early events during cancer progression to cachexia, with implications for therapy.
中性粒细胞与淋巴细胞比值升高对癌症患者的预后具有负面预测作用，且与恶病质（终末期消耗综合征）相关。在此，我们利用结直肠癌和胰腺癌的小鼠模型系统表明，循环系统和多个器官中的嗜中性粒细胞增多，伴有髓外造血，是癌症进展过程中的早期事件。转录组学和代谢评估显示，荷瘤动物中的中性粒细胞利用有氧糖酵解，类似于癌细胞。尽管对有氧糖酵解的药理学抑制减缓了C26荷瘤小鼠的肿瘤生长，但它会引发恶病质，从而缩短总生存期。这种负面影响可能可以通过我们的观察来解释，即恶病质前期小鼠中性粒细胞的急性耗竭会损害全身葡萄糖稳态，这是由于肝脏脂质处理改变所致。因此，中性粒细胞数量、分布和代谢的变化在癌症进展过程中对宿主代谢稳态起到适应性作用。我们的研究结果为癌症进展至恶病质的早期事件提供了见解，对治疗具有启示意义。
