Carotid body tumors (CBTs) are rare tumors with a 1–2 incidence per 100,000 individuals. CBTs may initially present without apparent symptoms, and symptoms begin to arise since tumors grow bigger to compress surrounding tissue, such as recurrent laryngeal nerve and esophagus. Also, the etiology of CBTs remains unclear since it is more likely to occur in those who live in high-altitude areas or suffer from chronic hypoxic diseases such as COPD. SDH mutations and familial inheritance have been reported to be related to CBTs. SDH complexes play crucial roles in aerobic respiration, and SDH mutations in CBTs have been reported to be associated with hypoxia. Hypoxic signaling pathways, specifically hypoxic markers, have attracted more research attention in tumor exploration. However, the existing literature on these signaling and markers lacks a systematic review. Also, therapeutic approaches in CBTs based on hypoxic signaling are rarely used in clinics. In this review, we concluded the role of hypoxic signaling and markers and their potential implications in the initiation and progression of CBTs. Our findings underscore the involvement of the SDH family, the HIF family, VEGFs, and inflammatory cytokines (ICs) in tumorigenesis and treatment. Of particular interest is the role played by SDHx, which has recently been linked to oxygen sensing through mutations leading to hereditary CBTs. Among the SDH family, SDHB and SDHD exhibit remarkable characteristics associated with metastasis and multiple tumors. Besides SDH mutations in CBTs, the HIF family also plays crucial roles in CBTs via hypoxic signaling pathways. The HIF family regulates angiogenesis during mammalian development and tumor growth by gene expression in CBTs. HIF1α could induce the transcription of pyruvate dehydrogenase kinase 1 (PDK1) to inhibit pyruvate dehydrogenase kinase (PDH) by inhibiting the TCA cycle. Then, carotid body cells begin to hyperplasia and hypertrophy. At the same time, EPAS1 mutation, an activating mutation, could decrease the degradation of HIF2α and result in Pacak–Zhuang syndrome, which could result in paraganglioma. HIFs can also activate VEGF expression, and VEGFs act on Flk-1 to control the hyperplasia of type I cells and promote neovascularization. ICs also play a pivotal signaling role within the CB, as their expression is induced under hypoxic conditions to stimulate CB hyperplasia, ultimately leading to CBTs detecting hypoxic areas in tumors, and improving the hypoxic condition could enhance photon radiotherapy efficacy. Moreover, this review offers valuable insights for future research directions on understanding the relationship between hypoxic signaling pathways and CBTs.
颈动脉体瘤（CBTs）是一种罕见肿瘤，发病率约为每10万人中1-2例。CBTs初期可能无明显症状，随着肿瘤增大压迫周围组织（如喉返神经和食管）后症状逐渐显现。目前其病因尚未完全明确，但多见于高海拔地区居民或患有慢性缺氧性疾病（如慢性阻塞性肺疾病）的人群。研究表明SDH基因突变和家族遗传与CBTs相关。SDH复合体在有氧呼吸中起关键作用，而CBTs中的SDH突变已被证实与缺氧相关。在肿瘤研究中，缺氧信号通路特别是缺氧标志物日益受到关注，但现有文献缺乏对这些信号通路和标志物的系统性综述。同时，基于缺氧信号通路的CBTs治疗方法在临床中应用甚少。本综述系统阐述了缺氧信号通路及标志物的作用机制，及其在CBTs发生发展中的潜在影响。研究发现SDH家族、HIF家族、VEGFs及炎症细胞因子（ICs）在肿瘤发生和治疗中具有重要作用。值得注意的是，SDHx基因通过突变导致遗传性CBTs，近期研究揭示其与氧感知功能相关。在SDH家族中，SDHB和SDHD基因表现出与肿瘤转移和多发性肿瘤密切相关的特征。除SDH突变外，HIF家族也通过缺氧信号通路在CBTs中发挥关键作用。该家族通过基因表达调控哺乳动物发育和肿瘤生长过程中的血管生成：HIF1α可诱导丙酮酸脱氢酶激酶1（PDK1）转录，通过抑制TCA循环抑制丙酮酸脱氢酶激酶（PDH），进而引发颈动脉体细胞增生肥大。同时，EPAS1基因的激活突变会降低HIF2α降解，导致副神经节瘤综合征（Pacak-Zhuang综合征）。HIFs还能激活VEGF表达，VEGFs通过作用于Flk-1受体调控I型细胞增生并促进新生血管形成。ICs在颈动脉体内发挥关键信号传导作用，其在缺氧条件下被诱导表达，可刺激颈动脉体增生最终导致CBTs。通过检测肿瘤缺氧区域并改善缺氧状态，可增强光子放疗疗效。本综述为深入探索缺氧信号通路与CBTs的关联提供了重要的研究方向参考。
肿瘤(癌症)患者之家