The importance of cytochrome P450 (CYP)-derived arachidonic acid (AA) metabolites, 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs) as tumor growth promotors has already been described in several cancer types. The aim of this study was to evaluate the role of these compounds in the biology of pheochromocytoma/paraganglioma. These tumors originate from chromaffin cells derived from adrenal medulla (pheochromocytomas) or extra-adrenal autonomic paraganglia (paragangliomas), and they represent the most common hereditary endocrine neoplasia. According to mutations in the driver genes, these tumors are divided in two clusters: pseudo-hypoxic and kinase-signaling. EETs, but not 20-HETE, exhibited a potent ability to sustain growth in a murine pheochromocytoma cell line (MPC) in vitro, EETs promoted an increase in cell proliferation and a decrease in cell apoptosis. In a mouse model of pheochromocytoma, the inhibition of CYP-mediated AA metabolism using 1-aminobenzotriazol resulted in slower tumor growth, a decreased vascularization, and a lower final volume. Also, the expression of AA-metabolizing CYP monooxygenases was detected in tumor samples from human origin, being their apparent abundance and the production of both metabolites higher in tumors from the kinase-signaling cluster. This is the first evidence of the importance of CYP- derived AA metabolites in the biology and development of pheochromocytoma/paraganglioma tumors.

中文翻译：

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花生四烯酸（20-HETE，11,12-EET和14,15-EET）的细胞色素450代谢产物促进嗜铬细胞瘤细胞生长和肿瘤相关的血管生成。

细胞色素P450（CYP）衍生的花生四烯酸（AA）代谢产物，20-羟基二十碳四烯酸（20-HETE）和环氧二十碳三烯酸（EET）作为肿瘤生长促进剂的重要性已经在几种癌症类型中得到了描述。这项研究的目的是评估这些化合物在嗜铬细胞瘤/副神经节瘤生物学中的作用。这些肿瘤起源于肾上腺髓质（嗜铬细胞瘤）或肾上腺自主神经节旁神经节（paragangliomas）的嗜铬细胞，它们代表了最常见的遗传性内分泌肿瘤。根据驱动基因的突变，这些肿瘤分为两类：假性低氧和激酶信号。EETs（而非20-HETEs）在鼠嗜铬细胞瘤细胞系（MPC）上具有强大的维持体外生长的能力，EETs促进细胞增殖的增加和细胞凋亡的减少。在嗜铬细胞瘤的小鼠模型中，使用1-氨基苯并三唑抑制CYP介导的AA代谢会导致肿瘤生长变慢，血管生成减少和最终体积降低。同样，在人类来源的肿瘤样品中检测到了AA代谢的CYP单加氧酶的表达，这是它们的明显丰度以及激酶信号簇中肿瘤中两种代谢产物的产生较高。这是CYP衍生的AA代谢产物在嗜铬细胞瘤/神经节瘤肿瘤的生物学和发展中的重要性的第一个证据。血管生成减少，最终体积降低。同样，在来自人源的肿瘤样品中检测到了AA代谢的CYP单加氧酶的表达，这是它们的明显丰度以及激酶信号簇中肿瘤中两种代谢产物的产生较高。这是CYP衍生的AA代谢产物在嗜铬细胞瘤/神经节瘤肿瘤的生物学和发展中的重要性的第一个证据。血管生成减少，最终体积降低。同样，在人类来源的肿瘤样品中检测到了AA代谢的CYP单加氧酶的表达，这是它们的明显丰度以及激酶信号簇中肿瘤中两种代谢产物的产生较高。这是CYP衍生的AA代谢产物在嗜铬细胞瘤/神经节瘤肿瘤的生物学和发展中的重要性的第一个证据。