Hypoxia Correlates With Poor Survival and M2 Macrophage Infiltration in Colorectal Cancer.
Hypoxia Correlates With Poor Survival and M2 Macrophage Infiltration in Colorectal Cancer.
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缺氧与结直肠癌存活率低和 M2 巨噬细胞浸润相关
DOI：
10.3389/fonc.2020.566430
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发表时间：
2020
影响因子：
4.7
通讯作者：
Hu W
中科院分区：
文献类型：
--
作者：
Qi L;Chen J;Yang Y;Hu W
人们普遍认为，肿瘤组织中的氧含量明显低于相邻的正常组织，因此被称为缺氧。肿瘤内缺氧是癌症进展、复发、转移和生存率降低的主要驱动力。尽管在头颈部癌、乳腺癌和肺癌等多种癌症类型中，已经建立了多种反映细胞对缺氧复杂反应的基因特征，但结直肠癌（CRC）中的缺氧全貌仍知之甚少。
通过系统的文献检索，建立了一个由356个基因组成的缺氧特征，其中包括典型的缺氧反应基因肾上腺髓质素（ADM）、血管生成素样蛋白4（ANGPTL4）、碳酸酐酶9（CA9）和血管内皮生长因子A（VEGFA）。来自四个独立队列的共1730例结直肠癌样本被用于非负矩阵分解聚类和分型。对各亚型之间的预后、分子特征、信号通路和肿瘤浸润淋巴细胞进行了比较。
结直肠癌主要分为两个亚组，一个为缺氧组，另一个为常氧组。缺氧与结直肠癌预后不良相关，会使部分Ⅱ期患者的风险升高至常氧Ⅲ期患者的水平。此外，缺氧与RAS信号通路的激活密切相关，且不依赖于KRAS突变。更多的M2巨噬细胞浸润是另一个缺氧标志物，这表明M2巨噬细胞水平高的部分患者可能从巨噬细胞靶向治疗中获益。
这些发现将有助于在不久的将来制定以缺氧为导向的治疗策略，以提高治疗效果。
Background It is widely accepted that the oxygen level in tumor tissue is significantly lower than the adjacent normal tissue, thus termed hypoxia. Intratumoral hypoxia represents a major driving force in cancer progression, recurrence, metastasis, and decreased survival. Though multiple gene signatures reflect the complex cellular response to hypoxia have been established in several cancer types such as head and neck, breast, and lung cancers, the hypoxic panorama in colorectal cancer (CRC) remains poorly understood. Methods A hypoxic signature constituted by a total of 356 genes, including canonical hypoxia-responsive ADM, ANGPTL4, CA9, and VEGFA, was established based on systemic literature search. A total of 1,730 CRC samples across four independent cohorts were used for nonnegative matrix factorization clustering and subtyping. Prognosis, molecular signatures, pathways, and tumor-infiltrating lymphocytes were compared between the subtypes. Results CRCs mainly fell into two subgroups, one indicated as hypoxia and the other one designated as normoxia. Hypoxia was correlated with poor outcomes in CRC and will increase the risk of a subset of stage II patients to the level of normoxic stage III. Additionally, hypoxia was closely associated with activation of RAS signaling pathway independent of KRAS mutation. More M2 macrophage infiltration was another hypoxic marker indicated that subsets of patients with high M2 macrophages may benefit from macrophage-targeting therapy. Conclusions These findings will facilitate the development of a hypoxia-oriented therapy strategy to enhance the treatment effect in the near future.
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