颈动脉体瘤(CBT)是罕见的肿瘤,每100,000个体发病率为1-2。CBT最初可能没有明显的症状,症状开始出现,因为肿瘤变大压迫周围组织,如喉返神经和食道。此外,CBT的病因尚不清楚,因为它更可能发生在生活在高海拔地区或患有慢性低氧疾病如COPD的人群中.据报道,SDH突变和家族遗传与CBT有关。SDH复合物在有氧呼吸中起着至关重要的作用,据报道,CBTs中的SDH突变与缺氧有关。低氧信号通路,特别是缺氧标志物,在肿瘤探索中引起了更多的研究关注。然而,关于这些信号和标志物的现有文献缺乏系统评价.此外,基于缺氧信号的CBTs治疗方法很少在临床中使用.在这次审查中,我们总结了缺氧信号和标志物在CBT启动和进展中的作用及其潜在意义.我们的发现强调了SDH家族的参与,HIF家族,VEGFs,和炎症细胞因子(IC)在肿瘤发生和治疗中的作用。特别令人感兴趣的是SDHx所扮演的角色,最近通过导致遗传性CBTs的突变与氧感应有关。在SDH家族中,SDHB和SDHD表现出与转移和多发性肿瘤相关的显着特征。除了CBTs中的SDH突变,HIF家族也通过缺氧信号通路在CBTs中发挥关键作用。HIF家族通过在CBT中的基因表达调节哺乳动物发育和肿瘤生长期间的血管生成。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)。然后,颈动脉体细胞开始增生和肥大。同时,EPAS1突变,激活突变,可以减少HIF2α的降解并导致Pacak-庄综合征,这可能会导致副神经节瘤。HIFs还可以激活VEGF的表达,和VEGF作用于Flk-1以控制I型细胞的增生并促进新生血管形成。IC在CB中也起着关键的信号作用,因为它们的表达在低氧条件下被诱导以刺激CB增生,最终导致CBTs检测肿瘤中的缺氧区域,改善缺氧条件可以提高光子放疗的疗效。此外,这篇综述为理解缺氧信号通路与CBT之间关系的未来研究方向提供了有价值的见解。
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.