De novo expression of EphA2 in osteosarcoma modulates activation of the mitogenic signaling pathway

Raphaela Fritsche (1) , Aurelia Noske , Ute Ungethüm , Ralf-Jürgen Kuban , Peter M Schlag , Per-Ulf Tunn , Janine Karle , Veit Jonas Krenn , Manfred Dietel , Christine Sers (2)

1 Institut of pathology
2 Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]

Aims: In osteosarcoma patients, the development of metastases, often to the lungs, is the most frequent cause of death. To improve this situation, a deeper understanding of the molecular mechanisms governing osteosarcoma development and dissemination and the identification of novel drug targets for an improved treatment are needed. Methods and results: Towards this aim, we characterized osteosarcoma samples using genome-wide microarrays and detected increased expression of the EphA2 receptor and its ligand EFNA1 in osteosarcoma tissues. In addition, increased expression of EFNB1, EFNB3 and EphA3 was suggested. Immunohistochemical staining revealed an absence of EphA2 from normal bone, and de novo expression in osteosarcomas. EFNA1 was expressed in normal bone, but significantly elevated in tumors. This pattern suggests a specific role for the EFNA1-EphA2-interaction in osteosarcoma. Further in vitro investigations on the functional role of EphA2 and EFNA1 showed that EFNA1 ligand binding induced increased tyrosine phoshorylation, receptor degradation and downstream MAPK activation. Interference with the MAPK pathway unraveled a potential autoregulatory loop governing mainly EFNA1 expression via the same pathway. Conclusion: Our results indicate that upregulation and de novo expression of ephrins in osteosarcomas are involved in oncogenic signaling and thus might stimulate osteosarcoma metastasis.

Mots clés: Medicine

Raphaela Fritsche, Aurelia Noske, Ute Ungethüm, Ralf-Jürgen Kuban, Peter M Schlag, et al.. De novo expression of EphA2 in osteosarcoma modulates activation of the mitogenic signaling pathway. Histopathology, 2010, 57 (6), pp.836. ⟨10.1111/j.1365-2559.2010.03713.x⟩. ⟨hal-00601183⟩