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Leinhäuser, I. ; Richter, A. ; Lee, M.S. ; Höfig, I. ; Anastasov, N. ; Fend, F.* ; Ercolino, T.* ; Mannelli, M.* ; Gimenez-Roqueplo, A.P.* ; Robledo, M.* ; de Krijger, R.R.* ; Beuschlein, F.* ; Atkinson, M.J. ; Pellegata, N.S.

Oncogenic features of the Bone Morphogenic Protein 7 (BMP7) in pheochromocytoma.

Oncotarget 6, 39111-39126 (2015)
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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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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Menx Rats ; Pi3k Pathway ; Bone Morphogenic Protein 7 ; Integrin Beta 1 ; Pheochromocytoma
ISSN (print) / ISBN 1949-2553
e-ISSN 1949-2553
Journal OncoTarget
Quellenangaben Volume: 6, Issue: 36, Pages: 39111-39126 Article Number: , Supplement: ,
Publisher Impact Journals LLC
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Pathology (PATH)
Institute of Radiation Biology (ISB)