Heck Dorothee, Wortmann Sebastian, Kraus Luitgard, Ronchi Cristina L, Sinnott Richard O, Fassnacht Martin, Sbiera Silviu
Horm Cancer. 2015 Dec;6(5-6):225-36. doi: 10.1007/s12672-015-0236-z.
Angiogenesis is essential for tumor growth and metastasis. Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) is an angiogenic factor predominantly expressed in steroidogenic organs like the adrenal gland, ovary, testes, and placenta. EG-VEGF has antiapoptotic, mitogenic, and chemoattractive properties mediated via the two G protein-coupled receptors prokineticin receptor 1 (PKR1) and prokineticin receptor 2 (PKR2). We investigated the expression of EG-VEGF and its receptors in a large number of normal adrenal glands (NAG), adrenocortical adenomas (ACA), and carcinomas (ACC) using real-time PCR (NAG, n = 12; ACA, n = 24; and ACC, n = 30) and immunohistochemistry (NAG, n = 9; ACA, n = 23; and ACC, n = 163) and evaluated its impact on patients' survival. EG-VEGF, PKR1, and PKR2 mRNA and protein are expressed in NAG and the vast majority of ACA and ACC samples. The mean EG-VEGF mRNA expression was significantly lower in ACC (606.5 ± 77.1 copies) compared to NAG (4,043 ± 1,111) and cortisol-producing adenomas (CPA) (4,433 ± 2,378) (p < 0.01 and p < 0.05, respectively). However, cytoplasmic and nuclear EG-VEGF protein expression was either significantly higher or similar in ACC (H score 2.4 ± 0.05, p < 0.05 and 1.7 ± 0.08, n.s., respectively) compared to NAG (1.8 ± 0.14 and 1.7 ± 0.2). Nuclear protein expression of either EG-VEGF or PKR1 or both is predictive for a higher mortality compared to patients without nuclear expression (hazard ratio (HR) = 5.15; 95% confidence interval (CI) = 1.24-21.36, n = 100, p = 0.02 independent of age, sex, and tumor stage). These findings suggest that EG-VEGF and its receptor PKR1 might play a role in the pathogenesis of adrenocortical tumors and could serve as prognostic markers for this rare malignant disease.
血管生成对于肿瘤的生长和转移至关重要。内分泌腺源性血管内皮生长因子（EG-VEGF）是一种血管生成因子，主要在肾上腺、卵巢、睾丸和胎盘等类固醇生成器官中表达。EG-VEGF具有抗凋亡、促有丝分裂和趋化特性，通过两种G蛋白偶联受体促胃动素受体1（PKR1）和促胃动素受体2（PKR2）介导。我们使用实时PCR（正常肾上腺[ NAG ]，n = 12；肾上腺皮质腺瘤[ ACA ]，n = 24；肾上腺皮质癌[ ACC ]，n = 30）和免疫组织化学（NAG，n = 9；ACA，n = 23；ACC，n = 163）研究了大量正常肾上腺、肾上腺皮质腺瘤和癌中EG-VEGF及其受体的表达，并评估了其对患者生存的影响。EG-VEGF、PKR1和PKR2的mRNA和蛋白在NAG以及绝大多数ACA和ACC样本中均有表达。与NAG（4,043 ± 1,111）和产皮质醇腺瘤（CPA）（4,433 ± 2,378）相比，ACC中EG-VEGF mRNA的平均表达显著降低（606.5 ± 77.1拷贝）（分别为p < 0.01和p < 0.05）。然而，与NAG（1.8 ± 0.14和1.7 ± 0.2）相比，ACC中细胞质和细胞核EG-VEGF蛋白表达要么显著升高，要么相似（H评分分别为2.4 ± 0.05，p < 0.05和1.7 ± 0.08，无统计学差异）。与无细胞核表达的患者相比，EG-VEGF或PKR1或两者的细胞核蛋白表达可预测更高的死亡率（风险比[ HR ] = 5.15；95%置信区间[ CI ] = 1.24 - 21.36，n = 100，p = 0.02，与年龄、性别和肿瘤分期无关）。这些发现表明，EG-VEGF及其受体PKR1可能在肾上腺皮质肿瘤的发病机制中起作用，并可作为这种罕见恶性疾病的预后标志物。
