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Rationale for Anti-angiogenic Therapy in Pheochromocytoma and Paraganglioma

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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.

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Acknowledgments

This work was supported by the Programme Hospitalier de Recherche Clinique grant COMETE 3 (AOM 06 179) and by the Agence Nationale de la Recherche (ANR 08 GENOPATH 029 MitOxy). This work is part of the national program ‘Cartes d’Identité des Tumeurs’ funded and developed by the ‘Ligue Nationale contre le Cancer’ (http://cit.ligue-cancer.net). The authors thank Dr Jean-Marie Gasc and Pr Pierre Corvol for launching this study, more than 10 years ago.

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Authors and Affiliations

  1. INSERM, UMR970, Paris Cardiovascular Research Center, Paris, France

    Judith Favier, Nelly Burnichon, Laurence Amar, Cécile Badoual, Pierre-François Plouin, Xavier Jeunemaitre & Anne-Paule Gimenez-Roqueplo

  2. Université Paris Descartes, Faculté de Médecine, Paris, France

    Judith Favier, Nelly Burnichon, Cécile Badoual, Frédérique Tissier, Xavier Jeunemaitre & Anne-Paule Gimenez-Roqueplo

  3. 2nd Department of Medicine, Faculty of Medicine, Semmelweis University, Szentkirályi str. 46, 1088, Budapest, Hungary

    Peter Igaz

  4. Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, Paris, France

    Nelly Burnichon, Xavier Jeunemaitre & Anne-Paule Gimenez-Roqueplo

  5. Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service d’Hypertension Artérielle, Paris, France

    Laurence Amar & Pierre-François Plouin

  6. INSERM, U567, Département d’Endocrinologie, Métabolisme & Cancer, Institut Cochin, Paris, France

    Rossella Libé, Frédérique Tissier & Jérôme Bertherat

  7. Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Centre de Référence Maladies Rares de la Surrénale, Service des Maladies Endocriniennes et Métaboliques, Paris, France

    Rossella Libé & Jérôme Bertherat

  8. Rare Adrenal Cancer Network-Cortico Médullosurrénale Tumeur Endocrine, Institut National du Cancer, Paris, France

    Rossella Libé, Jérôme Bertherat, Pierre-François Plouin & Anne-Paule Gimenez-Roqueplo

  9. Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service d’Anatomo-pathologie, Paris, France

    Cécile Badoual

  10. Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Service d’Anatomie Pathologique, Paris, France

    Frédérique Tissier

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  1. Judith Favier
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Correspondence to Judith Favier.

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For submission for the Proceedings of the 3rd International Symposium on Pheochromocytoma and Paraganglioma

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Favier, J., Igaz, P., Burnichon, N. et al. Rationale for Anti-angiogenic Therapy in Pheochromocytoma and Paraganglioma. Endocr Pathol 23, 34–42 (2012). https://doi.org/10.1007/s12022-011-9189-0

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