Endocrine Abstracts

Introduction: Rats affected by the MENX syndrome develop bilateral pheochromocytoma (PCC) with complete penetrance. Transcriptome profiling of rat PCC identified Bmp7 (bone morphogenetic protein 7) as highly expressed in the tumors. Interestingly, 72% of human PCCs also showed elevated BMP7 expression. BMP7 plays pro- or anti-oncogenic roles in cancer in a cell type-dependent manner. To address the role of Bmp7 in PCC, its level was modulated in PCC cell lines and functional assays were conducted. The results showed that Bmp7 promotes oncogenic features in PCC.

Methods: We modulated Bmp7 expression and checked for integrin b1 expression. We knocked-down integrin b1 and performed in vitro functional assays. We treated PCC cell lines, primary PCC cells and tumor tissues with DMH1, a small molecule inhibitor of BMP type I receptors. Following DMH1 treatment, functional in vitro assays or immunohistochemistry were performed.

Result: Integrin b1 mediates Bmp7-dependent increase in PCC cell motility. Treatment of MTT cells with DMH1 suppressed cell proliferation and migration in a dose- and time-dependent manner. Concomitantly, a down regulation of molecular readouts of active BMP signaling in PCC cells was observed. The treatment of rat primary PCC cells with DMH1 was associated with a dose-dependent decrease in cell viability. Isolated rat tumor tissues were inserted into a rotary cell culture system (RCCS, Synthecon^TM) and treated with DMH1. Immunohistochemistry on the fixed tissues confirmed the downregulation of BMP signaling by the inhibitor.

Conclusion: BMP signaling may represent a novel therapeutic target in PCC. Pathway blockade by DMH1 elicits anti-proliferative and anti-migratory responses in PCC cells in vitro and should in the future be evaluated in PCC models in vivo.