Oncogenic features of the bone morphogenic protein 7 (BMP7) in pheochromocytoma.
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.
Institute of Pathology, Helmholtz Zentrum München, Neuherberg, Germany.|Institute of Radiation Biology, Helmholtz Zentrum München, Neuherberg, Germany.
Ines
I
Leinhäuser
Institute of Pathology, Helmholtz Zentrum München, Neuherberg, Germany.
Andrea
A
Richter
Institute of Pathology, Helmholtz Zentrum München, Neuherberg, Germany.
Misu
M
Lee
Institute of Radiation Biology, Helmholtz Zentrum München, Neuherberg, Germany.
Ines
I
Höfig
Institute of Radiation Biology, Helmholtz Zentrum München, Neuherberg, Germany.
Nataša
N
Anastasov
Institute of Pathology and Neuropathology Comprehensive Cancer Center Tübingen and University of Tübingen, Tübingen, Germany.
Falko
F
Fend
Azienda Ospedaliero-Universitaria di Careggi, Endocrine Unit, Florence, Italy.
Tonino
T
Ercolino
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
Massimo
M
Mannelli
INSERM, UMR U970, Paris Cardiovascular Research Center-PARCC, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.|Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Department of Genetics, Paris, France.
Anne-Paule
AP
Gimenez-Roqueplo
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Mercedes
M
Robledo
Department of Pathology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Ronald
R
de Krijger
Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, München, Germany.
Felix
F
Beuschlein
Institute of Radiation Biology, Helmholtz Zentrum München, Neuherberg, Germany.
Michael J
MJ
Atkinson
Institute of Pathology, Helmholtz Zentrum München, Neuherberg, Germany.
Natalia S
NS
Pellegata
D000310:Adrenal Gland Neoplasms / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D055419:Bone Morphogenetic Protein 7 / Q000378:metabolism*; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000502:physiology; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D016716:PC12 Cells; D010673:Pheochromocytoma / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D014162:Transfection
D055419:Bone Morphogenetic Protein 7; D019869:Phosphatidylinositol 3-Kinases
MENX rats; PI3K pathway; bone morphogenic protein 7; integrin beta 1; pheochromocytoma