title: Rationale for anti-angiogenic therapy in pheochromocytoma and paraganglioma.
abstract: 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.
authors.affiliation: INSERM, UMR970, Paris Cardiovascular Research Center, Paris, France. judith.favier@inserm.fr
authors.forename: Judith
authors.initials: J
authors.lastname: Favier
authors.forename: Peter
authors.initials: P
authors.lastname: Igaz
authors.forename: Nelly
authors.initials: N
authors.lastname: Burnichon
authors.forename: Laurence
authors.initials: L
authors.lastname: Amar
authors.forename: Rossella
authors.initials: R
authors.lastname: Libé
authors.forename: Cécile
authors.initials: C
authors.lastname: Badoual
authors.forename: Frédérique
authors.initials: F
authors.lastname: Tissier
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
authors.forename: Pierre-François
authors.initials: PF
authors.lastname: Plouin
authors.forename: Xavier
authors.initials: X
authors.lastname: Jeunemaitre
authors.forename: Anne-Paule
authors.initials: AP
authors.lastname: Gimenez-Roqueplo
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014408:Biomarkers, Tumor / Q000032:analysis; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D010235:Paraganglioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010673:Pheochromocytoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis
chemical_list: D014408:Biomarkers, Tumor; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D058570:TOR Serine-Threonine Kinases