INSERM, UMR970, Paris Cardiovascular Research Center, Paris, France.
Endocr Pathol. 2012 Mar;23(1):34-42. doi: 10.1007/s12022-011-9189-0.
Pheochromocytomas and paragangliomas are highly vascularized tumors which are candidates for anti-angiogenic therapies. Several studies have reported the association of vascular endothelial growth factor (VEGF) overexpression with malignancy, but none took into account the genetic status of the patients or tumors, which may have a major influence on such observations. Transcriptome studies indeed revealed that pheochromocytomas and paragangliomas can be classified into two major clusters depending on their gene expression profile: Cluster 1 comprises samples associated with a hypoxic signature such as SDHx- and VHL-related tumors and cluster 2 includes RET, NF1, and TMEM127-mutated tumors, as well as most of sporadic tumors. The aim of this study was to provide a comprehensive rationale for the targeting of angiogenesis in patients with malignant forms of the disease. We used in situ hybridization, immunohistochemistry, and microarray gene expression profiling to evaluate angiogenesis and the expression of several angiogenic factors in a large cohort of pheochromocytomas and paragangliomas. We also studied the activation of mTOR by assessing the phosphorylation of its targets, P70 S6 kinase and 4E-BP1. These results were correlated with both malignancy and transcription signature. Our results reveal that cluster 1 tumors display a marked increase in both vascularization and in the expression of major angiogenic molecules, including VEGF, its receptors, HIF2α, Angiopoietin-2, and the endothelin receptors ETA and ETB. These overexpressions were observed in both benign and malignant samples of cluster 1 and thus appeared to be mainly dependent on the pseudo-hypoxic status of these tumors. The mTOR pathway was potentially activated in half of the tumors studied, with a slight increase in cluster 2 pheochromocytomas. Our results suggest that there is a strong rationale for anti-VEGF-based therapeutic strategies in malignant pheochromocytomas and paragangliomas, in particular in those associated with mutations in the SDHB gene.
嗜铬细胞瘤和副神经节瘤是高度血管化的肿瘤，是抗血管生成治疗的候选者。几项研究报告了血管内皮生长因子（VEGF）过度表达与恶性肿瘤之间的关联，但都没有考虑到患者或肿瘤的遗传状态，这可能对这些观察结果有重大影响。转录组研究确实表明，根据基因表达谱，嗜铬细胞瘤和副神经节瘤可分为两个主要簇：簇 1 包含与缺氧特征相关的样本，如 SDHx- 和 VHL 相关肿瘤，簇 2 包括 RET、NF1 和 TMEM127 突变肿瘤，以及大多数散发性肿瘤。本研究的目的是为靶向治疗恶性疾病患者的血管生成提供全面的依据。我们使用原位杂交、免疫组织化学和微阵列基因表达谱分析来评估一大群嗜铬细胞瘤和副神经节瘤中的血管生成和几种血管生成因子的表达。我们还通过评估其靶标 P70 S6 激酶和 4E-BP1 的磷酸化来研究 mTOR 的激活。这些结果与恶性肿瘤和转录特征相关。我们的结果表明，簇 1 肿瘤的血管生成和主要血管生成分子的表达都明显增加，包括 VEGF、其受体、HIF2α、血管生成素-2 以及内皮素受体 ETA 和 ETB。这些过表达在簇 1 的良性和恶性样本中都观察到，因此似乎主要依赖于这些肿瘤的假性缺氧状态。mTOR 途径在研究的一半肿瘤中被潜在激活，簇 2 嗜铬细胞瘤略有增加。我们的结果表明，在恶性嗜铬细胞瘤和副神经节瘤中，特别是在与 SDHB 基因突变相关的肿瘤中，基于抗 VEGF 的治疗策略具有很强的合理性。
