Oncogenic features of the bone morphogenic protein 7 (BMP7) in pheochromocytoma
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Ines Leinhäuser1,2, Andrea Richter1, Misu Lee1, Ines Höfig2, Nataša Anastasov2, Falko Fend3, Tonino Ercolino4, Massimo Mannelli5, Anne-Paule Gimenez-Roqueplo6,7,8, Mercedes Robledo9, Ronald de Krijger10, Felix Beuschlein11, Michael J. Atkinson2, Natalia S. Pellegata1
1Institute of Pathology, Helmholtz Zentrum München, Neuherberg, Germany
2Institute of Radiation Biology, Helmholtz Zentrum München, Neuherberg, Germany
3Institute of Pathology and Neuropathology Comprehensive Cancer Center Tübingen and University of Tübingen, Tübingen, Germany
4Azienda Ospedaliero-Universitaria di Careggi, Endocrine Unit, Florence, Italy
5Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
6INSERM, UMR U970, Paris Cardiovascular Research Center-PARCC, Paris, France
7Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France
8Assistance Publique Hôpitaux de Paris, Hôpital européen Georges Pompidou, Department of Genetics, Paris, France
9Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
10Department of Pathology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
11Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, München, Germany
Natalia S. Pellegata, e-mail: firstname.lastname@example.org
Keywords: pheochromocytoma, bone morphogenic protein 7, PI3K pathway, integrin beta 1, MENX rats
Received: May 22, 2015 Accepted: August 07, 2015 Published: August 18, 2015
BMP7 is a growth factor playing pro- or anti-oncogenic roles in cancer in a cell type-dependent manner. We previously reported that the BMP7 gene is overexpressed in pheochromocytomas (PCCs) developing in MENX-affected rats and human patients. Here, analyzing a large cohort of PCC patients, we found that 72% of cases showed elevated levels of the BMP7 protein. To elucidate the role of BMP7 in PCC, we modulated its levels in PCC cell lines (overexpression in PC12, knockdown in MPC and MTT cells) and conducted functional assays. Active BMP signaling promoted cell proliferation, migration, and invasion, and sustained survival of MENX rat primary PCC cells. In PCC, BMP7 signals through the PI3K/AKT/mTOR pathway and causes integrin β1 up-regulation. Silencing integrin β1 in PC12 cells suppressed BMP7-mediated oncogenic features. Treatment of MTT cells with DMH1, a novel BMP antagonist, suppressed proliferation and migration. To verify the clinical applicability of our findings, we evaluated a dual PI3K/mTOR inhibitor (NVP-BEZ235) in MENX-affected rats in vivo. PCCs treated with NVP-BEZ235 had decreased proliferation and integrin β1 levels, and higher apoptosis. Altogether, BMP7 activates pro-oncogenic pathways in PCC. Downstream effectors of BMP7-mediated signaling may represent novel targets for treating progressive/inoperable PCC, still orphan of effective therapy.
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