ECTS2016 Poster Presentations Cancer and bone: basic, translational and clinical (37 abstracts)
Menin is a tumor suppressor in bone -- a novel benign jaw tumor mouse model
Sooyeon Lee 1, , Peng Liu 1, , Miriam Tschaffon 1 , Alpaslan Tasdogan 3 , Rainer Wittig 4 , Lucien Frappart 2, , Jeanette Knoll 2 , Philippe Bertolino 6 , Chang Zhang 6 & Jan Tuckermann 1,
1Institute of Comparative Molecular Endocrinology, University of Ulm, Ulm, Germany; 2Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany; 3Institute for Immunology, University Hospital Ulm, Ulm, Germany; 4Institute for Laser Technologies in Medicine & Metrology (ILM) at Ulm University, Ulm, Germany; 5INSERM, Oncogenèseet Progression Tumorale, Universitè Claude Bernard Lyon I, Lyon, France; 6Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR5286, Université Lyon 1, Lyon, France.
Benign jaw tumors including ossifying fibroma (OF) can be often incidentally diagnosed due to their slow-growing and painless characteristics. In cases of massive growing jaw tumors, it can result in deformity of teeth, infection and intracranial complications. Depending on the location of tumor lesion, it may not completely resected and recur after the primary operation, which may require subsequent operations.
Molecular mechanisms and the etiology of those bone tumors are scarce and their eludication will allow to developing new alternative therapies to reduce complicated facial surgery.
Here we established the tumor suppressor gene Men1 (multiple endocrine neoplasia type1) as a novel gate keeper for the development of OF. We found that Men1 deletion in mesenchymal stromal cells/osteoblast progenitors caused benign jaw tumor OF in mice with 100% incidence. This tumor lesion was characterized by less bone mass along with high bone resorption, and expanded stroma. Consistently, mesenchymal stromal cells isolated from OF (OFMSCs) were not able to perform mineralization, explaining low bone mass in the tumor lesion. OFMSCs are excessively proliferative which was reduced by Men1 overexpression, showing a slower transition from G0/G1 to S-phase in Men1-overexpressed OFMSCs.
We found TGF-β target gene expression was upregulated in tumor-bearing mandibles and OFMSCs lacking Men1 displayed an increased sensitivity towards TGF-β treatment. Finally, we discovered that Men1-deficient OFMSCs down regulated the cyclin dependent kinase (CDK) inhibitor p21, explaining increased proliferation.
Our findings show for the first time that osteoblast lineage specific Men1 deletion causes jaw tumors in mice by inhibiting differentiation of osteoblast progenitor cells and by promoting proliferation, presumably through affecting TGF-β signaling and p21 expression. We developed here a new mouse model of rare ossifying fibromas in the jaw that can be exploitet to develop novel treatment strategies.
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Bone Abstracts
ISSN 2052-1219 (online)
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