Hypoxia-Associated GPNMB+ Macrophages Promote Malignant Progression of Colorectal Cancer and Its Related Risk Signature Are Powerful Predictive Tool for the Treatment of Colorectal Cancer Patients.

IF 4.4 3区 医学 Q2 ENVIRONMENTAL SCIENCES
Junli Zhang, Shangshang Hu, Xinxin Jin, Yiwen Zheng, Lianchen Yu, Junrao Ma, Biao Gu, Fen Wang, Wenjuan Wu
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Abstract

Colorectal cancer (CRC) is a highly malignant tumor with hypoxia being a crucial feature during its progression. This study utilized multiple independent CRC cohorts for bioinformatics analysis and in vitro experiments to investigate the role of hypoxia-related subgroups in CRC. Machine learning was employed to construct risk features associated with this subgroup and further explore its therapeutic value in CRC. The study identified the GPNMB+ Macrophage (GPNMB+ Macr) subgroup as most relevant to hypoxia. GPNMB+ Macr showed significantly higher infiltration in tumor tissues compared to non-tumor tissues, increasing with CRC stage. High infiltration of GPNMB+ Macr was associated with poor prognosis in terms of overall and recurrence-free survival in CRC patients. GPNMB+ Macrophages exhibit M2-like characteristics and have the ability to promote 5-FU resistance, proliferation, and metastasis of CRC cells. The study developed the Hypoxia-Related Macrophage Risk Score (HMRS), which not only served as an independent prognostic factor for CRC patients but also demonstrated robust prognostic performance compared to 84 previously published prognostic features. Patients with low HMRS were sensitive to fluorouracil, oxaliplatin (FOLFOX), and anti-PD-1 immunotherapy, while those with high HMRS showed resistance. Additionally, HMRS was identified as an independent prognostic factor in other digestive tract tumors (hepatocellular carcinoma, pancreatic cancer, esophageal cancer, and gastric cancer), indicating potential extrapolation to other tumor types. In conclusion, GPNMB+ Macr promotes the malignant progression of CRC, and HMRS serves as a powerful predictive tool for prognosis, chemotherapy, and immunotherapy in CRC patients, aiding in improving the quality of survival.

缺氧相关 GPNMB+ 巨噬细胞促进结直肠癌恶性进展及其相关风险特征是治疗结直肠癌患者的有力预测工具
结直肠癌(CRC)是一种高度恶性肿瘤,缺氧是其发展过程中的一个关键特征。本研究利用多个独立的 CRC 队列进行生物信息学分析和体外实验,研究缺氧相关亚群在 CRC 中的作用。该研究利用机器学习构建了与该亚群相关的风险特征,并进一步探讨了其在 CRC 中的治疗价值。研究发现,GPNMB+巨噬细胞(GPNMB+ Macr)亚群与缺氧最相关。与非肿瘤组织相比,GPNMB+ Macr在肿瘤组织中的浸润率明显更高,并随着CRC分期的增加而增加。GPNMB+ Macr的高浸润与CRC患者总生存期和无复发生存期的不良预后有关。GPNMB+巨噬细胞具有M2样特征,能促进CRC细胞对5-FU的耐药性、增殖和转移。该研究制定了缺氧相关巨噬细胞风险评分(HMRS),它不仅是 CRC 患者的独立预后因素,而且与之前发表的 84 个预后特征相比,表现出了强大的预后性能。HMRS低的患者对氟尿嘧啶、奥沙利铂(FOLFOX)和抗PD-1免疫疗法敏感,而HMRS高的患者则表现出耐药性。此外,在其他消化道肿瘤(肝癌、胰腺癌、食管癌和胃癌)中,HMRS也被确定为一个独立的预后因素,这表明它有可能被推广到其他类型的肿瘤中。总之,GPNMB+ Macr 会促进 CRC 的恶性进展,而 HMRS 则是预测 CRC 患者预后、化疗和免疫治疗的有力工具,有助于提高患者的生存质量。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Environmental Toxicology
Environmental Toxicology 环境科学-毒理学
CiteScore
7.10
自引率
8.90%
发文量
261
审稿时长
4.5 months
期刊介绍: The journal publishes in the areas of toxicity and toxicology of environmental pollutants in air, dust, sediment, soil and water, and natural toxins in the environment.Of particular interest are: Toxic or biologically disruptive impacts of anthropogenic chemicals such as pharmaceuticals, industrial organics, agricultural chemicals, and by-products such as chlorinated compounds from water disinfection and waste incineration; Natural toxins and their impacts; Biotransformation and metabolism of toxigenic compounds, food chains for toxin accumulation or biodegradation; Assays of toxicity, endocrine disruption, mutagenicity, carcinogenicity, ecosystem impact and health hazard; Environmental and public health risk assessment, environmental guidelines, environmental policy for toxicants.
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