Qi Lina, Chen Jiani, Yang Yanmei, Hu Wangxiong
Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Key Laboratory of Reproductive and Genetics, Ministry of Education, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Front Oncol. 2020 Nov 20;10:566430. doi: 10.3389/fonc.2020.566430. eCollection 2020.
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.
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 Prognosis, molecular signatures, pathways, and tumor-infiltrating lymphocytes were compared between the subtypes.
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 mutation. More M2 macrophage infiltration was another hypoxic marker indicated that subsets of patients with high M2 macrophages may benefit from macrophage-targeting therapy.
These findings will facilitate the development of a hypoxia-oriented therapy strategy to enhance the treatment effect in the near future.
肿瘤组织中的氧水平显著低于相邻正常组织，即所谓的缺氧，这一点已被广泛接受。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、乳腺和肺癌等几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，建立了一个由总共356个基因组成的缺氧特征，包括典型的缺氧反应基因ADM、ANGPTL4、CA9和VEGFA。四个独立队列中的总共1730份CRC样本用于比较亚型之间的预后、分子特征、信号通路和肿瘤浸润淋巴细胞。
CRC主要分为两个亚组，一个被标记为缺氧组，另一个被标记为常氧组。缺氧与CRC的不良预后相关，并会将一部分II期患者的风险增加到常氧III期的水平。此外，缺氧与RAS信号通路的激活密切相关，与突变无关。更多的M2巨噬细胞浸润是另一个缺氧标志物，表明高M2巨噬细胞亚组的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。
